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EMBO Molecular Medicine

All articles accepted from 14 August 2012 are published under the terms of the Creative Commons Attribution License.   Articles accepted before this date were published under the agreement as stated in the final article.

Cover image for Vol. 8 Issue 7

Edited By: Stefanie Dimmeler (Chief Editor), Roberto Buccione and Céline Carret (EMBO Editors)

Online ISSN: 1757-4684

Virtual Issue: Cancer

Cancer is a very heterogeneous disease, and this virtual Cancer issue compiles new and exciting developments in a variety of cancers using in vitro and in vivo approaches. Our handpicked assorted articles and reviews cover all aspects of the disease, from epigenetics and genomics approaches to molecular characterization of factors and pathways involved in cancer formation and progression. We hope you will enjoy our selection!

 


Targeting the androgen receptor with siRNA promotes prostate cancer metastasis through enhanced macrophage recruitment via CCL2/CCR2-induced STAT3 activation
Kouji Izumi, Lei-Ya Fang, Atsushi Mizokami, Mikio Namiki, Lei Li, Wen-Jye Lin and Chawnshang Chang
EMBO Mol Med 2013, 5(9), 1383–1401

EMBO Molecular Medicine - Targeting the androgen receptor with siRNA promotes prostate cancer metastasis through enhanced macrophage recruitment via CCL2/CCR2-induced STAT3 activation

Ablation of androgen receptor in myeloid or prostate cells promotes metastatic progression of prostate cancer cells through induction of CCL2 via STAT3 activation by down-regulation of the STAT3 inhibitor PIAS3.


Oncogenic roles of PRL-3 in FLT3-ITD induced acute myeloid leukaemia
Jung Eun Park, Hiu Fung Yuen, Jian Biao Zhou, Abdul Qader O. Al-aidaroos, Ke Guo, Peter J. Valk, Shu Dong Zhang, Wee Joo Chng, Cheng William Hong, Ken Mills and Qi Zeng
EMBO Mol Med 2013, 5(9), 1351–1366

EMBO Molecular Medicine - Oncogenic roles of PRL-3 in FLT3-ITD induced acute myeloid leukaemia

PRL-3, a downstream target of FLT3-ITD, controls leukemia development and higher PRL-3 expression was significantly associated with shorter survival in AML patients. When targeted with an antibody, tumor burden in a leukemia mouse model is reduced.


Ret inhibition decreases growth and metastatic potential of estrogen receptor positive breast cancer cells
Albana Gattelli, Ivan Nalvarte, Anne Boulay, Tim C. Roloff, Martin Schreiber, Neil Carragher, Kenneth K. Macleod, Michaela Schlederer, Susanne Lienhard, Lukas Kenner, Maria I. Torres-Arzayus and Nancy E. Hynes
EMBO Mol Med 2013, 5(9), 1335–1350

EMBO Molecular Medicine - Ret inhibition decreases growth and metastatic potential of estrogen receptor positive breast cancer cells

Receptor tyrosine kinases (RTK) are validated targets for cancer therapy, but only subsets of patients are eligible for this treatment. Ret inhibition blocks a novel Ret-IL6 feed-forward loop, tumor growth and metastasis of ER+ breast cancers.


A novel epigenetic CREB-miR-373 axis mediates ZIP4-induced pancreatic cancer growth
Yuqing Zhang, Jingxuan Yang, Xiaobo Cui, Yong Chen, Vivian F. Zhu, John P. Hagan, Huamin Wang, Xianjun Yu, Sally E. Hodges, Jing Fang, Paul J. Chiao, Craig D. Logsdon, William E. Fisher, F. Charles Brunicardi, Changyi Chen, Qizhi Yao, Martin E. Fernandez-Zapico and Min Li
EMBO Mol Med 2013, 5(9), 1322–1334

EMBO Molecular Medicine - A novel epigenetic CREB-miR-373 axis mediates ZIP4-induced pancreatic cancer growth

Zinc importer ZIP4 enhancement of cell proliferation, invasion, and tumor growth in pancreatic cancer occurs through the induction of miR-373 expression by the zinc-dependent transcription factor CREB.


STIM1 and STIM2-mediated Ca2+ influx regulates antitumour immunity by CD8+ T cells
Carl Weidinger, Patrick J. Shaw and Stefan Feske
EMBO Mol Med 2013, 5(9), 1311–1321

EMBO Molecular Medicine - STIM1 and STIM2-mediated Ca2+ influx regulates antitumour immunity by CD8+ T cells

Cytotoxic lymphocytes are critical for antitumor immunity. Here, store operated calcium entry (SOCE) mediated by STIM1 and -2 is shown essential to CD8+ T cells antitumor immune responses, arguing against the use of drugs inhibiting SOCE.

Accompanying Closeup
Anti-tumour activity and store operated calcium entry: new roles in immunology
Kavisha Singh and Paul Rosenberg
EMBO Mol Med 2013, 5(9), 1297–1299


IgAEGFR antibodies mediate tumour killing in vivo
Peter Boross, Stefan Lohse, Maaike Nederend, Johannes Hendrik Marco Jansen, Geert van Tetering, Michael Dechant, Matthias Peipp, Louise Royle, Li Phing Liew, Louis Boon, Nico van Rooijen, Wim K. Bleeker, Paul W. H. I. Parren, Jan G. J. van de Winkel, Thomas Valerius and Jeanette H. W. Leusen
EMBO Mol Med 2013, 5(8), 1213–1226

EMBO Molecular Medicine - IgAEGFR antibodies mediate tumour killing in vivo

The study reveals that IgA antibodies directed against EGFR and engaging Fcalpha receptor (FcaRI) on effector cells, have in vivo anti-cancer activity. These data support the development of novel immunotherapeutic strategies based on targeting FcaRI.


The ZEB1 pathway links glioblastoma initiation, invasion and chemoresistance
Florian A. Siebzehnrubl, Daniel J. Silver, Bugra Tugertimur, Loic P. Deleyrolle, Dorit Siebzehnrubl, Matthew R. Sarkisian, Kelly G. Devers, Antony T. Yachnis, Marius D. Kupper, Daniel Neal, Nancy H. Nabilsi, Michael P. Kladde, Oleg Suslov, Simone Brabletz, Thomas Brabletz, Brent A. Reynolds and Dennis A. Steindler
EMBO Mol Med 2013, 5(8), 1196–1212

EMBO Molecular Medicine - The ZEB1 pathway links glioblastoma initiation, invasion and chemoresistance

Glioblastoma have a poor prognosis, mainly due to infiltrating and therapy resistant cells leading to cancer recurrence. Here, tumor formation, invasion and resistance are not independent but intertwined processes regulated by the EMT activator ZEB1.


Identification of a novel BET bromodomain inhibitor-sensitive, gene regulatory circuit that controls Rituximab response and tumour growth in aggressive lymphoid cancers
Anouk Emadali, Sophie Rousseaux, Juliana Bruder-Costa, Claire Rome, Samuel Duley, Sieme Hamaidia, Patricia Betton, Alexandra Debernardi, Dominique Leroux, Benoit Bernay, Sylvie Kieffer-Jaquinod, Florence Combes, Elena Ferri, Charles E. McKenna, Carlo Petosa, Christophe Bruley, Jérôme Garin, Myriam Ferro, Rémy Gressin, Mary B. Callanan and Saadi Khochbin
EMBO Mol Med 2013, 5(8), 1180–1195

EMBO Molecular Medicine - Identification of a novel BET bromodomain inhibitor-sensitive, gene regulatory circuit that controls Rituximab response and tumour growth in aggressive lymphoid cancers

The nuclear factor CYCLON is a new MYC cooperating factor that drives tumor growth and Rituximab resistance in lymphoma. This resistance mechanism can be targeted by next-generation epigenetic therapy by BET bromodomain inhibition downstream of MYC.


