STARNEL · supracellular contractility of myofibroblasts in gut homeostasis and cancer invasion

There has been tremendous progress in understanding the importance of the microenvironment and its chemical signals for homeostasis of stem cell niche in the intestine and for tumor invasion and metastasis formation in many different tissues. However, the way stromal cells such as myofibroblasts or cancer-associated fibroblasts (CAFs) use mechanical forces to shape the extracellular matrix and consequently dictate the response of epithelial cells remains unexplored at the single-cell level mainly due to limited imaging tools. Here we propose a multi-disciplinary approach, at the interface of cancer cell biology and physics, aimed to understand how myofibroblasts contractility influences epithelial cell functions in physiological (homeostasis) and pathological (cancer) conditions using the gut as a model.Specific aims:1. Characterize myofibroblasts in gut mucosa. Using omics analysis, mouse models and optogenetic tools we will obtain molecular signatures of myofibroblasts, characterize their migration, proliferation and contractile capacities.2. Determine the role of myofibroblasts contractility in gut epithelial homeostasis. Using gut-on-chip and intravital imaging we will determine if supracellular contractility of myofibroblasts is necessary to maintain crypt shape upon mechanical stimuli.3. Determine the role of CAF alignment in cancer progression. We will use 3D in vitro models to explore if CAFs alignment prevents or stimulates cancer cell invasion. Using mesentery metastasis mouse model, we will test if CAFs alignment can generate collagen bundles that cancer cells use to metastasize.4. Explore if CAF alignment can induce therapy resistance and tumor relapse. Using human samples of rectal cancer before and after chemo-radiotherapy we will determine if CAFs alignment can protect cancer cells from therapy and stimulate metastasis formation.