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.
October 3rd, 2019
PlexinD1 and Sema3E determine laminar positioning of heterotopically projecting callosal neurons.
September 28th, 2018
Keeping up with advances in axon guidance
June 4th, 2018
Developmental Upregulation of Ephrin-B1 Silences Sema3C/Neuropilin-1 Signaling during Post-crossing Navigation of Corpus Callosum Axons.
February 22nd, 2017
Post-endocytic sorting of Plexin-D1 controls signal transduction and development of axonal and vascular circuits
January 15th, 2017
Neuropilin-dependent and -independent signaling of the guidance molecule Sema3E
October 28th, 2016
Characterizing Semaphorin Signaling Using Isolated Neurons in Culture
June 3rd, 2015
Microtubule-associated protein 6 mediates neuronal connectivity through Semaphorin 3E-dependent signalling for axonal growth
May 18th, 2015
Dysfunctional SEMA3E signaling underlies gonadotropin-releasing hormone neuron deficiency in Kallmann syndrome
June 27th, 2014
Sema3E/PlexinD1 regulates the migration of hem-derived Cajal-Retzius cells in developing cerebral cortex
November 11th, 2013
Semaphorin 3E Suppresses Tumor Cell Death Triggered by the Plexin D1 Dependence Receptor in Metastatic Breast Cancers.
October 16th, 2013
The Declaration of Independence of the Neurovascular Intimacy
May 1st, 2013
Navigation rules for vessels and neurons: cooperative signaling between VEGF and neural guidance cues.
February 1st, 2013
Pathfinding of corticothalamic axons relies on a rendezvous with thalamic projections.
January 1st, 2012
Integration of repulsive guidance cues generates avascular zones that shape mammalian blood vessels.
December 1st, 2011
Semaphorin 3C is not required for the establishment and target specificity of the GABAergic septohippocampal pathway in vitro.
May 1st, 2011
Sema3E-PlexinD1 signaling selectively suppresses disoriented angiogenesis in ischemic retinopathy in mice.
April 1st, 2010
VEGFR2 (KDR/Flk1) signaling mediates axon growth in response to semaphorin 3E in the developing brain.
October 1st, 2009
Transient neuronal populations are required to guide callosal axons: a role for semaphorin 3C.
December 1st, 2008
PlexinD1 glycoprotein controls migration of positively selected thymocytes into the medulla.
December 1st, 2007
Gating of Sema3E/PlexinD1 signaling by neuropilin-1 switches axonal repulsion to attraction during brain development.
July 1st, 2007
Mechanisms of axon guidance: membrane dynamics and axonal transport in semaphorin signalling.
June 1st, 2007
Semaphorins in development and adult brain: Implication for neurological diseases.
April 1st, 2005
A semaphorin code defines subpopulations of spinal motor neurons during mouse development.
January 1st, 2005
Semaphorin 3E and plexin-D1 control vascular pattern independently of neuropilins.
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