Neuronal signatures in cancer

Despite advances in the treatment of solid tumors, the prognosis of patients with many cancers remains poor, particularly of those with primary and metastatic brain tumors. In the last years, “Cancer Neuroscience” emerged as novel field of research at the crossroads of oncology and classical neuroscience. In primary brain tumors, including glioblastoma (GB), communicating networks that render tumor cells resistant against cytotoxic therapies were identified. To build these networks, GB cells extend neurite‐like protrusions called tumor microtubes (TMs). Synapses on TMs allow tumor cells to retrieve neuronal input that fosters growth. Single cell sequencing further revealed that primary brain tumors recapitulate many steps of neurodevelopment. Interestingly, neuronal characteristics, including the ability to extend neurite‐like protrusions, neuronal gene expression signatures and interactions with neurons, have now been found not only in brain and neuroendocrine tumors but also in some cancers of epithelial origin. In this review, we will provide an overview about neurite‐like protrusions as well as neurodevelopmental origins, hierarchies and gene expression signatures in cancer. We will also discuss how “Cancer Neuroscience” might provide a framework for the development of novel therapies.

mechanisms involved in proliferation, migration and network formation are exploited by tumor cells to thrive. 3 Brain metastasis of solid tumors is tenfold more common than primary brain tumors. Although of nonnervous system origin, brain-metastatic cells adopt to the brain microenvironment and can acquire neuronal characteristics. [9][10][11][12] Importantly, increasing evidence suggests that this exploitation does not seem to be limited to brain tumors.
In this review, we will discuss how brain and some other tumors use neurite-like protrusions for invasion and the formation of multicellular networks, which neurodevelopmental pathways are exploited for the extension of these protrusions, how distinct neurodevelopmental origins provide an explanation for the heterogeneous brain tumor entities and which neurodevelopmental subpopulations can be found in different tumor entities. Recent findings demonstrate that these protrusions, pathways and subpopulations are also relevant in some tumor entities outside the brain, hence providing the basis for the field of "Cancer Neuroscience." Together this provides a framework for a better understanding of the fundamental biology of these cancers, including crucial mechanisms of progression and resistance, and finally new ideas how to target them.

| NEURITE-LIKE PROTRUSIONS IN PRIMARY BRAIN TUMORS
A few years ago, our group described that tumor cells of adult incurable gliomas extend neurite-like cellular protrusions which are not just used as leading structures for the diffuse infiltration of the brain parenchyma but also interconnect tumor cells to dense multicellular networks 13 (Figure 1). Functional brain tumor cell networks have now been confirmed by other groups, 14,15 and also in pediatric gliomas, particularly in those entities which are incurable and particularly malignant. 16 These cellular protrusions have growth cone-like tips and were named "tumor microtubes" (TMs), as they are distinct from other protrusions described to play a role in glioma cells such as filopodia or invadopodia. 3,13,17 The formation of TMs and multicellular networks is widely absent in 1p/19q-codeleted oligodendroglioma, 13 which are characterized by sensitivity to cytotoxic therapies and a more benign course of disease. 18,19 Recently, the neurite-like nature of TMs has been underlined by the identification of bona fide glutamatergic synapses on TMs. Here, tumor cells always constitute the postsynaptic partner, hence suggesting a dendrite-like function of TMs. 20,21 Synaptic input partially drives intercellular calcium waves between connected tumor cells. 20,21 These networks are of potential clinical significance as it could be demonstrated that interconnected cells are highly resistant against cytotoxic therapies, 13,22 hence disconnection could emerge as a novel therapeutic paradigm. 23,24 In addition, TMs allow efficient invasion of the brain parenchyma 13,15,25 and lead to a repair response after surgery, which contributes to treatment resistance and glioma recurrence. 22 A recent work by the group of Peter Friedl suggests that effective brain colonization even depends on the network formation by allowing a novel mechanism of collective cell migration: network invasion. 15 In line with the neurite-like characteristics of TMs, Gap43, 13 Ttyh1 25 and p120 catenin 15 have been identified as potent drivers of TM outgrowth ( Figure 1). While Gap43 and Ttyh1 directly promote neurite extension during neurodevelopment, 3 p120 catenin seems to be an upstream regulator of neuronal morphogenesis. 15 Gap43 13 and p120 catenin 15 downregulation reduced both network formation and tumor cell invasion, whereas Ttyh1 knockdown reduced TM-dependent tumor cell invasion but promoted interconnection. 25 These differences suggest that different subtypes of TMs exist. In a drosophila model of GB, tumor cells use TMs to enwrap neurons and deplete them of WNT thereby leading to F I G U R E 1 Neurite-like protrusions in cancer. Schematic overview about functions and known molecular drivers of neurite-like protrusions in cancer. Neuritelike protrusions are used by tumor cells for collective as well as single cell invasion. After cell division, nuclei are transported along neurite-like protrusions. In addition, tumor cells use these protrusions to form dense communicating networks. Direct synaptic connections with neurons enable these networks to receive neuronal input. While some molecular drivers seem to be involved in many known functions of neurite-like protrusions (such as Gap43), others (such as p120 catenin and Fez1) seem to play a role for neurite-like protrusions involved in invasion only. Cx43, connexin 43; Fez1, fasciculation and elongation protein zeta-1; Gap43, growth associated protein 43; p120, p120 catenin; Ttyh1, tweety homolog 1 neurodegeneration. 26 In addition to impaired peritumoral neurotransmitter signaling, [27][28][29] this mechanism provides novel insights into how even single invading glioma cells could lead to cognitive dysfunction and potentially also epileptic seizures which are frequent in glioma patients.

