MECHANOMETMOT: Understanding the crosstalk between mechano-sensing and metabolic reprogramming during tumour dissemination

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Metastasis is responsible for most cancer deaths. Abnormal cell migration and invasion underlie metastatic dissemination while interactions between cancer cells and the surrounding extracellular matrix (ECM) guide these processes. Migrating cancer cells sense and translate physical clues into intracellular signals, which trigger changes in gene expression. Such cues can also alter cellular metabolism. Nevertheless, how ECM signals are integrated by the cytoskeleton and translated into metabolic changes needed for cell migration is unclear. I hypothesize that external physical forces lead to metabolic adaptations for optimal 3Dimensional (3D) migration and successful metastasis. In this proposal, I will undertake a highly innovative and multidisciplinary approach, combining biochemistry, molecular and cellular biology, NMR/MS-based metabolomics and digital pathology. I will perform extensive NMR/MS- based metabolomics and lipidomics analyses of cancer cells to uncover metabolic pathways that are dysregulated in cancer cells growing and invading into 3D collagen matrices.This project has three aims:1. to uncover metabolic pathways key for aggressive cancer cells to find their vulnerabilities;2. to understand how these cells modify invasive traits and metabolism in response to physicochemical changes of the 3D matrices, which mimic ECM of human tissues and/or disease stages;3. to investigate altered expression of pro-invasive enzymes/transcriptional regulators of metabolism and mechano- transducers in the invasive fronts of tumours and in the metastatic lesions.The ultimate goal is to reveal specific metabolic pathways controlling cancer invasiveness, which may pave the way for novel treatments that target specifically metastatic cells.