ERBB4 confers metastatic capacity in Ewing sarcoma
Ariadna Mendoza-Naranjo, Amal El-Naggar, Daniel H. Wai, Priti Mistry, Nikola Lazic, Fernanda Rocha Rojas Ayala, Isabela Werneck da Cunha, Pablo Rodriguez-Viciana, Hongwei Cheng, Jose H. Tavares Guerreiro Fregnani, Patrick Reynolds, Robert J. Arceci, Andrew Nicholson, Timothy J. Triche, Fernando A. Soares, Adrienne M. Flanagan, Yuzhuo Z. Wang, Sandra J. Strauss and Poul H. Sorensen
EMBO Mol Med 2013, 5(7), 1087–1102

EMBO Molecular Medicine - ERBB4 confers metastatic capacity in Ewing sarcoma

The Authors show that ERBB4 is a biological driver of metastasis in the pediatric bone tumour Ewing sarcoma and identify a novel ERBB4-PI3K-Akt-FAK-Rac1 pathway associated with aggressive disease.


Functional genomics identifies five distinct molecular subtypes with clinical relevance and pathways for growth control in epithelial ovarian cancer
Tuan Zea Tan, Qing Hao Miow, Ruby Yun-Ju Huang, Meng Kang Wong, Jieru Ye, Jieying Amelia Lau, Meng Chu Wu, Luqman Hakim Bin Abdul Hadi, Richie Soong, Mahesh Choolani, Ben Davidson, Jahn M. Nesland, Ling-Zhi Wang, Noriomi Matsumura, Masaki Mandai, Ikuo Konishi, Boon-Cher Goh, Jeffrey T. Chang, Jean Paul Thiery and Seiichi Mori
EMBO Mol Med 2013, 5(7), 1051–1066

EMBO Molecular Medicine - Functional genomics identifies five distinct molecular subtypes with clinical relevance and pathways for growth control in epithelial ovarian cancer

Ovarian carcinomas remain a leading cause of cancer death among woman worldwide. Here, a novel rational patient stratification is proposed to unravel the heterogeneity of these cancers and provide means to guide novel intervention strategies.


Combined mutation of Vhl and Trp53 causes renal cysts and tumours in mice
Joachim Albers, Michal Rajski, Désirée Schönenberger, Sabine Harlander, Peter Schraml, Adriana von Teichman, Strahil Georgiev, Peter J. Wild, Holger Moch, Wilhelm Krek, Ian J. Frew
EMBO Mol Med 2013, 5(6), 949–964

EMBO Molecular Medicine - Combined mutation of Vhl and Trp53 causes renal cysts and tumours in mice

The Authors demonstrate that secondary genetic alterations can cooperate with loss of VHL to cause kidney tumour formation and implicate TP53 mutations in the pathogenesis of a subset of clear cell renal cell carcinomas in humans.


Inhibition of endotrophin, a cleavage product of collagen VI, confers cisplatin sensitivity to tumours
Jiyoung Park, Thomas S. Morley, Philipp E. Scherer
EMBO Mol Med 2013, 5(6), 935–948

EMBO Molecular Medicine - Inhibition of endotrophin, a cleavage product of collagen VI, confers cisplatin sensitivity to tumours

Endotrophin, secreted from stromal adipocytes in the tumor microenvironment, confers cisplatin resistance by enhancing EMT, fibrosis and angiogenesis. Thiazolidinediones neutralize endotrophin activities and improve the therapeutic response.


The neural crest transcription factor Brn3a is expressed in melanoma and required for cell cycle progression and survival
Tobias Hohenauer, Carola Berking, Andreas Schmidt, Sebastian Haferkamp, Daniela Senft, Claudia Kammerbauer, Sabine Fraschka, Saskia Anna Graf, Martin Irmler, Johannes Beckers, Michael Flaig, Achim Aigner, Sabrina Höbel, Franziska Hoffmann, Heiko Hermeking, Simon Rothenfusser, Stefan Endres, Thomas Ruzicka, Robert Besch
EMBO Mol Med 2013, 5(6), 919–934

EMBO Molecular Medicine - The neural crest transcription factor Brn3a is expressed in melanoma and required for cell cycle progression and survival

Brn3a, a POU family transcription factor normally involved in neuronal development, is reported here to promote melanoma survival by playing a role in cell cycle progression. Targeting Brn3a and its regulated genes could offer therapeutic value.


SRSF1 and SRSF9 RNA binding proteins promote Wnt signalling-mediated tumorigenesis by enhancing β-catenin biosynthesis
Yu Fu, Binlu Huang, Zhen Shi, Jiayu Han, Ying Wang, Jieqiong Huangfu, Wei Wu
EMBO Mol Med 2013, 5(5), 737–750

EMBO Molecular Medicine - SRSF1 and SRSF9 RNA binding proteins promote Wnt signalling-mediated tumorigenesis by enhancing ß-catenin biosynthesis

Serine/arginine-rich splicing factors SRSF1 and SRSF9 promote β-catenin accumulation via enhancing β-catenin mRNA translation. Furthermore, similarly to SRSF1, SRSF9 has oncogenic activity, in part due to the promotion of β-catenin accumulation.


Inhibition of redox/Fyn/c-Cbl pathway function by Cdc42 controls tumour initiation capacity and tamoxifen sensitivity in basal-like breast cancer cells
Maura Sonego, Monica Schiappacassi, Sara Lovisa, Alessandra Dall'Acqua, Marina Bagnoli, Francesca Lovat, Massimo Libra, Sara D'Andrea, Vincenzo Canzonieri, Loredana Militello, Marco Napoli, Giorgio Giorda, Barbara Pivetta, Delia Mezzanzanica, Mattia Barbareschi, Barbara Valeri, Silvana Canevari, Alfonso Colombatti, Barbara Belletti, Giannino Del Sal, Gustavo Baldassarre
EMBO Mol Med 2013, 5(5), 723–736

EMBO Molecular Medicine - Inhibition of redox/Fyn/c-Cbl pathway function by Cdc42 controls tumour initiation capacity and tamoxifen sensitivity in basal-like breast cancer cells

Restoration of the redox/Fyn/c-Cbl pathway via suppression of Cdc42 function in basal-like breast cancer (BLBC) cells and tumours confers tamoxifen sensitivity in vitro and in vivo.


Stathmin regulates mutant p53 stability and transcriptional activity in ovarian cancer
Maura Sonego, Monica Schiappacassi, Sara Lovisa, Alessandra Dall'Acqua, Marina Bagnoli, Francesca Lovat, Massimo Libra, Sara D'Andrea, Vincenzo Canzonieri, Loredana Militello, Marco Napoli, Giorgio Giorda, Barbara Pivetta, Delia Mezzanzanica, Mattia Barbareschi, Barbara Valeri, Silvana Canevari, Alfonso Colombatti, Barbara Belletti, Giannino Del Sal, Gustavo Baldassarre
EMBO Mol Med 2013, 5(5), 707–722

EMBO Molecular Medicine - Stathmin regulates mutant p53 stability and transcriptional activity in ovarian cancer

In high-grade epithelial ovarian carcinomas (the most lethal gynecological cancers), p53 gain-offunction mutation is a driving oncogenic event. Here, Stathmin is shown to control p53 stability by modulating p53mut/DNA-PK interaction.


GLI1 regulates a novel neuropilin-2/a6β1 integrin based autocrine pathway that contributes to breast cancer initiation
Hira Lal Goel, Bryan Pursell, Cheng Chang, Leslie M. Shaw, Junhao Mao, Karl Simin, Prashant Kumar, Craig W. Vander Kooi, Leonard D. Shultz, Dale L. Greiner, Jens Henrik Norum, Rune Toftgard, Charlotte Kuperwasser, Arthur M. Mercurio
EMBO Mol Med 2013, 5(4), 488–508

EMBO Molecular Medicine - GLI1 regulates a novel neuropilin-2/a6ß1 integrin based autocrine pathway that contributes to breast cancer initiation

The Authors describe a novel mechanism that contributes to the initiation of aggressive breast carcinomas providing a rationale for the use of anti-NRP2 therapy for the treatment of aggressive breast carcinomas.

Accompanying Closeup
GLI1 finds a new role in cancer stem cell biology
Martin E. Fernandez-Zapico
EMBO Mol Med 2013, 5(4), 483–485


Reactive astrocytes promote the metastatic growth of breast cancer stem-like cells by activating Notch signalling in brain
Fei Xing, Aya Kobayashi, Hiroshi Okuda, Misako Watabe, Sudha K. Pai, Puspa R. Pandey, Shigeru Hirota, Andrew Wilber, Yin-Yuan Mo, Brian E. Moore, Wen Liu, Koji Fukuda, Megumi Iiizumi, Sambad Sharma, Yin Liu, Kerui Wu, Elizabeth Peralta, Kounosuke Watabe
EMBO Mol Med 2013, 5(3), 384–396

EMBO Molecular Medicine - Reactive astrocytes promote the metastatic growth of breast cancer stem-like cells by activating Notch signalling in brain

In the mouse brain, metastatic breast cancer cells secrete IL-1beta, which induces the Notch pathway promoting breast cancer cell stemness and thereby leading to metastasis. The Notch inhibitor Compound E is shown to suppress brain metastasis growth.


