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-doc_0,"Leading Edge Commentary Roadmap for the Emerging Field of Cancer Neuroscience Michelle Monje,1,*Jeremy C. Borniger,2Nisha J. D’Silva,3Benjamin Deneen,4Peter B. Dirks,5Faranak Fattahi,6 Paul S. Frenette,7Livia Garzia,8David H. Gutmann,9Douglas Hanahan,10Shawn L. Hervey-Jumper,11 Hubert Hondermarck,12Jonathan B. Hurov,13Adam Kepecs,2Sarah M. Knox,14Alison C. Lloyd,15Claire Magnon,16 Jami L. Saloman,17Rosalind A. Segal,18Erica K. Sloan,19Xin Sun,20Michael D. Taylor,21Kevin J. Tracey,22 Lloyd C. Trotman,2David A. Tuveson,2Timothy C. Wang,23Ruth A",202
-doc_1,"White,24and Frank Winkler25 1Departments of Neurology & Neurological Sciences, Pediatrics, Pathology, Neurosurgery, and Psychiatry & Behavioral Sciences, Stanford University, Stanford, CA 94305, USA 2Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA 3Department of Periodontics and Oral Medicine, School of Dentistry, Department of Pathology, School of Medicine, University of Michigan, Ann Arbor, MI 48109, USA 4Center for Cell and Gene Therapy, Department of Neurosurgery, Baylor College of Medicine, Houston, TX 77030, USA 5Division of Neurosurgery, Arthur and Sonia Labatt Brain Tumor Research Center, Departments of Surgery and Molecular Genetics, Hospital for Sick Children, Toronto, ON M5G1X8, Canada 6Department of Biochemistry and Biophysics",182
-doc_2,"Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94115, USA 7Departments of Medicine and Cell Biology, Ruth L",44
-doc_3,"and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY 10461, USA 8Cancer Research Program, Research Institute of the McGill University Health Center and Department of Surgery, McGill University, Montreal, QC, Canada 9Department of Neurology, Washington University School of Medicine, St",73
-doc_4,"Louis, MO 63110, USA 10Swiss Institute for Experimental Cancer Research, Swiss Federal Institute of Technology Lausanne, Ludwig Institute for Cancer Research, Swiss Cancer Center Leman, Lausanne, Switzerland 11Department of Neurosurgery, University of California, San Francisco, San Francisco, CA 94115, USA 12School of Biomedical Sciences and Pharmacy, Hunter Medical Research Institute, University of Newcastle, Callaghan, NSW 2308, Australia 13Cygnal Therapeutics, Cambridge, MA 02139, USA 14Program in Craniofacial Biology, Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA 94143, USA 15MRC Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, UK 16UMR1274 (Equipe Cancer et Microenvironnement-INSERM-CEA)",191
-doc_5,"Institut de Radiobiologie Cellulaire et Mole ´culaire, Institut de Biologie Franc ¸ ois Jacob, Direction de la Recherche Fondamentale, Paris, France 17Departments of Medicine and Neurobiology, University of Pittsburgh, Pittsburgh, PA 15260, USA 18Department of Neurobiology, Harvard Medical School and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA 19Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, VIC 3052, Australia 20Departments of Pediatrics and Biological Sciences, University of California at San Diego, La Jolla, CA 92093, USA 21Division of Neurosurgery, Arthur and Sonia Labatt Brain Tumor Research Center, Developmental and Stem Cell Biology Program, Departments of Surgery",171
-doc_6,"Laboratory Medicine & Pathology and Medical Biophysics, Hospital for Sick Children, Toronto, ON M5G1X8, Canada 22The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY 11030, USA 23Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA 24Division of Hematology and Oncology, Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA 25Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, DKTK & Clinical Cooperation Unit Neurooncology, German Cancer Research Center, Heidelberg, Germany *Correspondence: mmonje@stanford",159
-doc_7,"edu https://doi.org/10.1016/j.cell.2020.03.034 Mounting evidence indicates that the nervous system plays a central role in cancer pathogenesis. In turn, cancers and cancer therapies can alter nervous system form and function. This Commentary seeks to describe the burgeoning field of ‘‘cancer neuroscience’’ and encourage multidisciplinary collaboration for the study of cancer-nervous system interactions. A growing appreciation that nervous system activity regulates development, ho-meostasis, plasticity, and regeneration in diverse tissues has prompted investigations of similar roles for dictating cancerformation and progression",122
-doc_8,"Numerous examples have now come to light that revealmechanistic parallels in the way the nervous system regulates normal and neoplastic cellular function across a rangeof tissue types. As such, nervous systemcancer crosstalk—both systemically andwithin the local tumor microenvironment—is now emerging as a crucial regulator of cancer initiation and progression. Cell181, April 16, 2020 ª2020 Elsevier Inc. 219",89