| NEURODEVELOPMENTAL FEATURES OF EXTRACRANIAL MALIGNANCIES AND BRAIN METASTASES
Neurite-and TM-like protrusions, which are also driven by neurodevelopmental pathways including Gap43, have recently been found in small cell lung cancer (SCLC), 30 where they promoted invasion and metastasis. It needs to be seen whether those protrusions are also used for the formation of multicellular networks and for interconnection with host cells, for example, those of the brain, an organ where these tumors frequently metastasize to. Even at their primary sites, SCLC cells are characterized by neuronal characteristics 31 and are thought to arise from neuroendocrine cells, 32 thereby providing one explanation for the activation of programs of neuronal morphogenesis. Neurite-like protrusions seem not to be limited to cells with neuronal characteristics though as they were also detected in breast cancer cells, which are of epithelial origin. Here the neurite-like protrusions are induced by the sodium channel β1 subunit and promoted metastasis and tumor cell growth. 33 Tunneling nanotube (TNT)-like protrusions, which are thinner, shorter and less stable then TMs 23 and neurite-like protrusions, have been described in a variety of cell types, including colon, 34 pancreatic 35 and prostate cancer 36 and also GB 17 in vitro. Although the in vivo relevance of these structures still remains to be elucidated, in vitro studies suggest that TNT-like structures promote resistance against cytotoxic therapies, 35-37 much as described for TMs. In drosophila, specialized neurite-like protrusions called cytonemes have been described during tissue development 38,39 and tumorigenesis. 40 Similar to TMs and neurites, glutamatergic synapses on cytonemes induce intracellular calcium transients. 41 Finally, even in brain metastasis, only a minority of cells manages to colonize the brain, 42 and these cells are genomically distinct from extracranial metastases, 43 suggesting that certain preexisting expression profiles of cancers might promote brain colonization. Interestingly, gene expression analyses suggest that brain metastases of breast cancer gain neuronal and neurogenic features, including Gap43 and neurotransmitter receptor expression in comparison to the primary tumor 9-12 or bone metastases. 44 In nonsmall cell lung cancer, expression of Gap43 was associated with a higher risk for brain metastasis. 45 The upregulation of neurodevelopmental pathways in the brain colonizing, pre-(macro)metastatic breast cancer cells 46 suggests that these properties might enable cells to better integrate into the brain microenvironment, including the recently described formation of pseudo-tripartite synapses. 47 In addition, breast and lung cancer cells are able to form gap junctions with brain astrocytes, thereby promoting metastasis growth and chemoresistance. 48 The brain microenvironment seems to be responsible for the reversible induction of the expression of neuronal genes. 11 In summary, neurite-like protrusions and other neuronal features are increasingly recognized as being important for different aspects of cancer biology, and their therapeutic targeting emerges as novel paradigm in the treatment of various malignancies. It remains to be seen whether this applies to only some or many tumor entities and/or tumor cell subpopulations in a given tumor.

