Research projects

Melanoma is the most lethal form of skin cancer. Although RAS pathway activation is a central event in melanoma development and progression, the p38 pathway plays a relevant role in a number of processes related with melanoma development (UV irradiation), melanoma cells proliferation and signaling of cytokines involved in immune response regulation. Our results showed that spontaneous mouse tumors and human samples harbor genetic alterations in this pathway, including the upregulation of p38a. Importantly, p38a upregulation is associated to poor survival in an independent manner, reducing the survival of patients harboring BRAF^V600E and NRAS^Q61 mutations. We also show the functional status of the different components of the stress pathway, in several melanoma cell lines. Our results showed that p38a mediated the expression regulation of immuno-checkpoint molecules in response to interferon-g. To study the in vivo contributions of p38a to UV induced melanoma development and progression we generated the following inducible melanocyte specific mouse models: Tyr::Cre^ERT2;p38^F/F, Tyr::Cre^ERT2;BRAF^CA/CA, Tyr::Cre^ERT2;BRAF^CA/CA;p38^F/F.  The loss of p38a impaired the pro-apoptotic response to genotoxic damage mediated by UV radiation, resulting in an increased tumor multiplicity. Importantly, melanoma progression in Tyr::Cre^ERT2;BRAF^CA/CA;p38^F/F compared to Tyr::Cre^ERT2;BRAF^CA/CA mice was limited leading to smaller tumors. This data was in agreement with the previously dual role of p38a in tumor development and progression. Further studies of the antitumoral immune response showed that depletion of p38a regulates the expression of immune checkpoint molecules in tumor cells, and limits the antitumoral cytotoxic response modifying specific immune cell populations of tumor inflammatory infiltrates (CD8+ T effector and NK and NK-T cells) providing a rational for immunotherapy sensitization. This hypothesis has been investigated where anti-PD1 therapy was more effective in tumors lacking p38a expression. Interestingly, gene expression profiling of BRAF^CA/CA;p38^F/F tumors compare to BRAF^CA/CA correlated with an IFN-g signature (previously described in patients that responded to immunotherapy (anti PD1, anti-CTLA4). Importantly, we are currently applying for an academic clinical trial to test his strategy in melanoma patients