-doc_9,"However, much remains to be learned. The finding that neurons constitute an important non-neoplastic cell type in a broad range of cancers galvanized arecent Banbury meeting on the NervousSystem and Cancer (December 10–13, 2019), engaging members of the neuroscience and cancer biology commu-nities. We have written this Commentary in an effort to elucidate emerging principles, identify pressing unansweredquestions, and define the scope of this burgeoning new field of ‘‘cancer neuroscience.’’ Nervous System Activity Controls Cancer Initiation and Progression The nervous system branches as exten-sively as the circulatory system, and this dense innervation of nearly all tissues—from bone marrow ( Katayama et al., 2006 ) to salivary glands ( Knox et al",169
-doc_10,", 2010 )—is essential to regulate normal tissue function. Analogous to its role in organogenesis, tissue homeosta-sis, plasticity, and regeneration, the nervous system can also control malignant tumor initiation, growth, and metastasis.While the molecular mechanisms by which neural cells influence cancer cellsvary by tissue type, one unifying principle is that the functional effect of the neuralcancer interaction can typically be predicted by the influence of nervous sys-tem elements on the normal cellularcounterpart of a given cancer. This principle is illustrated by the parallel influences of neuronal activity on normaland neoplastic glial cell proliferation. In the central nervous system (CNS), where glutamatergic neuronal activity promotesglial precursor cell proliferation ( Gibson et al",170
-doc_11,", 2014 ), the activity of glutamatergic neurons similarly drives the growth ofmalignant gliomas in experimental model systems ( Venkatesh et al., 2015, 2019 ). The underlying mechanisms involveboth paracrine signaling and direct elec-trochemical communication ( Figures 1 A and 1B). Neuronal-activity-dependent secretion of growth factors from neuronsand from activity-sensing glial cells promotes glioma progression ( Venkatesh et al., 2015 ). In addition, malignant cells can electrically integrate into neural circuitry through bona fide neuron-to-glioma synapses ( Venkataramani et al., 2019; Venkatesh et al., 2019 )",155
-doc_12,"Malignant glioma cells are themselves coupled by gap junctions, such that neuronalactivity-dependent currents propagate through an extensively interconnected neural-glioma network ( Venkataramani et al., 2019; Venkatesh et al., 2019 ). Post-synaptic electrical signaling pro-motes cancer progression through glioma cell membrane potential depolarization ( Venkatesh et al., 2019 ) and consequent voltage-sensitive mechanisms that remain to be elucidated. The cancer-promoting effect of excitatory neurotransmission extends to brain metastases as well",115
-doc_13,"Breast cancer cells that have metastasized to the brain upre-gulate neurotransmitter receptor expression and extend perisynaptic processes to receive neuronal-activity-dependentneurotransmitter signals that trigger areceptor-mediated signaling cascade, induce inward currents in the malignant cells, and drive growth of breast cancerbrain metastases ( Zeng et al., 2019 ). How other types of metastatic cancer may interact with CNS neurons remainsto be determined. Outside of the CNS, peripheral-nervederived neurotransmitter and growthfactor signaling similarly regulate the pro-gression of diverse cancers, including pancreatic, gastric, colon, prostate, Figure 1. Interactions between the Nervous System and Cancer (A) Synaptic communication between neurons and brain cancer cells (e.g",154
-doc_14,", malignant glioma, red) can regulate cancer growth through neurotransmitt er and voltage-regulated mechanisms. Whether synaptic interactions occur between peripheral nervous system (PNS) axons and cancer cells outside of the C NS remains to be explored. (B) Paracrine signaling between nerve cells (gray) and cancer cells (red), fo r example, neuronal-activity-dependent release of neurotransmitter s or growth factors, regulates cancer growth in a wide range of tissues. The influence of neurons on malignant cells may be direct or may be mediated through effects on other cell types (yellow) in the tumor microenvironment. Cancer-derived par acrine factors remodel the nervous system to promot e increased neural activity in the tumor microen vironment",152
-doc_15,"(C) Circulating factors from cancer (red) can influence nervous system (gray) functions, such as sleep, while the nervous system can influence cancer p rogression through circulating factors such as hormones and progenitor cells or through altered immune system (blue) function. (D) Cancer therapies frequently cause nervous system toxicities, from peripheral neuropathy to cognitive impairment. Molecular and cellular mech anisms of nervous system toxicities and the putative role that such disruption in nervous system function may play in cancer treatment efficacy require further study. 220 Cell181, April 16, 2020",132