A human tRNA methyltransferase 9-like protein prevents tumour growth by regulating LIN9 and HIF1-a
Ulrike Begley, Maria Soledad Sosa, Alvaro Avivar-Valderas, Ashish Patil, Lauren Endres, Yeriel Estrada, Clement T.Y. Chan, Dan Su, Peter C. Dedon, Julio A. Aguirre-Ghiso, Thomas Begley
EMBO Mol Med 2013, 5(3), 366–383

EMBO Molecular Medicine - A human tRNA methyltransferase 9-like protein prevents tumour growth by regulating LIN9 and HIF1-a

A newly identified RAD51 inhibitor leading to degradation of RAD51 via the proteasome pathway inhibits cancer cell survival and greatly increases life spans in a mouse chronic myeloid leukaemia model.


A novel small molecule RAD51 inactivator overcomes imatinib-resistance in chronic myeloid leukaemia
Jiewen Zhu, Longen Zhou, Guikai Wu, Heiko Konig, Xiaoqin Lin, Guideng Li, Xiao-Long Qiu, Chi-Fen Chen, Chun-Mei Hu, Erin Goldblatt, Ravi Bhatia, A. Richard Chamberlin, Phang-Lang Chen, Wen-Hwa Lee
EMBO Mol Med 2013, 5(3), 353–365

EMBO Molecular Medicine - A novel small molecule RAD51 inactivator overcomes imatinib-resistance in chronic myeloid leukaemia

A newly identified RAD51 inhibitor leading to degradation of RAD51 via the proteasome pathway inhibits cancer cell survival and greatly increases life spans in a mouse chronic myeloid leukaemia model.


TSC22D4 is a molecular output of hepatic wasting metabolism
Allan Jones, Kilian Friedrich, Maria Rohm, Michaela Schäfer, Carolyn Algire, Philipp Kulozik, Oksana Seibert, Karin Müller-Decker, Tjeerd Sijmonsma, Daniela Strzoda, Carsten Sticht, Norbert Gretz, Geesje M. Dallinga-Thie, Barbara Leuchs, Manfred Kögl, Wolfgang Stremmel, Mauricio Berriel Diaz, Stephan Herzig
EMBO Mol Med 2013, 5(2), 294–308

EMBO Molecular Medicine - TSC22D4 is a molecular output of hepatic wasting metabolism

Specific molecular programs in the liver significantly impact overall systemic energy availability and thereby further promote an energy-deficient state in response to tumour development.


Targeting aurora kinases limits tumour growth through DNA damage-mediated senescence and blockade of NF-ΚB impairs this drug-induced senescence
Yan Liu, Oriana E. Hawkins, Yingjun Su, Anna E. Vilgelm, Tammy Sobolik, Yee-Mon Thu, Sara Kantrow, Ryan C. Splittgerber, Sarah Short, Katayoun I. Amiri, Jeffery A. Ecsedy, Jeffery A. Sosman, Mark C. Kelley, Ann Richmond
EMBO Mol Med 2013, 5(1), 149–166

EMBO Molecular Medicine - Targeting aurora kinases limits tumour growth through DNA damage-mediated senescence and blockade of NF-KB impairs this drug-induced senescence

The authors suggest that aurora kinase inhibitors may effectively slow tumour growth via senescence to provide effective therapy for certain melanoma patients.


Haematopoietic stem cell survival and transplantation efficacy is limited by the BH3-only proteins Bim and Bmf
Verena Labi, Daniela Bertele, Claudia Woess, Denise Tischner, Florian J. Bock, Sven Schwemmers, Heike L. Pahl, Stephan Geley, Mirjam Kunze, Charlotte M. Niemeyer, Andreas Villunger, Miriam Erlacher
EMBO Mol Med 2013, 5(1), 122–136

EMBO Molecular Medicine - Haematopoietic stem cell survival and transplantation efficacy is limited by the BH3-only proteins Bim and Bmf

Many haematological diseases can only be cured by blood stem cell transplantation. The authors show that apoptosis inhibition at the level of Bcl-2 proteins leads to an extended life span of blood stem cells and facilitates engraftment in vivo.


Sphingosine analogue drug FTY720 targets I2PP2A/SET and mediates lung tumour suppression via activation of PP2A-RIPK1-dependent necroptosis
Sahar A. Saddoughi, Salih Gencer, Yuri K. Peterson, Katherine E. Ward, Archana Mukhopadhyay, Joshua Oaks, Jacek Bielawski, Zdzislaw M. Szulc, Raquela J. Thomas, Shanmugam P. Selvam, Can E. Senkal, Elizabeth Garrett-Mayer, Ryan M. De Palma, Dzmitry Fedarovich, Angen Liu, Amyn A. Habib, Robert V. Stahelin, Danilo Perrotti, Besim Ogretmen
EMBO Mol Med 2013, 5(1), 105–121

EMBO Molecular Medicine - Sphingosine analogue drug FTY720 targets I2PP2A/SET and mediates lung tumour suppression via activation of PP2A-RIPK1-dependent necroptosis

The authors show that targeting I2PP2A/SET by FTY720 suppresses lung tumour growth via PP2A-dependent RIPK1 activation leading to necroptosis.


Acute B lymphoblastic leukaemia-propagating cells are present at high frequency in diverse lymphoblast populations
Klaus Rehe, Kerrie Wilson, Simon Bomken, Daniel Williamson, Julie Irving, Monique L. den Boer, Martin Stanulla, Martin Schrappe, Andrew G. Hall, Olaf Heidenreich, Josef Vormoor
EMBO Mol Med 2013, 5(1), 38–51

EMBO Molecular Medicine - Acute B lymphoblastic leukaemia-propagating cells are present at high frequency in diverse lymphoblast populations

Leukemia propagating cells (LPCs) in B-ALL are frequent and phenotypically diverse and do not follow a hierarchically organized cancer stem cell model, clarifying a controversial area.

Accompanying Closeup
The cancer stem cell model: B cell acute lymphoblastic leukaemia breaks the mould
James Scott McClellan and Ravindra Majeti
EMBO Mol Med 2013, 5(1), 7-9


The isolation and characterization of renal cancer initiating cells from human Wilms' tumour xenografts unveils new therapeutic targets
Naomi Pode-Shakked, Rachel Shukrun, Michal Mark-Danieli, Peter Tsvetkov, Sarit Bahar, Sara Pri-Chen, Ronald S. Goldstein, Eithan Rom-Gross, Yoram Mor, Edward Fridman, Karen Meir, Amos Simon, Marcus Magister, Naftali Kaminski, Victor S. Goldmacher, Orit Harari-Steinberg and Benjamin Dekel
EMBO Mol Med 2013, 5(1), 18–37

EMBO Molecular Medicine - The isolation and characterization of renal cancer initiating cells from human Wilms' tumour xenografts unveils new therapeutic targets

Here, the authors report the isolation and characterisation of Wilms' tumour stem cells and show that targeting a cancer cell population enriched for cancer-initiating cell activity leads to tumour eradication in a mouse model.

Accompanying Closeup
The stem and roots of Wilms' tumours
Peter Hohenstein
EMBO Mol Med 2013, 5(1), 4-6


WLS inhibits melanoma cell proliferation through the β-catenin signalling pathway and induces spontaneous metastasis
Pei-Tzu Yang, Jamie N. Anastas, Rachel A. Toroni, Michi M. Shinohara, Jamie M. Goodson, Anja K. Bosserhoff, Andy J. Chien, Randall T. Moon
EMBO Mol Med 2012, 4(12), 1294–1307

EMBO Molecular Medicine - WLS inhibits melanoma cell proliferation through the ß-catenin signalling pathway and induces spontaneous metastasis

Recent evidence indicates that WNT/β-catenin signaling may be downregulated during melanoma progression. However, melanomas express high levels of endogenous WNT ligands. Here, the authors show that reduced expression of the WNT secretory receptor WLS could be the cause of loss of WNT/β-catenin signaling in malignant melanoma.


