Immune cell migration and differentiation, and therapy resistance in cancer

Molecular Oncology
Centro de Investigaciones Biológicas CSIC (CIB)

Melanoma displays alterations in the mitogen-activated protein kinase (MAPK) pathway, especially the BRAFV600E mutation, causing MAPK hyperactivation and contributing to tumor growth. Targeted therapy with combined BRAF and MEK inhibitors has improved the survival of melanoma patients, but resistance is frequent, leading to serious clinical threats. The concept of cancer resistance only based in genetic evolution has been challenged by several studies showing that non-genetic mechanisms of transcriptional reprogramming and adaptation were also responsible for cancer resistance. Non-genetic resistance is a reversible state of early therapeutic drug tolerance, that includes cancer cells with slow cycling and minimal growth, later developing in genetically-based resistance with strong tumor growth. Drug tolerance is represented by drug-tolerant persister (DTP) cells, defined as those that regenerate the tumor, but remain treatment-sensitive. This early DTP state opens a promising therapeutic window to inhibit the subsequent genetically-based resistance. The transcriptomic and functional characterization of DTP cells is important to identify novel targets, and for the design of improved therapies against melanoma. To provide a genetic, transcriptional and functional view of DTP cells and their progression to fully resistant cells, we have set up an immunocompetent in vivo mouse model of melanoma showing resistance to combined BRAF/MEK inhibitors, and encompassing cells in the DTP state and in progression to full resistance. Identification of DTP markers for therapeutic studies, and confirmation in human clinical samples from melanoma patients treated with BRAF/MEK inhibitors will validate our data and provide relevance for cancer research and treatment. The candidate will join research in the laboratory focusing on characterization of molecular mechanisms involved in development of drug-tolerant persistence and full resistance states in melanoma.

Molecular Biomedicine
Joaquin Teixidó Calvo