Axon plasticity in development and cancer

Group leader : F. Mann

Our team is studying the development of neural networks and their ability to reorganize in organs affected by cancer.


The functioning of the nervous system is based on extremely sophisticated neural networks that are formed during fetal life and childhood. During development, neurons emit long cables, called axons, to reach their target cells and make synaptic contacts. This process is controlled by specialized cells (or groups of cells) that express guidance signals and direct axons along specific trajectories. The nerve projections thus established are maintained throughout adult life. Far from being static, they retain a certain degree of plasticity that allows them to change according to our experiences or in response to diseases such as cancer. Indeed, malignant tumors are able to stimulate the regrowth of mature axons and thus promote their own innervation.

The importance of this phenomenon on the evolution of the disease is only beginning to be understood: the nervous system has a protective or, on the contrary, accelerating effect on tumor development, which depends both on the type of cancer and the biochemical properties of the infiltrated axons.


These results raise fundamental questions that we seek to answer:

  • How do neuronal networks remodel in an organ with cancer?
  • How do axon guidance molecules control the development of neural networks and their plasticity in cancer?
  • How do neurons interact with cells in the tumor microenvironment and contribute to disease progression?



3D imaging of neural network remodeling

We are studying neuronal plasticity in mouse models of pancreatic ductal adenocarcinoma (PDAC). We use 3D light sheet fluorescence microscopy to visualize in whole pancreas the architecture of neural networks and their interactions with adjacent cells and structures (blood vessels, glial cells, macrophages). We discovered that axons of the sympathetic nervous system remodel very early in the development of PDAC, emitting numerous collaterals that innervate pre-cancerous lesions and the periphery of invasive tumors.



Role of axonal guidance molecules

Our previous work has highlighted the multiple roles played by guidance molecules of the Semaphorin family in the development of axonal projections (Chauvet et al., 2007; Bellon et al., 2010; Burk et al., 2017; Mire et al., 2018). The overexpression of these signals in many cancers suggests that they could contribute to tumor progression. We have already shown that Semaphorin 3E confers to cancer cells a resistance to apoptosis (Luchino et al., 2013). We are now testing the hypothesis of a role of guidance signals in the structural plasticity of adult networks and the innervation of PDAC.

Functional crosstalk between nerves and cancer 

Nerves have recently emerged as new regulators of cancer progression. While in many cases, nerves stimulate tumor growth and spread, we have shown that the sympathetic nervous system has an opposite protective function against PDAC. Indeed, the selective ablation of the sympathetic innervation of the pancreas accelerates tumor progression via the reprogramming of tumor-associated macrophages. A pre-print of these results is available here.

Selected publications


Cancer induces a stress ileopathy depending on B-adrenergic receptors and promoting dysbiosis that contribute to carcinogenesis

Yonekura S, Terrisse S, Alves Costa Silva C, Lafarge A, Iebba V, Ferrere G, Goubet AG, Fahrner JE, Lahmar I, Ueda K, Mansouri G, Pizzato E, Ly P, Mazzenga M, Thelemaque C, Fidelle M, Jaulin F, Cartry J, Deloger M, Aglave M, Droin N, Opolon P, Puget A, Mann F, Neunlist M, Bessard A, Aymeric L, Matysiak-Budnik T, Bosq J, Hofman P, Duong CPM, Ugolini S, Quiniou V, Berrard S, Ryffel B, Kepp O, Kroemer G, Routy B, Lordello L, Bani MA, Segata N, Yousef Yengej F, Clevers H, Scoazec JY, Pasolli E, Derosa L, Zitvogel L. 34930787


PlexinD1 and Sema3E determine laminar positioning of heterotopically projecting callosal neurons.

Velona T, Altounian M, Roque M, Hocine M, Bellon A, Briz CG, Salin P, Nieto M, Chauvet S, Mann F.
Mol Cell Neurosci. 2019 Oct;100:103397. doi: 10.1016/j.mcn.2019.103397. PMID: 31454665


Keeping up with advances in axon guidance

Anaïs Bellon, Fanny Mann
Curr Opin Neurobiol . 2018 Dec;53:183-191. doi: 10.1016/j.conb.2018.09.004. PMID: 30273799


Developmental Upregulation of Ephrin-B1 Silences Sema3C/Neuropilin-1 Signaling during Post-crossing Navigation of Corpus Callosum Axons.