Tumour inflammasome-derived IL-1β recruits neutrophils and improves local recurrence-free survival in EBV-induced nasopharyngeal carcinoma
Lih-Chyang Chen, Li-Jie Wang, Nang-Ming Tsang, David M. Ojcius, Chia-Chun Chen, Chun-Nan OuYang, Chuen Hsueh, Ying Liang, Kai-Ping Chang, Chiu-Chin Chen, Yu-Sun Chang
EMBO Mol Med 2012, 4(12), 1276–1293

EMBO Molecular Medicine - Tumour inflammasome-derived IL-1ß recruits neutrophils and improves local recurrence-free survival in EBV-induced nasopharyngeal carcinoma

Inflammasomes detect infection and trigger inflammation. The authors find that in Epstein-Barr virusassociated nasopharyngeal carcinoma, inflammasomes recruit neutrophils, which produce IL-1beta and thereby inhibit tumor growth.


miR-10b*, a master inhibitor of the cell cycle, is down-regulated in human breast tumours
Francesca Biagioni, Noa Bossel Ben-Moshe, Giulia Fontemaggi, Valeria Canu, Federica Mori, Barbara Antoniani, Anna Di Benedetto, Raffaela Santoro, Sabrina Germoni, Fernanda De Angelis, Anna Cambria, Roi Avraham, Giuseppe Grasso, Sabrina Strano, Paola Muti, Marcella Mottolese, Yosef Yarden, Eytan Domany, Giovanni Blandino
EMBO Mol Med 2012, 4(11), 1214–1229



The authors show that miR-10b* downregulation is an alteration common to the three major breast cancer subtypes and might represent a critical molecular event for breast cancer establishment.


Activation of rapid oestrogen signalling in aggressive human breast cancers
Coralie Poulard, Isabelle Treilleux, Emilie Lavergne, Katia Bouchekioua-Bouzaghou, Sophie Goddard-Léon, Sylvie Chabaud, Olivier Trédan, Laura Corbo, Muriel Le Romancer
EMBO Mol Med 2012, 4(11), 1200–1213



The authors demonstrate that estrogen non-genomic signaling occurs in breast tissue and is deregulated in a subset of breast tumors, which could influence treatment.


A complex of a6 integrin and E-cadherin drives liver metastasis of colorectal cancer cells through hepatic angiopoietin-like 6
Serena Marchiò, Marco Soster, Sabrina Cardaci, Andrea Muratore, Alice Bartolini, Vanessa Barone, Dario Ribero, Maria Monti, Paola Bovino, Jessica Sun, Raffaella Giavazzi, Sofia Asioli, Paola Cassoni, Lorenzo Capussotti, Piero Pucci, Antonella Bugatti, Marco Rusnati, Renata Pasqualini, Wadih Arap, Federico Bussolino
EMBO Mol Med 2012, 4(11), 1156–1175



Advanced colorectal cancer metastasizes and remains a leading cause of death. By discovering that circulating angiopoietin-like 6 binds to α6 integrin/E-cadherin complex and contributes to liver colonization, the authors provide a novel antimetastasis therapeutic opportunity for patients.


Homotypic cell cannibalism, a cell-death process regulated by the nuclear protein 1, opposes to metastasis in pancreatic cancer
Carla E. Cano, María José Sandí, Tewfik Hamidi, Ezequiel L. Calvo, Olivier Turrini, Laurent Bartholin, Céline Loncle, Véronique Secq, Stéphane Garcia, Gwen Lomberk, Guido Kroemer, Raul Urrutia, Juan L. Iovanna
EMBO Mol Med 2012, 4(9), 964–979



Cell-in-cells arise from cell cannibalism found in samples from patients with pancreatic cancer who develop less metastasis. Mechanistically, cell cannibalism is repressed by TGFbeta-mediated Nupr1 but induced by TGFbeta in the absence of Nupr1. Inactivation of Nupr1 provokes a genetic reprogramming in PDAC cells that could be used as metastasis suppressor.


Casein kinase I epsilon interacts with mitochondrial proteins for the growth and survival of human ovarian cancer cells
Noah Rodriguez, Junzheng Yang, Kathleen Hasselblatt, Shubai Liu, Yilan Zhou, Jose A. Rauh-Hain, Shu-Kay Ng, Pui-Wah Choi, Wing-Ping Fong, Nathalie Y. R. Agar, William R. Welch, Ross S. Berkowitz, Shu-Wing Ng
EMBO Mol Med 2012, 4(9), 952–963



Chemotherapy related toxicity and drug resistant tumors are barriers to treatment of ovarian cancers. Here, the authors found that CKIε is overexpressed in ovarian tumors and interacts with mitochondrial ANT2, participating in development of resistance and poor patients outcome.


A statin-regulated microRNA represses human c-Myc expression and function
Apana A. L. Takwi, Yan Li, Lindsey E. Becker Buscaglia, Jingwen Zhang, Saibyasachi Choudhury, Ae Kyung Park, Mofang Liu, Ken H. Young, Woong-Yang Park, Robert C. G. Martin, Yong Li
EMBO Mol Med 2012, 4(9), 896–909



c-Myc overexpression in human cancers is one of the most common genetic aberrations. miR-33b is here identified as a negative regulator of c-Myc in medulloblastoma cells. In vivo, Lovastatin is shown to up regulate miR-33b, suppressing c-Myc expression and resulting in reduced tumor growth and increased survival.


p53 suppresses type II endometrial carcinomas in mice and governs endometrial tumour aggressiveness in humans
Peter J. Wild, Kristian Ikenberg, Thomas J. Fuchs, Markus Rechsteiner, Strahil Georgiev, Niklaus Fankhauser, Aurelia Noske, Matthias Roessle, Rosmarie Caduff, Athanassios Dellas, Daniel Fink, Holger Moch, Wilhelm Krek, Ian J. Frew
EMBO Mol Med 2012, 4(8), 808–824



Endometrial carcinomas of the uterus are the most common tumor type that develops in the female genital tract. The authors found that deletion of p53 is associated with the most aggressive type of endometrial carcinomas and involved dysregulation of the PI3K-mTOR pathway both in mice model and in humans.


Communication between host organism and cancer cells is transduced by systemic sphingosine kinase 1/sphingosine 1-phosphate signalling to regulate tumour metastasis
Suriyan Ponnusamy, Shanmugam Panneer Selvam, Shikhar Mehrotra, Toshihiko Kawamori, Ashley J. Snider, Lina M. Obeid, Yuan Shao, Roger Sabbadini, Besim Ogretmen
EMBO Mol Med 2012, 4(8), 761–775



Despite the fact that Alzheimer's disease (AD) is strongly associated with increased age, we still lack a molecular explanation to link aging with any of the known pathways causing AD. Here, the authors show that nitrosative stress is a major effector of the increased Aβ42/Aβ40 ratio in old neurons through modification of γ-secretase, providing a putative therapeutic target for both inherited and late-onset AD.


DIAPH3 governs the cellular transition to the amoeboid tumour phenotype
Martin H. Hager, Samantha Morley, Diane R. Bielenberg, Sizhen Gao, Matteo Morello, Ilona N. Holcomb, Wennuan Liu, Ghassan Mouneimne, Francesca Demichelis, Jayoung Kim, Keith R. Solomon, Rosalyn M. Adam, William B. Isaacs, Henry N. Higgs, Robert L. Vessella, Dolores Di Vizio, Michael R. Freeman
EMBO Mol Med 2012, 4(8), 743-760



Amoeboid motility is one of several modes adopted by disseminating tumor cells in metastatic cancers. For the first time, loss of a cytoskeleton remodeling protein (DIAPH3), encoded by a locus often lost in multiple tumors and associated with metastasis, results in acquisition of the amoeboid cancer cell phenotype, providing a putative prognostic value.


Igf2 pathway dependency of the Trp53 developmental and tumour phenotypes
Victoria L. Haley, David J. Barnes, Ionel Sandovici, Miguel Constancia, Christopher F. Graham, Francesco Pezzella, Claudia Bühnemann, Emma J. Carter, A. Bassim Hassan
EMBO Mol Med 2012, 4(8), 705–718



Inherited mutation of the p53 gene can predispose humans to early onset cancers (Li-Fraumeni syndrome, LFS). During tumor formation, the p53 wild-type allele is lost. Here, the Igf2 pathway is found to restore functionality when p53 function is lost. These findings could be therapeutically exploited and modify the age of onset of LFS.