| NEURODEVELOPMENTAL ORIGINS OF GLIOMAS
In contrast to brain metastases, malignant gliomas directly arise from cells of the brain, which provides a straightforward explanation for the reactivation of neurodevelopmental pathways. GB is the most common and, with a median survival of under 2 years, the most malignant glioma type in adults. 49 Based on bulk molecular and gene expression profiles, GBs can be divided into several subclasses, 50,51 namely a proneural, classical, mesenchymal and neural type. The delineation of the latter has been recently contested, 52  The intricate wiring of the mature CNS results from the temporally and spatially precisely orchestrated regulation of neurogenic and gliogenic processes during development. 59 The generation of different new cells in the brain occurs in waves, 59 is most pronounced after birth and declines with age. [60][61][62] One subtype of high-grade glioma (HGG), diffuse midline glioma (DMG; this group includes classical diffuse intrinsic pontine gliomas) which accounts for nearly 50% of HGGs in children and young adults and which is virtually exclusive for these age-groups, arises mainly in the ventral brainstem and thalamus ( Figure 2). [63][64][65] Distinct from other pediatric HGGs, DMGs bear a characteristic histone H3 K27M mutation and exhibit a specific gene expression profile that includes the expression of developmentally regulated cellular pathways such as regulators of brainstem development. [66][67][68] Pontine DMGs occur in the ventral pons in a narrow time window between the age of 5 and 9 years. 69,70 Before this, that is, during the time period between birth and the age of 5, there has been marked growth of the pons. 71 A distinct progenitor cell population was identified that showed a decline in cell number after the age of 2, but exhibited again an increase in the ventral pons around the age of 6. This developmental pattern corresponds with the temporal and spatial incidence of pontine DMG. 68,69,72 Interestingly, DMGs in other midline structures such as the thalamus show a later peak incidence in the young adulthood, 70 possibly reflecting that different progenitor cells exhibit variable susceptibility for malignancy. The distinct origin and associated molecular biology of DMGs provides the basis for more targeted therapeutic approaches, such as Chimeric Antigen Receptor T-cell 73 or histone deacetylase inhibitor therapy. 16,[74][75][76] In adults, the majority of diffuse (WHO II ) and anaplastic (WHO III ) gliomas but less than 10% of GBs (WHO IV ) harbor a mutation in the isocitrate dehydrogenase (IDH) genes. 7 The incidence of IDH mutant glioma increases abruptly in the third decade of life, and decreases in the fourth and fifth decade. 77 These tumors are, in contrast to G34 mutant and IDH wild-type tumors, commonly located in the frontal lobes. 63,77 Tumors harboring an IDH1 mutation show a distinct gene expression profile resembling that of lineage-committed progenitor cells found in the frontal lobe. 77 These oligodendrocyte precursor cells (OPCs) in the frontal lobes, which are characterized by proliferative capacity and lineage plasticity, 78,79 might be involved in the developmental processes that support the extensive maturation in the prefrontal cortex during late adolescence. 80 A decrease in progenitor cell activity following adolescence is paralleled by the decreased incidence of IDH mutant glioma with higher age. 77,80,81 Finally, GBs that lack an IDH mutation represent the most common type of malignant primary brain tumors. Their incidence increases with age and is most often found in patients >55 years. 7 In contrast to IDH mutant gliomas, IDH wild-type glioma often display a gene expression profile resembling that of neural stem cells (NSCs) (in particular the most aggressive "mesenchymal" and "proneural" molecular subtypes). [50][51][52]82,83 NSCs, which accumulate alterations F I G U R E 2 Spatiotemporal links between neurogenesis and brain tumor development. Schematic summary of links between specific neuronal progenitor cells and subtypes of brain tumors. Specific neurogenic cells in certain locations (marked in different colors in the brain silhouette on the left side), their neurogenic activity in a restricted period of time (indicated by colored sections on the "life clock," which is shown in detail in the left lower corner) and the associated physiological (developmental) processes (marked by the construction sign) are shown on the left side. (Epi-)genetic alterations (with some characteristic mutations being specified and marked by the "explosion" symbol) during these events lead to different subtypes of brain tumors, which again occur in a certain time window (indicated again on the "life clock"). The curved arrow indicates that time windows of tumor manifestation follow the physiological developmental phases of the putative cells of origin and of a specific location (as marked in color on the schematic brain silhouette). Key facts further arguing for a certain cell origin are specified for each tumor subtype. DIPG, diffuse intrinsic pontine glioma; DMG, diffuse midline glioma; IDH, isocitrate dehydrogenase; NPC, neural progenitor cell; NSC, neural stem cell; OPC, oligodendrocyte precursor cell; SVZ, subventricular zone with age, 84 are thus likely the origin of IDH wild-type GBs. This is supported by the finding that the mutation burden in adult HGGs is approximately 3-fold higher than in childhood HGGs. 85 Hence, apparently fewer alterations are required in children to reach the oncogenic threshold, possibly due to a more permissive microenvironment and the propensity to proliferate of the cell of origin.
