Understanding non-genetic processes remodelling the tumor ecosystem, cancer cell death and immune escape mechanisms

Efficient tumor clearance by anticancer therapies requires effective therapy-mediated debulking along with the engagement of the immune system. The induction of regulated cancer cell death (RCD) able to reinstate, rather than suppressing, anticancer immune responses -so called immunogenic cell death - is therefore a highly desirable therapeutic effect. However, the recognition and clearance of residual cancer cells by the immune system, requires the inactivation of various immunoresistance mechanisms. Among these processes, the capability of cancer cells to reversibly change cellular phenotypes and states to adapt to their local and distal environment, is emerging as a major therapeutic barrier. Metabolic plasticity, tumor-driven inflammation and resistance to therapy, are chiefly supported by autophagy, which is commonly heightened in tumors, both in the cancer cells and in the tumor vasculature. The overarching goal of our research is to unveil how key cell-fate decision networks (i.e. regulated cell death pathways, metabolic and quality control mechanisms) in cancer cells and the tumor vasculature impact the tumor microenvironment (TME), then immuno-vascular dialogue and (immuno)therapy responses. Our experimental approach combines hypothesis-driven studies with global scale methodologies, integrating information derived from dynamic and multi-layered studies at molecular, (inter)organellar, single cell, tissue (spatial omics) and organism/ cancer patient levels. We generate and use state-of the art transgenic mouse models to integrate and explore mechanistic data into preclinical models and validate these findings in clinical samples. With these approaches we strive to establish new connections, cross boundaries and disciplines and look at the complexity of cancer from different angles. We believe that answering fundamental questions of cancer cell biology is central to introduce new therapeutic opportunities against cancer.