Accompanying Closeup
IGF2: The Achilles' heel of p53-deficiency?
Frederic Clermont, David Nittner, Jean-Christophe Marine
EMBO Mol Med 2012, 4(8), 688–690


Role of intratumoural heterogeneity in cancer drug resistance: molecular and clinical perspectives
Nicholas A. Saunders, Fiona Simpson, Erik W. Thompson, Michelle M. Hill, Liliana Endo-Munoz, Graham Leggatt, Rodney F. Minchin, Alexander Guminski
EMBO Mol Med 2012, 4(8), 675–684



Tumor heterogeneity contributes to drive resistance to cancer drugs. This review focuses on our current knowledge of the field and how this could be used to help clinicians and researchers alike in making better therapeutics.


The tumour suppressor and chromatin-remodelling factor BRG1 antagonizes Myc activity and promotes cell differentiation in human cancer
Octavio A. Romero, Fernando Setien, Sam John, Pol Gimenez-Xavier, Gonzalo Gómez-López, David Pisano, Enric Condom, Alberto Villanueva, Gordon L. Hager, Montse Sanchez-Cespedes
EMBO Mol Med 2012, 4(7), 603-616



Lung cancer is the main cause of death from cancer in most western countries, in part because of the low efficacy of most current therapies. This study demonstrates important mechanistic insight into the role of BRG1 and the SWI/SNF complex, which are frequently mutated in a common type of lung cancer, as well as in other cancers. By showing that BRG1 controls retinoic acid and glucocorticoid-induced cell differentiation in lung and other cancers, the study provides therapeutic avenue for improving drug regimen.


Inhibitors of mitochondrial Kv1.3 channels induce Bax/Bak-independent death of cancer cells
Luigi Leanza, Brian Henry, Nicola Sassi, Mario Zoratti, K. George Chandy, Erich Gulbins, Ildikò Szabo
EMBO Mol Med 2012, 4(7), 577-593



Tumor cells deficient in both Bax and Bak are protected against mitochondriamediated apoptosis that can be induce by a certain number of drugs. Thus, there is a need to develop novel treatments that would induce cell death downstream of Bax and Bak. Here, membrane-permeant Kv1.3 inhibitors are shown potent inducers of intrinsic apoptosis in tumor cells expressing mitochondrial Kv1.3, which mode of action is Bax and Bak independent.


Selective killing of p53-deficient cancer cells by SP600125
Mohamed Jemaà, Ilio Vitale, Oliver Kepp, Francesco Berardinelli, Lorenzo Galluzzi, Laura Senovilla, Guillermo Mariño, Shoaib Ahmad Malik, Santiago Rello-Varona, Delphine Lissa, Antonio Antoccia, Maximilien Tailler, Frederic Schlemmer, Francis Harper, Gérard Pierron, Maria Castedo and Guido Kroemer
EMBO Mol Med 2012, 4(6), 500-514



P53 is the tumor suppression protein whose function is most frequently lost in human cancers. Loss of p53 reduces the efficacy of several conventional anticancer drugs. In an attempt to identify small molecules that preferentially kill cancer cells lacking p53, SP600125 is a promising candidate. This small molecule induces abortive mitosis only in p53 deficient cells ultimately leading to cell death, while p53-sufficicent cells survive.


TROP2 is epigenetically inactivated and modulates IGF-1R signalling in lung adenocarcinoma
Jau-Chen Lin, Yi-Ying Wu, Jing-Yi Wu, Tzu-Chieh Lin, Chen-Tu Wu, Yih-Leong Chang, Yuh-Shan Jou, Tse-Ming Hong and Pan-Chyr Yang
EMBO Mol Med 2012, 4(6), 472-485



Non-small-cell lung cancer remains a major cause of cancer mortality worldwide. Here, the authors show that epigenetic inactivation of TROP2 in lung cancer enhances IGF-1R signaling, which may lead to cancer progression via its downstream mediators β-catenin and Slug.


P-selectin genotype is associated with the development of cancer cachexia
Benjamin H. L. Tan, Torill Fladvad, Theodore P. Braun, Antonio Vigano, Florian Strasser, D. A. Christopher Deans, Richard J. E. Skipworth, Tora S. Solheim, Sambasivarao Damaraju, James A. Ross, Stein Kaasa, Daniel L. Marks, Vickie E. Baracos, Frank Skorpen, Kenneth C. H. Fearon, European Palliative Care Research Collaborative
EMBO Mol Med 2012, 4(6), 462-471



More than half of cancer patients suffer from cachexia, and it is responsible for death in up to 20% of cases. However, up to now it is impossible to predict which patient will suffer from it and which will not. In a large-scale genetic association study, the C allele of the rs6136 (Pselectin) SNP was found to be associated with weight loss >10% of patients. Experimental validation confirms the participation of Pselectin in the induction of the skeletal muscle atrophy.

Accompanying Closeup
Selecting for predisposition to cancer cachexia
Ioannis Gioulbasanis, Panagiotis J. Vlachostergios, Christos N. Papandreou
EMBO Mol Med 2012, 4(6), 451-452


Antibody detection of translocations in Ewing sarcoma
Wen Luo, Brett Milash, Brian Dalley, Richard Smith, Holly Zhou, Natalie Dutrow, Bradley R. Cairns and Stephen L. Lessnick
EMBO Mol Med 2012, 4(6), 453-461



Chromosomal translocations in cancer are traditionally detected by challenging methods that often present with low sensitivity and specificity to frozen or formalin/paraffin fixed tissues. ADOT is a novel accurate and sensitive technique to detect and identify translocations associated with cancers, irrespective of sample types.


Nardilysin and ADAM proteases promote gastric cancer cell growth by activating intrinsic cytokine signalling via enhanced ectodomain shedding of TNF-α
Keitaro Kanda, Hideyuki Komekado, Tateo Sawabu, Shoko Ishizu, Yuki Nakanishi, Masato Nakatsuji, Reiko Akitake-Kawano, Mikiko Ohno, Yoshinori Hiraoka, Mayumi Kawada, Kenji Kawada, Yoshiharu Sakai, Kyoichi Matsumoto, Makoto Kunichika, Takeshi Kimura, Hiroshi Seno, Eiichiro Nishi and Tsutomu Chiba
EMBO Mol Med 2012, 4(5), 396-411



Gastric cancer is one of the leading causes of cancer-related deaths worldwide, mainly because localized gastric cancer is usually asymptomatic, most of patients are only diagnosed when the disease has progressed to advanced stages. Despite few therapeutic strategies, patients' prognosis remains poor, prompting further elucidation of the underlying molecular mechanism. Here, the authors show Nardilysin (NRDc) as a new biomarker of gastric cancer. Functionally, NRDc enhances the sheddase activity of ADAM proteases, which promotes the ectodomain shedding of TNF-α, resulting in TNF-α/NF-κB and IL-6/STAT3 signaling pathways activation that drive tumor proliferation.


Hedgehog-EGFR cooperation response genes determine the oncogenic phenotype of basal cell carcinoma and tumour-initiating pancreatic cancer cells
Markus Eberl, Stefan Klingler, Doris Mangelberger, Andrea Loipetzberger, Helene Damhofer, Kerstin Zoidl, Harald Schnidar, Hendrik Hache, Hans-Christian Bauer, Flavio Solca, Cornelia Hauser-Kronberger, Alexandre N. Ermilov, Monique E. Verhaegen, Christopher K. Bichakjian, Andrzej A. Dlugosz, Wilfried Nietfeld, Maria Sibilia, Hans Lehrach, Christoph Wierling and Fritz Aberger
EMBO Mol Med 2012, 4(3), 218-233



The Hedgehog pathway is currently very intensely studied in oncology and molecular medicine. Combining Hedgehog antagonists with inhibitors targeting cooperative signals may prove an efficient therapeutic strategy. Here the authors show that inhibition of EGFR signaling reduces tumor development in mouse models of Hedgehog/GLI driven skin cancer and identify novel downstream mechanisms mediating the oncogenic effect of synergistic Hedgehog-EGFR signal interactions.


