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

FOR BEGINNERS

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?

FOR SPECIALISTS

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.

• 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