Molecular and biological characterization of pro-metastatic adaptive-responses in primary tumors

A considerable effort has been devoted over the last decades to the search of genetic determinants of metastatic spread. However, the absence of major genetic differences between primary tumors and metastases, as well as the discovery that metastatic spreading can occur at early stages of tumor development, argue against the selection of metastasis-specific driver mutations. We hypothesize that the metastatic process is the result of the phenotypic and functional adaptation of cancer cells to the harsh tumor microenvironment, such as nutrient and oxygen shortage, and/or to therapeutic treatments. Adaptive responses in primary tumors result in the acquisition of migratory and invasive properties, coincidentally endowing tumor cells with stem cell-like properties and metastatic potential. With this research proposal, we aim at obtaining a spatially and kinetically resolved genomic description of adaptive responses and at dissecting cellular mechanisms of adaptation that are relevant for the metastatic phenotype. We will use in vitro (spheroids and organoids) and in vivo (Patient-Derived Xenografts, PDXs) tumor models of breast (BC), colorectal (CRC) and pancreatic (PDAC) carcinomas, and we will model adaptation of tumor cells to different environmental stresses (e.g. energy deprivation and chemotherapy). We will analyze the effects of environmental perturbations on transcriptional regulation (by spatial transcriptomics and epigenetic analyses), cell migration and dissemination, cancer-stem cell dormancy and cell plasticity. We expect to increase our understanding of the adaptive responses responsible for cancer cell dissemination in human tumors, defining their genetic and molecular bases and directly assessing in vivo the impact of their inactivation. The project is designed to unravel mechanism-based biomarkers which might enable novel targeted treatments to control cancer dissemination and/or enhance the efficacy of available anti-cancer treatments. A future clinical implementation of inhibitors targeting adaptation mechanisms is poised to contribute to the treatment of metastatic disease and, in prospect, to generate new strategies for prevention of metastatic spreading. Notably, even though the proposed program is focused on colorectal, pancreatic and breast carcinomas, its main findings might be likely translatable to the treatment of a broad range of epithelial and non-epithelial cancers.