MicroRNA dysregulation in cancer: diagnostics, monitoring and therapeutics. A comprehensive review
Marilena V. Iorio and Carlo M. Croce
EMBO Mol Med 2012, 4(3), 143-159



This review is part of a miRNA-review series that comprehensively reports the current knowledge about the role of microRNAs in cancer. From diagnostic to therapeutic applications, miRNAs in cancer are a promising tool for clinicians and basic science researchers alike, all of which is nicely reported here.


Concerted functions of HDAC1 and microRNA-574-5p repress alternatively spliced ceramide synthase 1 expression in human cancer cells
Marisa Meyers-Needham, Suriyan Ponnusamy, Salih Gencer, Wenhui Jiang, Raquela J. Thomas, Can E. Senkal and Besim Ogretmen
EMBO Mol Med 2012, 4(2), 78-92



Histone deacetylases and microRNAs have a pro-survival role, but the mechanism remains unclear. C18-ceramide generation is altered following CerS1 repression, which was linked to chemotherapy-drug resistance. Here, the authors show that HDAC1 and miR-574-5p cooperate to mediate CerS1 repression, thereby blocking the anti-tumor effect of C18-ceramide generation and suggest a novel therapeutic approach against cancer.


Reconstruction of nuclear receptor network reveals that NR2E3 is a novel upstream regulator of ESR1 in breast cancer
Yun-Yong Park, Kyounghyun Kim, Sang-Bae Kim, Bryan T. Hennessy, Soo Mi Kim, Eun Sung Park, Jae Yun Lim, Jane Li, Yiling Lu, Ana Maria Gonzalez-Angulo, Woojin Jeong, Gordon B. Mills, Stephen Safe and Ju-Seog Lee
EMBO Mol Med 2012, 4(1), 52-67



In this article, the authors identify a new role for NR2E3 bound to PIAS3 , as a novel regulator of ESR1 gene expression. NR2E3, an orphan nuclear receptor, is further correlated with recurrence free survival of breast cancer patients.


The Wnt secretion protein Evi/Gpr177 promotes glioma tumourigenesis
Iris Augustin, Violaine Goidts, Angelika Bongers, Grainne Kerr, Gordon Vollert, Bernhard Radlwimmer, Christian Hartmann, Christel Herold-Mende, Guido Reifenberger, Andreas von Deimling and Michael Boutros
EMBO Mol Med 2012, 4(1), 38-51



The authors establish a functional role of Evi/GPR177 in the molecular pathogenesis of human astrocytic gliomas. Evi regulates both canonical and non-canonical Wnt signalling in glioma cells with both branches likely contributing to malignancy. With its GPCR-like structural features Evi may serve an attractive novel target for therapeutic interventions.


DNA methylation profiling reveals a predominant immune component in breast cancers
Sarah Dedeurwaerder, Christine Desmedt, Emilie Calonne, Sandeep K. Singhal, Benjamin Haibe-Kains, Matthieu Defrance, Stefan Michiels, Michael Volkmar, Rachel Deplus, Judith Luciani, Françoise Lallemand, Denis Larsimont, Jérôme Toussaint, Sandy Haussy, Françoise Rothé, Ghizlane Rouas, Otto Metzger, Samira Majjaj, Kamal Saini, Pascale Putmans, Gérald Hames, Nicolas van Baren, Pierre G. Coulie, Martine Piccart, Christos Sotiriou and François Fuks
EMBO Mol Med 2011, 3(12), 726-741



Breast cancer is a very heterogeneous disease at both histological and molecular levels. Despite considerable efforts to classify breast cancers into different groups, patients with the same "prolife" can still respond differently to chemotherapies and have different clinical outcomes. In here, the authors explored DNA methylation landscapes of phenotypically heterogeneous breast tumors and describe epigenetic portraits that could help t improve breast cancer patient management.


A serum circulating miRNA diagnostic test to identify asymptomatic high-risk individuals with early stage lung cancer
Fabrizio Bianchi, Francesco Nicassio, Matteo Marzi, Elena Belloni, Valentina Dall'Olio, Loris Bernard, Giuseppe Pelosi, Patrick Maisonneuve, Giulia Veronesi and Pier Paolo Di Fiore
EMBO Mol Med 2011, 3(8), 495-503



Non-small cell lung carcinoma is the leading cause of cancer mortality worldwide, largely due to a lack of effective tools for early diagnosis. The authors developed a blood test for lung cancer diagnosis in asymptomatic high-risk individuals based on the detection of miRNAs from serum.

Accompanying Closeup
Circulating miRNA signature for early diagnosis of lung cancer
Pei-Ying Lin and Pan-Chyr Yang
EMBO Mol Med 2011, 3(8), 436-437


The adhesion molecule NCAM promotes ovarian cancer progression via FGFR signalling
Silvia Zecchini, Lorenzo Bombardelli, Alessandra Decio, Marco Bianchi, Giovanni Mazzarol, Fabio Sanguineti, Giovanni Aletti, Luigi Maddaluno, Vladimir Berezin, Elisabeth Bock, Chiara Casadio, Giuseppe Viale, Nicoletta Colombo, Raffaella Giavazzi and Ugo Cavallaro
EMBO Mol Med 2011, 3(8), 480-494



Epithelial ovarian carcinoma (EOC) represents an outstanding challenge for clinical oncologists, due to the difficulty of early diagnosis and to the high rate of relapse that follows the dissemination of cancer cells to the peritoneal cavity. Here, the authors show that the NCAM/FGFR interplay represents a therapeutic target that can be efficiently inactivated, resulting in repression of EOC metastasis.


Genomic biomarkers in predictive medicine. An interim analysis
Richard Simon
EMBO Mol Med 2011, 3(8), 429-435



Current genomics and biotechnology promise the development of biomarkers to predict individual disease risk, enable early detection of disease, and improve diagnostic classification to better inform individualized treatment. Here, the author provides an interim analysis and identifies some of the roadblocks to progress.


Pml represses tumour progression through inhibition of mTOR
Rosa Bernardi, Antonella Papa, Ainara Egia, Nadia Coltella, Julie Teruya-Feldstein, Sabina Signoretti and Pier Paolo Pandolfi
EMBO Mol Med 2011, 3(5), 249-257



The authors generated a compound knockout mouse model lacking two tumor suppressors that are known to negatively regulate mTOR and suggest that hyperactivation of mTORC1 does not self-sufficiently trigger kidney cystogenesis and tumor initiation.


ZNF703 is a common Luminal B breast cancer oncogene that differentially regulates luminal and basal progenitors in human mammary epithelium
Daniel G. Holland, Angela Burleigh, Anna Git, Mae A. Goldgraben, Pedro A. Perez-Mancera, Suet-Feung Chin, Antonio Hurtado, Alejandra Bruna, H. Raza Ali, Wendy Greenwood, Mark J. Dunning, Shamith Samarajiwa, Suraj Menon, Oscar M. Rueda, Andy G. Lynch, Steven McKinney, Ian O. Ellis, Connie J. Eaves, Jason S. Carroll, Christina Curtis, Samuel Aparicio, Carlos Caldas
EMBO Mol Med 2011, 3(3), 167-180



Luminal B breast cancers are the clinically more aggressive ER-positive tumours and characterizing the genomic drivers (oncogenes) at chromosomal loci frequently altered in this subtype has been the subject of intense research. Here, the authors identify ZNF703 as the driver of the frequent amplification of a distal 8p12 locus, which occurs in around 1/3 of Luminal B breast cancers. ZNF703 behaves as a classical oncogene in that it transforms non-malignant cells and increases cellular proliferation.


ZNF703 gene amplification at 8p12 specifies luminal B breast cancer
Fabrice Sircoulomb, Nathalie Nicolas, Anthony Ferrari, Pascal Finetti, Ismahane Bekhouche, Estelle Rousselet, Aurélie Lonigro, José Adélaïde, Emilie Baudelet, Séverine Esteyriès, Julien Wicinski, Stéphane Audebert, Emmanuelle Charafe-Jauffret, Jocelyne Jacquemier, Marc Lopez, Jean-Paul Borg, Christos Sotiriou, Cornel Popovici, Fran&ccdil;ois Bertucci, Daniel Birnbaum, Max Chaffanet, Christophe Ginestier
EMBO Mol Med 2011, 3(3), 153-166



The heterogeneity of breast cancer renders prognosis and treatment difficult. Although both luminal A and B tumours express hormone receptors (oestrogen and progesterone), the risk of relapse in women treated by hormone therapy is greater in women with a luminal B tumour than in women with a luminal A tumour. Here, the authors show that amplification of the ZNF703 gene, located in chromosomal region 8p12, preferentially occurs in luminal B tumours. Moreover, expression of ZNF703 both stimulates cell proliferation and increases the stem cell population, therefore identifying ZNF703 as a new type of oncogene.