Recent molecular genetic evidence further underlines the distinct cell of origin of IDH mutant and IDH wild-type tumors. 86 In this study, Lee et al found low level driver mutations of IDH wild-type GB in the macroscopically unaffected subventricular zone (SVZ), the largest neurogenic region in adults, 87,88 which was not the case for IDH mutant GB. The data suggests that NSCs in the SVZ acquire mutations, such as Chromosome 7 gain, 9p or 10 loss, 89 and produce precancerous progeny that migrates away from the NSC niche leading to distant tumor development. 86 An interesting question is how the microenvironment influences glioma growth. 74,[90][91][92] Age-dependent changes during development might also account, at least in part, for growth arrest or even spontaneous regression reported for low-grade glioma in children. [93][94][95] The changes that occur normally during brain maturation in children might lead to a milieu that is no longer permissive for the growth of neoplastically transformed progenitor cells. This is in agreement with studies reporting a decrease in cancer cell proliferation with aging. 96 The comparatively stable microenvironment in adults on the other hand may facilitate sustained growth of gliomas of adulthood ( Figure 2).
Taken together, malignant gliomas seem to derive from distinct stem and progenitor cell populations under permissive microenvironmental conditions. Despite a certain degree of dysplasia, this cellular origin provides a plausible explanation for the ability of glioma cells to recapitulate steps of brain development. This includes the formation of communicating multicellular networks by neurite-like cellular protrusions, 3,13,22 the integration into existing networks of the brain 20,21 and the exploitation of developmental pathways to thrive. 3

| NEURONAL AND GLIAL SUBPOPULATIONS IN BRAIN TUMORS
Single cell analyses of different malignant gliomas revealed that these tumors are composed of diverse cellular subpopulations that resemble cells during neurodevelopment and in the adult brain. The diverse neuronal and glial cell populations in the brain originate from selfrenewing NSCs, which reside in neurogenic stem cell niches. During both, neuro-and gliogenesis, NSCs sit at the apex of the developmental hierarchy. NSCs produce transiently amplifying progenitor cell pools, which the gradually differentiate into cells of neuronal or glial lineages. 87,97 In malignant glioma, a subpopulation of stem-like cells (cancer

stem-like cells [CSCs]; brain tumor stem-like cells [BTSCs]) has been
identified, which was subsequently associated with tumor resistance and recurrence. [98][99][100][101][102] Although their significance for therapy failure in glioma is, if intriguing, an ongoing matter of debate, 103 they represent a plausible explanation for the heterogeneous and hierarchical composition of brain tumors. 104 These cells seem to represent the apex of the tumor cell hierarchy, are capable to undergo self-renewal and can be differentiated into neurons, astrocytes as well as oligodendrocytes in vitro, thus indicating their multipotency. 98,99,101,102 Recent single cell analyses reveal that broad expression of stemness programs in human glioma and the existence of different BTSC subsets within one tumor. 53 In addition, a mesenchymal (NSC-like)-to-proneural (OPClike) hierarchy of BTSCs has been identified, with in silico lineage tracing suggesting mesenchymal BTSCs as progenitors of proneural BTSCs. 105 Among the cell types found in gliomas are NSC/neural progenitor cell (NPC) (neural progenitor cell)-like, radial glia-like, OPC-like and different astrocytic subpopulations. 53,56,57,68,97,106,107 In one study, an average of 11 transcriptional cancer cell types could be found within a single tumor. 53 The glioma subtypes identified in bulk analyses 51 correspond to the expression profiles of cellular subpopulations and the classification depends on the relative frequency of the different cell states. 106 Interestingly, intratumoral heterogeneity seems not to be primarily driven by different genetic subclones. Instead, in vivo lineage tracing supports a plasticity between cell states. The cellular composition might represent a steady state of subpopulations that depends on inhibition or facilitation of certain states by genetic alterations and the microenvironment. 106 So far, the functional implications and behavior of the heterogeneous subpopulations remain widely unresolved. It was shown that the emergence of certain astrocytic subpopulations in malignant glioma correlates with the onset of epileptic seizures. 107 In addition, the extent of the subpopulations seems to differ between tumor regions such as the tumor core or the leading edge of tumor cell infiltration. 105,106 OPCs and OPC-like glioma cells are highly migratory cells during normal brain development 108 and in experimental models of malignant glioma. 109 In line, OPC-like cells were enriched at the infiltrative border of human glioma. 105 Several groups consistently reported that the OPC-like cellular population constitutes the actively proliferating fraction of glioma cells. 74,97,105,106 In addition, it will be interesting to elucidate if cellular subpopulations differ in the extent of therapy resistance and network integration.