Mire E, Hocine M, Bazellières E, Jungas T, Davy A, Chauvet S, Mann F.
Curr Biol. 2018 Jun 4;28(11):1768-1782.e4. doi: 10.1016/j.cub.2018.04.026. PMID: 29779877


Post-endocytic sorting of Plexin-D1 controls signal transduction and development of axonal and vascular circuits

Burk K, Mire E, Bellon A, Hocine M, Guillot J, Moraes F, Yoshida Y, Simons M, Chauvet S, Mann F.
Nat Commun. 2017 Feb 22;8:14508. doi: 10.1038/ncomms14508. PMID: 28224988


Neuropilin-dependent and -independent signaling of the guidance molecule Sema3E

Mann F, Chauvet S.
Neufeld G, Kessler O (Eds.) The Neuropilins: Role and Function in Health and Disease. 2017. Springer International Publishing. p.75-89


Characterizing Semaphorin Signaling Using Isolated Neurons in Culture

Chauvet S, Mire E, Mann F.
Methods Mol Biol. 2017;1493:223-235. PMID: 27787854


Microtubule-associated protein 6 mediates neuronal connectivity through Semaphorin 3E-dependent signalling for axonal growth

Deloulme JC, Gory-Fauré S, Mauconduit F, Chauvet S, Jonckheere J, Boulan B, Mire E, Xue J, Jany M, Maucler C, Deparis AA, Montigon O, Daoust A, Barbier EL, Bosc C, Deglon N, Brocard J, Denarier E, Le Brun I, Pernet-Gallay K, Vilgrain I, Robinson PJ, Lahrech H, Mann F, Andrieux A.
Nat Commun. 2015 Jun 3;6:7246. doi: 10.1038/ncomms8246. PMID: 26037503


Dysfunctional SEMA3E signaling underlies gonadotropin-releasing hormone neuron deficiency in Kallmann syndrome

Cariboni A, André V, Chauvet S, Cassatella D, Davidson K, Caramello A, Fantin A, Bouloux P, Mann F, Ruhrberg C.
J Clin Invest. 2015 Jun;125(6):2413-28. doi: 10.1172/JCI78448. PMID: 25985275


Sema3E/PlexinD1 regulates the migration of hem-derived Cajal-Retzius cells in developing cerebral cortex

Bribián A, Nocentini S, Llorens F, Gil V, Mire E, Reginensi D, Yoshida Y, Mann F, del Río JA2.
Nat Commun. 2014 Jun 27;5:4265. doi: 10.1038/ncomms5265. PMID: 24969029


Semaphorin 3E Suppresses Tumor Cell Death Triggered by the Plexin D1 Dependence Receptor in Metastatic Breast Cancers.

Luchino J, Hocine M, Amoureux MC, Gibert B, Bernet A, Royet A, Treilleux I, Lécine P, Borg JP, Mehlen P, Chauvet S, Mann F.
Cancer Cell. 2013 Nov 11;24(5):673-85. PMID: 24139859


The Declaration of Independence of the Neurovascular Intimacy

Chauvet S, Mann F.
Neuron. 2013 Oct 16;80(2):262-5. PMID: 24139030


Navigation rules for vessels and neurons: cooperative signaling between VEGF and neural guidance cues.

Chauvet S, Burk K, Mann F.
Cell Mol Life Sci. 2013 May;70(10):1685-703. PMID: 23475066


Pathfinding of corticothalamic axons relies on a rendezvous with thalamic projections.

Deck M, Lokmane L, Chauvet S, Mailhes C, Keita M, Niquille M, Yoshida M, Yoshida Y, Lebrand C,Mann F, Grove EA, Garel S.
Neuron. 2013 Feb 6;77(3):472-84. PMID: 23395374


Integration of repulsive guidance cues generates avascular zones that shape mammalian blood vessels.

Meadows SM, Fletcher PJ, Moran C, Xu K, Neufeld G, Chauvet S, Mann F, Krieg PA, Cleaver O.
Circ Res. 2012 Jan 6;110(1):34-46. PMID: 22076636


Semaphorin 3C is not required for the establishment and target specificity of the GABAergic septohippocampal pathway in vitro.

Rubio SE, Martínez A, Chauvet S, Mann F, Soriano E, Pascual M.
Eur J Neurosci. 2011 Dec;34(12):1923-33. PMID: 22092651


Sema3E-PlexinD1 signaling selectively suppresses disoriented angiogenesis in ischemic retinopathy in mice.

Fukushima Y, Okada M, Kataoka H, Hirashima M, Yoshida Y, Mann F, Gomi F, Nishida K, Nishikawa S, Uemura A.
J Clin Invest. 2011 May;121(5):1974-85. PMID: 21505259


VEGFR2 (KDR/Flk1) signaling mediates axon growth in response to semaphorin 3E in the developing brain.