-doc_16,"breast, oral, and skin cancers in experimental model systems ( Figure 1 B) (Magnon et al., 2013; Hayakawa et al., 2017; Renz et al., 2018 ). Signaling between sympathetic, parasympathetic, or sensory nerves in the tumor microenvironment and malignant cells may regulatecancer initiation, progression, or metas-tasis, often through neurotransmitterdependent signaling cascades. The function of a given nerve type must be un-derstood in a context-specific manner. For example, parasympathetic (i.e., cholinergic) nerves may exert oppositeeffects in different tumor tissue types, such as promoting growth in the cancer of one organ and inhibiting growth in thecancer of another. In this regard, cholin-ergic signaling inhibits the growth and progression of pancreatic adenocarcinoma ( Renz et al",190
-doc_17,", 2018 ) but strongly promotes adenocarcinoma of the stomach (Hayakawa et al., 2017 ), an organ in which parasympathetic innervation is dominant.It is not yet known whether peripheral nerve-cancer cell interactions exclusively reflect paracrine-signaling events orwhether nerve-to-cancer cell synapses, synapse-like structures, or electrical coupling exist outside of the CNS thatenable peripheral nerve to cancercommunication. Moreover, the roles of diverse peripheral glial cells in nerve-cancer interactions outside of the CNS arelargely unexplored. Nervous system-cancer crosstalk occurs both through direct nerve-cancer in-teractions and via nervous system regulation of other cell types within the tumor microenvironment (e.g., immune cells,endothelial cells)",167
-doc_18,"These neural-cancer in-teractions may occur between neurons or nerves in the local microenvironment (Figure 1 B) or through systemic signaling (Figure 1 C), such as through elevated circulating catecholamines (neurotransmitters). Neural regulation of angiogen-esis via endothelial cell metabolism ( Zahalka et al., 2017 ) or immune system function ( Borovikova et al., 2000 ) represent distinct mechanisms through which the nervous system may exert a systemic effect on the tumor environ-ment, and interdisciplinary effortsinvolving oncology, immunology, and neuroscience are needed to fully dissect these important neural-immune-cancerinteractions",137
-doc_19,"Cancers Influence Nervous System Function Nervous system-cancer crosstalk is bidirectional, and cancers may induce pro-found nervous system remodeling and dysfunction. Secreted signals from brain tumors (gliomas) influence the functionof invaded neural circuits by inducingaberrant synaptogenesis, increasing neuronal excitability, and causing seizures ( Yu et al., 2020 ). This pathological increase in neuronal activity promotes the activity-dependent signals that drive glioma growth ( Venkatesh et al., 2015, 2019; Venkataramani et al., 2019 ). Similarly, cancers outside of the CNS can act at a distance to disrupt normal brain func-tion (e.g., sleep) ( Figure 1 C) (Borniger et al., 2018 )",170
-doc_20,"In the peripheral nervous system (PNS), cancers induce axonal ingrowth (axonogenesis) into the tumormicroenvironment ( Figure 1 B) (Hayakawa et al., 2017 ), where nerve density strongly correlates with cancer aggressiveness inmany tumor types. Axonogenesis has been shown in several tumor types to be promoted by cancer cell secretion of neu-rotrophins (such as nerve growth factor), often through a feed-forward mechanism triggered by increased adrenergic orcholinergic signaling ( Hayakawa et al., 2017 ). Beyond axonogenesis, recent studies have described neurogenesis within the tumor microenvironment fromneural precursor cells detected only in the circulation of subjects with cancer (Mauffrey et al., 2019 )",155
-doc_21,"Cancers also exhibit a propensity to invade nerve fibers (‘‘perineural invasion’’), causing remodel-ing of these peripheral nerves and chronicpain syndromes. In both central and pe-ripheral cancers, this structural and functional remodeling of the nervous system amplifies neuron-cancer interactions andcontributes to cancer growth and to cancer-related symptoms. Influence of Cancer Therapies on the Nervous SystemElucidating the mechanisms by whichcancer therapy alters nervous system function ( Figure 1 D) is central to understanding the bidirectional interactionsbetween neural and malignant cells",127