| NEURONAL COMPONENTS OF EXTRACRANIAL TUMORS
In light of the increasing number of studies performing single cell analysis in various tumor entities outside the CNS, 113 it will also be fascinating to study whether at least some of them contain tumor cells with neuronal or glial features. Several studies suggest that tumorigenesis might represent a loss of the original cell identity, which can include a gain of neuronal characteristics. 114,115 In prostate cancer, varying subsets of neuroendocrine cancer cells are found within the tumors, and a neuronal trans-differentiation occurring during disease progression to metastatic and hormone resistant cancer. 116,117 Prostate cancer cells might even be able to fuse with nearby neuronal cells, thereby acquiring neuronal expression profiles and increasing intratumoral heterogeneity. 118 In ovarian cancer, the expression of mRNAs associated with neurogenesis and axon extension correlated with worse outcome. 119 In colon cancer, genes related with the nervous system increase with tumor stage. 120 As in GB, CSCs have now been identified in diverse cancer entities including pancreatic, colon and lung cancer, 121,122 which share characteristics with embryonic NPCs. 115,123 In experimental gastric and colorectal cancer, it could be demonstrated that CSCs could even give rise to neurons, thereby generating a nervous system within the tumor. 124 In GB, tumor cells are not only attracted toward the NSC niche, 90 but neural stem and progenitors show strong tropism toward the tumor bulk. 125 Interestingly, it was recently described that neural progenitors leave the SVZ of the brain to populate prostate tumors, where they give rise to neurons, and promote tumor growth and metastasis. 126 In addition, cancer tissue is strongly innervated compared to nonmalignant tissue with an increase during disease progression. [127][128][129][130]  1. Pharmacological or genetic (eg, by antisense oligonucleotides) targeting of neurodevelopmental pathways and molecules, such as Gap43, Fez1 or Ttyh1, could inhibit the outgrowth of neurite likeprotrusions. It remains to be elucidated if these protrusions also play a role for therapy resistance outside the brain, but first evidence exists that demonstrates that the inhibition of neurite-like protrusions can be used to reduce the metastatic potential. 30,33 Many molecules involved during neurodevelopment seem to be of limited importance in the mature brain and might hence be suitable targets for novel tumor-specific therapies. 3 Nonetheless, like always in Oncology, unwanted side effects need to be considered here, specifically on learning and CNS-regenerative processes. In Neuro-Oncology, one limitation of many therapeutic approaches is the limited CNS-penetrance of anticancer drugs. In contrast, in the case of treatment of cancers outside the brain, this might prove beneficial: the use of a non-CNS penetrant drug could prevent side effects which are expected to result from the inhibition of neurophysiological pathways within the brain.
2. Although gap junctions are found throughout the body, gap junction inhibition as monotherapy or in combination with cytotoxic therapies might be used to decrease tumor growth and resistance by targeting communicating tumor cell networks. In brain tumors, inhibition of gap junctions might not only disrupt the growth-and resistance-promoting effects of functional interconnection but could also be used to disrupt the downstream effects of synaptic input. 20,21 In preclinical models, gap junction inhibitors sensitized brain tumor cells for the effects of radio-and chemotherapy. [131][132][133] Besides tonabersat, which is well tolerated in humans and was studied in the prevention of migraine, 134 meclofenamate, which is used as anti-inflammatory drug in the United States, are interesting candidates to be studied in future trials. Of note, both drugs also inhibited the formation of heterocellular astrocyte-carcinoma gap junctions in a mouse model, thereby preventing brain metastasis and increasing therapy response to chemotherapy. 48 3. In the CNS, neuron-tumor synapses could be targeted by AMPA (in the case of glioma) 20,21 or NMDA (in the case of breast cancer metastasis) 47 receptor blockers. The AMPA receptor blocker perampanel is used as antiepileptic drug in the clinic. In a phase II clinical trial, the AMPA receptor inhibitor talampanel showed good tolerability and prolonged survival in combination with radiochemotherapy when compared to historical controls. 135 Overall, neurotransmitter signaling might be a challenging therapeutic target due to its versatile physiological functions and a small therapeutic window of drugs interfering with it. In the case of glioma, targeting specific calcium-permeable AMPA receptors, 20,21 which are otherwise just lowly expressed in the adult, is an interesting avenue. In the PNS, denervation strategies have shown promising results, 127,136,137 but the first evidence of tumor-intrinsic neurogenesis 124 , remodeling of existing nerves 2 or neurogenesis within the tumor by attraction of neuronal progenitors from distant places 126 suggests that the tumor is able to shape its own growthenhancing micromilieu.