Accompanying Closeup highlighting Holland et al and Sircoulomb et al
Divide and conquer: the genetic basis of molecular subclassification of breast cancer
Vessela N. Kristensen
EMBO Mol Med 2011, 3(4), 183-185


Deregulation of FoxM1b leads to tumour metastasis
Hyun Jung Park, Galina Gusarova, Zebin Wang, Janai R. Carr, Jing Li, Ki-Hyun Kim, Jin Qiu, Yoon-Dong Park, Peter R. Williamson, Nissim Hay, Angela L. Tyner, Lester F. Lau, Robert H. Costa, Pradip Raychaudhuri
EMBO Mol Med 2011, 3(1), 21-34



Metastasis of tumour cells is the major cause of cancer-related deaths worldwide. However, the molecular mechanisms and pathways that encourage tumour cells to leave the primary site of tumour development and undergo metastasis are poorly understood. Using liver cancer as a model, the authors identify that a combination of over-expression of FoxM1 and loss of Arf causes primary liver cancer cells to metastasize to the lung.


p21 loss blocks senescence following Apc loss and provokes tumourigenesis in the renal but not the intestinal epithelium
Alicia M. Cole, Rachel A. Ridgway, Sahra E. Derkits, Lee Parry, Nick Barker, Hans Clevers, Alan R. Clarke, Owen J. Sansom
EMBO Mol Med 2010, 2(11), 472-486



Senescence is thought to play a key tumour suppressor activity during carcinogenesis. In this article, the authors show that in the intestinal epithelium, APC loss alone was sufficient to drive adenoma formation, whilst within the kidney, additional loss of p21 was required to initiate renal carcinoma. Therefore, initiating mutations drive senescence in a tissue-specific manner and shape the evolutionary landscape for the subsequent mutations that allow tumour progression.


V600EBraf induces gastrointestinal crypt senescence and promotes tumour progression through enhanced CpG methylation of p16INK4a
Linda A. S. Carragher, Kimberley R. Snell, Susan M. Giblett, Victoria S. S. Aldridge, Bipin Patel, Simon J. Cook, Doug J. Winton, Richard Marais, Catrin A. Pritchard
EMBO Mol Med 2010, 2(11), 458-471



In the Vogelstein model, human colorectal cancer (CC) is initiated by mutations arising in the APC tumour suppressor gene. However, ∼12% of CC samples are not mutated in APC but have the V600EBRAF mutation and the CpG island methylator-high phenotype (CIMP-H). Here, the authors identify V600EBRAF as an early genetic driver of serrated CC and indicate that, unlike APC-mutated cancers, this subtype arises by the bypassing of a V600EBRAF driven, oncogene-induced senescence programme.


Annexin A1 attenuates EMT and metastatic potential in breast cancer
Sabine Maschler, Christoph A. Gebeshuber, Eva-Maria Wiedemann, Memetcan Alacakaptan, Martin Schreiber, Ivana Custic, Hartmut Beug
EMBO Mol Med 2010, 2(10), 401-414



Epithelial-mesenchymal transition (EMT) is considered a prerequisite for cancer cells to invade adjacent tissue and form metastases at distinct sites. Here, the authors investigated the role of Annexin A1 in EMT and metastasis and propose that Annexin A1 might be used as a marker for tumour progression in the clinical setting.


Oncolytic targeting of renal cell carcinoma via encephalomyocarditis virus
Frederik C. Roos, Andrew M. Roberts, Irene I. L. Hwang, Eduardo H. Moriyama, Andrew J. Evans, Stephanie Sybingco, Ian R. Watson, Leticia A. M. Carneiro, Craig Gedye, Stephen E. Girardin, Laurie E. Ailles, Michael A. S. Jewett, Michael Milosevic, Brian C. Wilson, John C. Bell, Sandy D. Der, Michael Ohh
EMBO Mol Med 2010, 2(7), 275-288



This pre-clinical study provides support for the use of EMCV as an oncolytic virus aimed at eradicating kidney tumours like clear-cell renal cell carcinoma and potentially other tumours with elevated HIF and NF- κ B pathways. Cancers that are particularly resistant to conventional cancer therapies may be paradoxically more susceptible to EMCV-induced killing since this virus exploits the very nature of cancer cells to evade cell death to exacerbate its own virulence.


Oxidative stress promotes myofibroblast differentiation and tumour spreading
Aurore Toullec, Damien Gerald, Gilles Despouy, Brigitte Bourachot, Melissa Cardon, Sylvain Lefort, Marion Richardson, Guillem Rigaill, Maria-Carla Parrini, Carlo Lucchesi, Dorine Bellanger, Marc-Henri Stern, Thierry Dubois, Xavier Sastre-Garau, Olivier Delattre, Anne Vincent-Salomon, Fatima Mechta-Grigoriou
EMBO Mol Med 2010, 2(6), 211-230



HER2-amplified human breast adenocarcinomas, a breast cancer molecular subtype associated with a very poor prognosis and lymph node metastases, express high levels of CXCL12 in the stroma. This study raises the intriguing possibility that, in addition to current treatments, CXCR4-blocking antibodies may be effective in combating tumour metastasis in lymph node-positive HER2 patients.


1q12 chromosome translocations form aberrant heterochromatic foci associated with changes in nuclear architecture and gene expression in B cell lymphoma
Alexandra Fournier, Anne McLeer-Florin, Christine Lefebvre, Samuel Duley, Leila Barki, Juliana Ribeyron, Kassambara Alboukadel, Sieme Hamaidia, Aurélie Granjon, Rémy Gressin, Alicia Lajmanovich, Thierry Bonnefoix, Stéphanie Chauvelier, Alexandra Debernardi, Sophie Rousseaux, Florence de Fraipont, Martin Figeac, Jean-Pierre Kerckaert, John De Vos, Yves Usson, Katia Delaval, Alexei Grichine, Claire Vourc'h, Saadi Khochbin, Robert Feil, Dominique Leroux, Mary B. Callanan
EMBO Mol Med 2010, 2(5), 159-171



Numerous cancers present chromosomal translocations that can be broadly divided into those that mediate proto-oncogene activation by position effect and those that generate oncogenic fusion products. Chromosomal translocations that target repetitive sequences of the human genome are described as well, although their pathogenic consequences remain unclear. Rearrangements affecting the pericentric heterochromatic band 1q12 are frequently observed in both haematological and solid tumours. In this study, 1q12 rearrangements, which are frequently encountered in a broad spectrum of human cancers, are shown to represent a new paradigm for long-range epigenetic deregulations in cancer.


Rapid targeted mutational analysis of human tumours: a clinical platform to guide personalized cancer medicine
Dora Dias-Santagata, Sara Akhavanfard, Serena S. David, Kathy Vernovsky, Georgiana Kuhlmann, Susan L. Boisvert, Hannah Stubbs, Ultan McDermott, Jeffrey Settleman, Eunice L. Kwak, Jeffrey W. Clark, Steven J. Isakoff, Lecia V. Sequist, Jeffrey A. Engelman, Thomas J. Lynch, Daniel A. Haber, David N. Louis, Leif W. Ellisen, Darrell R. Borger, A. John Iafrate
EMBO Mol Med 2010, 2(5), 146-158



One of the main challenges facing the oncology community is how to efficiently match each tumour with the right therapy and give all cancer patients the best chance at fighting their disease. In this article, the authors developed and extensively validated a simple and flexible multiplexed tumour genotyping assay that detects common mutations in some of the most important cancer genes.