Bellon A, Luchino J, Haigh K, Rougon G, Haigh J, Chauvet S, Mann F.
Neuron. 2010 Apr 29;66(2):205-19. PMID: 20434998


Transient neuronal populations are required to guide callosal axons: a role for semaphorin 3C.

Niquille M*, Garel S*, Mann F*, Hornung JP, Otsmane B, Chevalley S, Parras C, Guillemot F, Gaspar P, Yanagawa Y, Lebrand C. * equal contribution
PLoS Biol. 2009 Oct;7(10):e1000230. PMID: 19859539


PlexinD1 glycoprotein controls migration of positively selected thymocytes into the medulla.

Choi YI, Duke-Cohan JS, Ahmed WB, Handley MA, Mann F, Epstein JA, Clayton LK, Reinherz EL.
Immunity. 2008 Dec 19;29(6):888-98. PMID: 19027330


Gating of Sema3E/PlexinD1 signaling by neuropilin-1 switches axonal repulsion to attraction during brain development.

Chauvet S, Cohen S, Yoshida Y, Fekrane L, Livet J, Gayet O, Segu L, Buhot MC, Jessell TM, Henderson CE, Mann F.
Neuron. 2007 Dec 6;56(5):807-22. PMID: 18054858


Mechanisms of axon guidance: membrane dynamics and axonal transport in semaphorin signalling.

Mann F, Rougon G.
J Neurochem. 2007 Jul;102(2):316-23. PMID: 17442048


Semaphorins in development and adult brain: Implication for neurological diseases.

Mann F, Chauvet S, Rougon G.
Prog Neurobiol. 2007 Jun;82(2):57-79. PMID: 17537564


A semaphorin code defines subpopulations of spinal motor neurons during mouse development.

Cohen S, Funkelstein L, Livet J, Rougon G, Henderson CE, Castellani V, Mann F.
Eur J Neurosci. 2005 Apr;21(7):1767-76. PMID: 15869472


Semaphorin 3E and plexin-D1 control vascular pattern independently of neuropilins.

Gu C, Yoshida Y, Livet J, Reimert DV, Mann F, Merte J, Henderson CE, Jessell TM, Kolodkin AL, Ginty DD.
Science. 2005 Jan 14;307(5707):265-8. PMID: 15550623
  • Patent
    NETRIS PHARMA, CNRS, AMU. Antagonists of Sema3E/PlexinD1 interaction as anti-cancer agents. ROYET Amélie, MANN Fanny, CHAUVET Sophie, LUCHINO Jonathan. EPO Patent. EP2385121 (A1). 2010-05-06


  • Richard Tomasini, CRCM
  • Serge van de Pavert, CIML
  • Florence Hubert, I2M
  • Jean-Yves Scoazec, IGR
  • Anaïs Bellon, INMED
  • Gregor Kasprian, Medical University of Vienna

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    karen Sleiman Sophie Chauvet   Mélanie Hocine-ducros Angélique Puget  
Fanny Mann
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Fanny Mann


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Juliette Latulippe


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jeremy Perdrizet

Master - M1

karen Sleiman
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karen Sleiman

PhD student

Sophie Chauvet
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Sophie Chauvet


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Hiba Haidar

PhD student

Mélanie Hocine-ducros
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Mélanie Hocine-ducros

Technical staff

Angélique Puget
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Angélique Puget

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Martha montserrat Rangel Sosa

PhD student


  • Anaïs Bellon, Tenured researcher, Institute of Mediterranean Neurobiology (INMED), Marseille, France
  • Marion Benezech-Lapeyre, Technician, Innate Pharma, Marseille, France
  • Katja Burk, Group leader, Department of Neurology, University Medical Center Göttingen, Germany
  • Chloé Dominici, Postdoc, Institute for Research on Cancer and Aging (IRCAN), Nice, France
  • Jeremy Guillot, Postdoc, Federal Polytechnic School of Lausanne (EPFL), Switzerland
  • Adrien Lucchesi, Biotechnology instructor, France
  • Jonathan Luchino, Healthcare professional, France
  • Laura Miranda, Technician, Innate Pharma Marseille, France
  • Erik Mire, Group leader, Neuroscience & Mental Health Research Institute, Cardiff University, United Kingdom
  • Thi-Trang Huyen Nguyen, Lecturer, University of Science and Technology of Hanoi (USTH),Vietnam
  • Theodora Velona, Postdoc, University of Crete, Greece


Model organism
Biological process studied
  • Axon guidance
  • Neuroplasticity in cancer
Technical approaches
  • Neural tracing
  • Whole organ immunostaining and clearing
  • Light sheet fluorescence microscopy
  • Transcriptomics
  • Cell and tissue culture
Medical applications
  • Cancer