For the development of efficient therapies, it will be important to decipher the tumor cell-neuron cross talk and origin of cancerassociated nerves. In glioma, it was demonstrated that specific PI3KCA variants lead to the initiation of brain hyperexcitability and synaptic remodeling, 138 which might then foster brain tumor growth. In the PNS, this was illustrated recently by an elegant study, 2 which showed that adrenergic neonerves foster head and neck tumor growth. Sympathectomy did not inhibit tumor growth though, as the adrenergic neonerves originated from transdifferentiation of sensory nerves. 2 As an example for therapies that target nervous tumor microenvironment, first studies, 136,139 including a phase II clinical trial, 136 suggest potential efficacy of beta-adrenergic blockade in breast cancer. In general, organ-specific effects should be kept in mind though as, for example, cholinergic signaling promotes gastric cancer growth, 140 but suppresses pancreatic cancer tumorigenesis. 141 4. Despite recent advances in the stratification of gliomas based on molecular characteristics, genomics and epigenomics, such as DNA methylation, 8 which are partly linked to the cell of origin, these differences are not yet addressed by tumor type-specific treatments. A better stratification is likely a requirement for significant treatment advances in the future though. Only few first hints exist that these differences could very well matter: a retrospective analysis suggested that bevacizumab, an anti-VEGF-A antibody, which did not prolong overall survival in phase III studies for the entire population of GB patients, 142,143 appeared to provide a significant survival benefit for patients with proneural, IDH1 wild-type GB in a secondary retrospective analysis. 83 This benefit from an antiangiogenic therapy seems rather unexpected, as proneural GB do not exhibit an upregulation of angiogenic markers (including VEGF) compared to other subtypes. 83 Here, consideration of OPCs, which are thought to be the cells of origin, could again provide further clues, as VEGF-A is inter alia a potent regulator of OPC migration, 144,145 and trophic coupling between endothelial and OPCs in an oligovascular niche was proposed, 146 thereby making nonangiogenic effects and a selective sensitivity of these cells possible.
It will be important to investigate the biological behavior, that is, invasion, network formation and therapy resistance, as well as the cell type specific vulnerabilities of different cellular subpopulations. The plasticity of cell states 106 suggests that forced transition, for example, by modulation of the switches involved in glial cell diversification, 110 to a more therapy sensitive state might prove beneficial when combined with cytotoxic therapies. with neurodevelopmental pathways could potentially be used to prevent the acquisition of neuronal characteristics as well as interactions with the brain microenvironment during brain metastasis, thereby preventing the successful colonization of the brain.

| SUMMARY AND OUTLOOK
The findings reported in this article reach from molecular neuroscience to clinical aspects of oncological diseases. They highlight how the comprehension of the fundamental molecular and regulatory mechanisms of neurobiology, which provide the basis for and are recapitulated during malignant transformation, could help to appreciate and understand the heterogeneous nature of gliomas but also other cancers. In recent years, the field of Cancer Neuroscience has gained momentum, 148 but deeper insights into the tumor-specific mechanisms are requisite for clinical translation. 136 However, the general interest in this translation is now documented by first biotech start-ups working in the field of Cancer Neuroscience. 137 All in all, despite differences in the secreted neurotransmitters and other physiological factors, nerves and neurons are not limited to the brain, but ubiquitous throughout the body. The rapidly evolving discoveries of molecular, anatomical, functional and developmental neuronal features of cancers can provide a novel framework for a better understanding of both their fundamental biology and unexpected vulnerabilities.