-doc_22,"Traditional cancer therapies, such as radiation and chemotherapies, exertlong-lasting deleterious effects on nervous system function, evident as cancer-therapy-related cognitive impairment (colloquially known as ‘‘chemobrain’’ or ‘‘chemofog,’’ a syndrome characterized by impaired attention, memory, multi-tasking, and sometimes increased anxiety) and as peripheral neuropathies (sensory loss, motor weakness, or pain).Similar long-term nervous systemeffects of newer targeted therapies and cancer immunotherapies are incompletely understood and only now begin-ning to come to light. Cancer therapies differentially affect cognition, as well as the types of nerves predominantlyaffected in chemotherapy-associated peripheral neuropathy",143
-doc_23,"The underlying cellular and molecular etiologies of can-cer-therapy-induced neural toxicity arebecoming better understood, and therapeutic strategies aimed at neuroprotection or neural regeneration are now begin-ning to emerge ( Gibson et al., 2019; Pease-Raissi et al., 2017 ). However, to what extent chemotherapy-induced neu-ropathy modulates nerve-cancer interactions to limit malignant growth is not yet clear, and the potentially beneficial rolethat therapy-induced neurotoxicity may play in the anti-neoplastic efficacy of radiation and chemotherapy remains to beexplored",126
-doc_24,"A more complete elucidationof both the mechanisms and implications of cancer-therapy-induced neurotoxicity are needed in order to developoptimized therapeutic strategies aimed at both effectively treating cancer and minimizing the debilitating neurologicalside effects. Pressing Questions and a Call for Interdisciplinary Collaboration Much remains to be discovered with respect to the fundamental biology ofthe PNS and its role in normal tissue development, homeostasis, plasticity, and regeneration. The resulting knowl-edge from developmental and regenerative biology will be synergistic to understanding these interactions in cancer",107
-doc_25,"Analogous to circuit-mapping efforts ofthe CNS over the past decade, similar mapping of the cranial, peripheral, and enteric nervous systems is warranted, astheir complex anatomy remains poorly characterized. Moreover, single-cell analyses, coupled with the development ofnew tools for lineage analysis and pluripotent stem cell modeling, will be required to Cell181, April 16, 2020 221",82
-doc_26,"define and associate the myriad nerve types with specific cancer phenotypes. We are only beginning to uncover how the nervous system contributes to theinitiation, growth, spread, recurrence, and therapeutic resistance of cancers. The powerful tools of modern neurosci-ence, from electrophysiology to optoge-netics, should be leveraged toward an understanding of cancer pathophysiology. Tissue- and tumor-type-specific differ-ences underscore the need for careful investigation of each type of cancer over the course of its progression to elucidatethe ways in which malignancy and cancer-induced nervous system remodeling co-evolve",131
-doc_27,"A more complete understanding will require true interdisciplinary study and collaboration between the disciplines of neuroscience, developmental biology,immunology, and cancer biology. Attention should be given not only to direct neuron-cancer cell interactions, but alsoto the influence of the nervous system on other cells of the local stromal, immune, and systemic tumor environment",72
-doc_28,"At this intersection of fields, exciting opportunities exist for cancer biologists to complement the great strides made incancer genomics, immuno-oncology,and precision therapeutics with a new dimension in the armamentarium and for neuroscientists to take full advantage ofsophisticated modern neuroscience approaches for the benefit of millions of individuals suffering from cancer and the ef-fects of its current therapies. While much remains to be learned about neural regulation of tumor growth, early-phase clin-ical trials are already underway, targetingneural mechanisms that modulate tumor growth in specific tumor types. Precise targeting of neural-cancer interactionswill ultimately provide new opportunities for improving outcomes of many difficult-to-treat malignancies",154
-doc_29,"ACKNOWLEDGMENTS The authors would like to thank the National Cancer Institute (NCI) and Dr. Chamelli Jhappan forearly appreciation of nervous system-cancer interactions and organization of the foundational‘‘Nerves in Cancer’’ meeting in 2015. We appre-ciate the insightful input from Barbara Marte, Cha-melli Jhappan, Pearl Huang, Grazia Piizzi, ShanLou, Daniel Blom, and Alexandra Lantermannthroughout the meeting. We also thank RebeccaLeshan at Banbury Center and Pearl Huang at Cyg-nal Therapeutics for their support in organizing the2019 Banbury meeting. DECLARATION OF INTERESTS M.M., P.S.F., T.C.W, H.H., E.K.S. and D.A.T. are on the SAB for Cygnal Therapeutics. J.B.H. is anemployee of Cygnal Therapeutics. F.W. is co-founder of Divide & Conquer (DC Europa Ltd). REFERENCES Borniger, J.C",213
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