Accompanying Closeup
Mutations for the people
Vessela Kristensen, Anne-Lise Borresen-Dale
EMBO Mol Med 2010, 2(5), 143-145


Aurora-A expressing tumour cells are deficient for homology-directed DNA double strand-break repair and sensitive to PARP inhibition
Tony Sourisseau, Despina Maniotis, Afshan McCarthy, Chan Tang, Christopher J. Lord, Alan Ashworth, Spiros Linardopoulos
EMBO Mol Med 2010, 2(4), 130-142



The Aurora-A gene is frequently upregulated in a variety of cancers, including breast and colon cancer. The clinical application of inhibitors of Aurora-A kinase activity is now being evaluated in clinical trials. In this study, the authors show that deregulation of Aurora-A in normal and cancer cell lines affects DNA damage repair. Aurora-A represses the homologous recombination repair pathway and confers increased cellular sensitivity to PARP inhibitors (known to target cancer cells with deficient DNA repair pathways) in vitro and in vivo.


Stat5 is indispensable for the maintenance of bcr/abl-positive leukaemia
Andrea Hoelbl, Christian Schuster, Boris Kovacic, Bingmei Zhu, Mark Wickre, Maria A. Hoelzl, Sabine Fajmann, Florian Grebien, Wolfgang Warsch, Gabriele Stengl, Lothar Hennighausen, Valeria Poli, Hartmut Beug, Richard Moriggl, Veronika Sexl
EMBO Mol Med 2010, 2(3), 98-110



Acute lymphoid and chronic myelogenous leukaemia can be induced by the chimeric fusion gene product Bcr/Abl, a constitutively active tyrosine kinase. A complex signalling network downstream of Bcr/Abl supports proliferation and survival of the leukaemic cells. Bcr/Abl kinase inhibitors (e.g. Imatinib) can hamper these signals and induce cell death but several mutations were described that confer resistance to these inhibitors. Here, the authors identify the Stat5 transcription factor as an Achilles' heel in the signalling network downstream of Bcr/Abl.


Human colon cancer epithelial cells harbour active HEDGEHOG-GLI signalling that is essential for tumour growth, recurrence, metastasis and stem cell survival and expansion
Frédéric Varnat, Arnaud Duquet, Monica Malerba, Marie Zbinden, Christophe Mas, Pascal Gervaz, Ariel Ruiz i Altaba
EMBO Mol Med 2009, 1(6-7), 338-351



Early human colon tumors often progress to invasive colon carcinomas (CCs) and produce distant metastases, commonly in the liver. Whereas early and localized colon tumors can be effectively treated by surgery, metastatic CC remains largely incurable. In this article, the authors demonstrate the presence of active Hedgehog-GLI signalling in the epithelial tumour cells of patient-derived primary CCs and liver metastases. Morever, HH-GLI activity in epithelial tumour cells is essential for tumour growth, recurrence and metastatic growth.

Accompanying Closeup
Hedgehog signalling in colon cancer and stem cells
Alberto Gulino, Elisabetta Ferretti, Enrico De Smaele
EMBO Mol Med 2009, 1(6-7), 300-302


Methotrexate induces oxidative DNA damage and is selectively lethal to tumour cells with defects in the DNA mismatch repair gene MSH2
Sarah A. Martin, Afshan McCarthy, Louise J. Barber, Darren J. Burgess, Suzanne Parry, Christopher J. Lord, Alan Ashworth
EMBO Mol Med 2009, 1(6-7), 323-337



Defects in components of the DNA mismatch repair pathway, such as those caused by mutation of the MSH2 gene, predispose to a range of cancers and, in particular, hereditary non-polyposis colon cancer. In this article, the authors screened tumour cells with a library of commonly used drugs and drug-like compounds and show that MSH2 deficient tumour cells are particularly sensitive to methotrexate. Methotrexate treatment of MSH2-deficient tumour cells causes an accumulation of potentially lethal oxidative DNA damage. In cells with functional MSH2, this damage is efficiently repaired but in MSH2-deficient tumour cells, repair of oxidative DNA damage is impaired and this eventually limits the survival of tumour cells.


Synthetic lethal targeting of PTEN mutant cells with PARP inhibitors
Ana M. Mendes-Pereira, Sarah A. Martin, Rachel Brough, Afshan McCarthy, Jessica R. Taylor, Jung-Sik Kim, Todd Waldman, Christopher J. Lord, Alan Ashworth
EMBO Mol Med 2009, 1(6-7), 315-322



The tumour suppressor gene PTEN is one of the most commonly mutated genes in human cancers. Selective targeting of BRCA1- or BRCA2-deficient tumours has recently been demonstrated with Olaparib, a high-potency PARP inhibitor. In this article, the authors demonstrate that PTEN deficiency in human tumour cells leads to suppression of homologous recombination. Using in vitro approaches and in vivo tumour modelling in mice, the authors show that, as in BRCA-deficient tumours, the HR deficiency in PTEN-mutant cells can be exploited therapeutically using Olaparib.

Accompanying Closeup highlighting Martin et al and Mendes-Pereira et al
Converting cancer mutations into therapeutic opportunities
Tom O'Brien, David Stokoe
EMBO Mol Med 2009, 1(6-7), 297-299


Onco-miR-155 targets SHIP1 to promote TNFα-dependent growth of B cell lymphomas
Irene M. Pedersen, Dennis Otero, Elaine Kao, Ana V. Miletic, Christoffer Hother, Elisabeth Ralfkiaer, Robert C. Rickert, Kirsten Gronbaek, Michael David
EMBO Mol Med 2009, 1(5), 288-295



Diffuse large B-cell lymphoma (DLBCL) is clinically, morphologically and genetically a heterogeneous group of lymphomas involving malignant proliferation of large lymphoid B cells. Here, the authors identify the inositol phosphatase SHIP1 as a bonafide target of the oncogenic miR-155. They establish that cytokine-regulated miRs can function as a crucial link between inflammation and cancer, and illustrate the feasibility of anti-TNFα therapy as a novel and immediately accessible (co)treatment for DLBCL.


Integrative genomic analyses of neurofibromatosis tumours identify SOX9 as a biomarker and survival gene
Shyra J. Miller, Walter J. Jessen, Tapan Mehta, Atira Hardiman, Emily Sites, Sergio Kaiser, Anil G. Jegga, Hua Li, Meena Upadhyaya, Marco Giovannini, David Muir, Margaret R. Wallace, Eva Lopez, Eduard Serra, G. Petur Nielsen, Conxi Lazaro, Anat Stemmer-Rachamimov, Grier Page, Bruce J. Aronow, Nancy Ratner
EMBO Mol Med 2009, 1(4), 236-248



Neurofibromatosis type 1 (NF1) is one of the most common inherited human diseases worldwide. Neurofibromas are the hallmark of NF1, which can transform into a malignant form. Neurofibromas are composed of multiple cell types, including Schwann cells, the pathogenic cell type of NF1. Here, the authors used DNA microarrays to show that neurofibromas repress gene programmes normally expressed in late-developing immature Schwann cells, while malignant forms activate gene programmes normally expressed earlier in development at the neural crest stage.

Accompanying Closeup
Neurofibromatosis and lessons for the war on cancer
Karlyne M. Reilly
EMBO Mol Med 2009, 1(4), 198-200


Heterochromatin protein 1α: a hallmark of cell proliferation relevant to clinical oncology
Leanne De Koning, Alexia Savignoni, Charlène Boumendil, Haniya Rehman, Bernard Asselain, Xavier Sastre-Garau, Geneviève Almouzni
EMBO Mol Med 2009, 1(3), 178-191



Breast cancer is a clinically and genetically diverse disease. How alterations in chromatin organization contribute to its development should therefore be considered. Here, the authors focus on HP1α, β and γ, key components of compact heterochromatin regions, and suggest a unique function for the HP1α isoform, related to cell division and tumour growth. HP1α overexpression in breast cancer patient samples correlates with disease outcome and could be a new epigenetic marker for prognosis assessment.


Oxygen-independent degradation of HIF-α via bioengineered VHL tumour suppressor complex
Roxana I. Sufan, Eduardo H. Moriyama, Adrian Mariampillai, Olga Roche, Andrew J. Evans, Nehad M. Alajez, I. Alex Vitkin, Victor X. D. Yang, Fei-Fei Liu, Brian C. Wilson, Michael Ohh
EMBO Mol Med 2009, 1(1), 66-78



Under normal oxygen tension, von Hippel-Lindau (VHL) tumour suppressor protein promotes the degradation of the hypoxia-inducible factor HIF, which governs cellular adaptation to hypoxia or low oxygen tension. In the present study, the authors describe the bioengineering of a VHL protein that can recognize HIF and promote its degradation in the absence of oxygen.

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