Objective The entire intestinal epithelium is renewed every week due to cell division in the crypts coupled with cell migration towards the villi and loss of cells by apoptosis at the tip of villi. Uncoupling cell proliferation from apoptosis and possibly from cell migration can lead to pathologies such as cancer. In carcinoma in situ, the basement membrane (BM) represents a physical barrier that prevents spreading of the primary tumor to adjacent tissues. It is believed that cancer cells perforate BM, but stromal cells such as carcinoma-associated fibroblasts (CAFs) also secrete matrix proteinases. Thus, the question is who is invading whom – do cancer cells invade the stroma or is the stroma invading tumor cells?Here we propose an innovative multi-disciplinary approach, at the interface of cancer cell biology and physics, combined with recent advances in optics aimed to unravel the fundamental mechanisms of cell migration in 3D environments during intestinal homeostasis and tumor invasion. Our specific aims are:1. Determine the mechanism of epithelial cell migration in gut homeostasis. Using intestinal slice cultures and two-photon microscopy we will determine if epithelial cells migrate using cellular protrusions, are pushed by dividing cells, or are transported by underlying fibroblasts and BM.2. Examine if cancer cells and CAFs cooperate to break the BM. We will use a 3D in vitro model to determine which cell type is degrading BM and if distinct sub-populations of CAFs have different functions.3. Explore how cancer cells and CAFs cooperate during invasion of the stroma. 3D chemoattraction assays will be used to determine if CAFs can guide cancer cells towards blood vessels.4. Characterize cooperation of cancer cells and CAFs in vivo. Using intravital imaging we will analyze interactions between cancer cells and CAFs in the primary tumor. Ortotopic mouse models will be used to determine if a specific sub-population of CAFs can trigger metastasis of colon cancer. Fields of science natural sciencesbiological sciencescell biologynatural sciencesphysical sciencesopticsmicroscopymedical and health sciencesclinical medicineoncologycolorectal cancermedical and health sciencesbasic medicinepathologymedical and health sciencesbasic medicinephysiologyhomeostasis Programme(s) FP7-IDEAS-ERC - Specific programme: "Ideas" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Topic(s) ERC-SG-LS4 - ERC Starting Grant - Physiology, Pathophysiology and Endocrinology Call for proposal ERC-2012-StG_20111109 See other projects for this call Funding Scheme ERC-SG - ERC Starting Grant Host institution INSTITUT CURIE EU contribution € 1 499 600,00 Address RUE D ULM 26 75231 Paris France See on map Region Ile-de-France Ile-de-France Paris Activity type Research Organisations Administrative Contact Sylvie Le Coidic (Ms.) Principal investigator Danijela Matic Vignjevic (Dr.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data Beneficiaries (1) Sort alphabetically Sort by EU Contribution Expand all Collapse all INSTITUT CURIE France EU contribution € 1 499 600,00 Address RUE D ULM 26 75231 Paris See on map Region Ile-de-France Ile-de-France Paris Activity type Research Organisations Administrative Contact Sylvie Le Coidic (Ms.) Principal investigator Danijela Matic Vignjevic (Dr.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data