Added value of the extracellular matrix in solid tumors: how to target the matrisome for therapy – TheraMatrix

The study of solid tumor development and metastatic progression has mainly focused on biochemical signals regulating downstream signaling pathways. The power of the extracellular compartment, and especially the non-cellular fraction, has only recently been appreciated as a potential supply for pro- or anti-tumoral regulation depending on the context. It is now admitted that mechanical cues from the extracellular matrix (ECM), and overall tissue stiffness, can directly affect tumor cell behavior, such as epithelial-to-mesenchymal transition (EMT), invasion and metastasis via various mechanotransduction pathways.
This project first studies a well-known axon guidance protein and Laminin-family member, Netrin-1, for its potential new role as an ECM regulator. Our preliminary data shows that indeed Netrin-1 binds to ECM proteins and modifies the physical properties of the ECM. We will investigate for the first time the role of Netrin-1, independently of its receptor, in the regulation of ECM properties and thus its potential effects on cellular behavior in terms of EMT, invasion and metastasis. Development of the anti-Netrin-1 monoclonal antibody-based therapy, currently in phase II clinical trial, led our lab to develop radionuclide-labelled anti-Netrin-1 antibody for molecular imaging, as well as for vectorized radiotherapy. This proposal aims at identifying novel potential target for such technologies within the matrisome proteins of various solid tumors. To do so, we’ll perform mass spectrometry analyses of decellularized, ECM-enriched tumors samples and corresponding healthy tissues to determine promising targets in order to develop a theragnostic approach, combining molecular imaging as well as internal vectorized targeted radioelements as a therapeutic approach.
This original project will lead to the identification of new actionable targets in the tumor microenvironment and promote the development of novel imaging and therapeutic strategies.