Microenvironment, Signaling and Cancer (MicroCAN)

Our data attribute a novel role to the mechanical and fibrotic environment in the adaptation and therapeutic resistance of melanoma cells and establish an original link between the physicochemical properties of the extracellular matrix and the biology of melanoma cells.

Therapeutic inhibition of the BRAF oncogenic pathway in vivo induces a reprogramming of the matrix that leads to a stiffening of collagen, promoting the formation of resistance sites and metastatic relapse. The objectives of this project are to improve our knowledge of the mechanical dialogue between tumor cells and the matrix network, and to better understand the processes involved in the phenotypic and metabolic plasticity within the resistance niches. In this project, we are studying the involvement of actors that we have identified (collagen receptor DDR1/2 and pro-fibrotic cluster miR-143/145) and, in parallel, we are conducting global transcriptomic, metabolomic and proteomic analyses in order to identify new regulatory pathways involved in responses to stiffness changes and their role in the biology of melanoma cells.

In melanoma, the mutational burden due to UV exposure and a high proliferation index increase the dependence on mechanisms controlling proteotoxic stress, such as the ubiquitin-proteasome system (UPS). Targeting the UPS therefore represents a promising strategy against advanced and metastatic melanoma. The opposite reaction to ubiquitin conjugation is deubiquitination by proteases called DeUBiquitinases (DUBs). A strategy based on pharmacological and genetic screens has allowed us to identify several DUBs as drivers of melanoma cell survival, proliferation and drug tolerance. The objective of this project is to better understand the role of the identified DUBs in the biomechanical and metabolic reprogramming of melanoma and the therapeutic response.