Section: Application Domains

Oncology

In cancer, the most dreadful event is the formation of metastases that disseminate tumor cells throughout the organism. Cutaneous melanoma is a cancer, where the primary tumor can easily be removed by surgery. However, this cancer is of poor prognosis; because melanomas metastasize often and rapidly. Many melanomas arise from excessive exposure to mutagenic UV from the sun or sunbeds. As a consequence, the mutational burden of melanomas is generally high

RAC1 encodes a small GTPase that induces cell cycle progression and migration of melanoblasts during embryonic development. Patients with the recurrent P29S mutation of RAC1 have 3-fold increased odds at having regional lymph nodes invaded at the time of diagnosis. RAC1 is unlikely to be a good therapeutic target, since a potential inhibitor that would block its catalytic activity, would also lock it into the active GTP-bound state. This project thus investigates the possibility of targeting the signaling pathway downstream of RAC1.

Xpop is mainly involved in Task 1 of the project: Identifying deregulations and mutations of the ARP2/3 pathway in melanoma patients.

Association of over-expression or down-regulation of each marker with poor prognosis in terms of invasion of regional lymph nodes, metastases and survival, will be examined using classical univariate and multivariate analysis. We will then develop specific statistical models for survival analysis in order to associate prognosis factors to each composition of complexes. Indeed, one has to implement the further constraint that each subunit has to be contributed by one of several paralogous subunits. An original method previously developed by Xpop has already been successfully applied to WAVE complex data in breast cancer.

The developed models will be rendered user-friendly though a dedicated Rsoftware package.

This project can represent a significant step forward in precision medicine of the cutaneous melanoma.