Dans les tumeurs, les cellules cancéreuses invasives induisent l’expression de la métalloprotéase matricielle 11 (MMP-11) dans les adipocytes adjacents (cancer-associated adipocytes) entrainant leur « dédifférenciation » en fibroblastes, la MMP-11 régulant négativement l’adipogénèse. Au cours de ma thèse, j’ai étudié la fonction de la MMP-11 sur le développement mammaire postnatal. La structure de la glande ainsi que la production de lait sont altérées dans les souris déficientes pour la MMP-11. De plus, la MMP-11 régule l’homéostase du collagène. In vivo, des transplantations montrent une fonction locale paracrine de la MMP-11 essentielle à la morphogenèse mammaire. In vitro, la MMP-11 adipocytaire favorise le branchement d’organoïdes primaires. Ainsi, la MMP-11 est un facteur paracrine majeur pour le développement de la glande mammaire. Enfin, pour poursuivre ces travaux, j’ai établi des souris transgéniques conditionnelles ciblant l’expression de la MMP-11 dans les adipocytes. / In tumors, invasive cancer cells induce matrix metalloproteinase 11 (MMP-11) expression in adjacent adipocytes (cancer-associated adipocytes), leading to their « dedifferentiation » into fibroblast-like cells. Indeed, MMP-11 is a negative regulator of adipogenesis. During my PhD, I have investigated MMP-11 function during postnatal mammary gland development. The ductal tree and alveolar structures, and milk production are reduced in MMP-11-deficient mice. Moreover, MMP-11 plays a role in collagen homeostasis. Transplantation experiments show that MMP-11 exerts an essential local paracrine function for ductal morphogenesis. Using primary mammary organoids, I show that adipocyte-related MMP-11 is a pro-branching factor in vitro. Thus, MMP-11 is a master paracrine factor during mammary gland development. Finally, to further investigate the adipocyte-related MMP-11 function, I have developed conditional transgenic mice targeting MMP-11 expression specifically into adipocytes.

Salivary duct carcinoma (SDC) is an uncommon neoplasm showing extensive local invasion and metastasis. Histologically it exhibits ductal differentiation without myoepithelial participation and resembles intraductal and invasive ductal carcinoma of the breast. This study investigates the incidence of intraductal disease within invasive SDC and characterizes the expression of CK19, COX-2, MMP-2, 9 and 11 in intraductal and invasive SDC. 21 conventional SDC, 8 SDC arising as carcinoma ex-pleomorphic adenoma (CaExPA), 2 pure low-grade intraductal SDC, 1 pure high-grade intraductal SDC and 1 intraductal SDC with de-differentiation were studied. The presence of intraductal tumor in SDC is relatively common (52.4%) but is not a prominent component. SDC tumor cells were strongly positive for CK19 and COX-2. MMP-2 and 9 expression showed no significant pattern. MMP-11 was expressed by fibroblasts surrounding invasive tumor and was significantly associated with lymph node positivity (p=0.02).

Salivary duct carcinoma (SDC) is an uncommon neoplasm showing extensive local invasion and metastasis. Histologically it exhibits ductal differentiation without myoepithelial participation and resembles intraductal and invasive ductal carcinoma of the breast. This study investigates the incidence of intraductal disease within invasive SDC and characterizes the expression of CK19, COX-2, MMP-2, 9 and 11 in intraductal and invasive SDC. 21 conventional SDC, 8 SDC arising as carcinoma ex-pleomorphic adenoma (CaExPA), 2 pure low-grade intraductal SDC, 1 pure high-grade intraductal SDC and 1 intraductal SDC with de-differentiation were studied. The presence of intraductal tumor in SDC is relatively common (52.4%) but is not a prominent component. SDC tumor cells were strongly positive for CK19 and COX-2. MMP-2 and 9 expression showed no significant pattern. MMP-11 was expressed by fibroblasts surrounding invasive tumor and was significantly associated with lymph node positivity (p=0.02).

Dans les tumeurs, les cellules cancéreuses invasives induisent l'expression de la métalloprotéase matricielle 11 (MMP-11) dans les adipocytes adjacents (cancer-associated adipocytes) entrainant leur " dédifférenciation " en fibroblastes, la MMP-11 régulant négativement l'adipogénèse. Au cours de ma thèse, j'ai étudié la fonction de la MMP-11 sur le développement mammaire postnatal. La structure de la glande ainsi que la production de lait sont altérées dans les souris déficientes pour la MMP-11. De plus, la MMP-11 régule l'homéostase du collagène. In vivo, des transplantations montrent une fonction locale paracrine de la MMP-11 essentielle à la morphogenèse mammaire. In vitro, la MMP-11 adipocytaire favorise le branchement d'organoïdes primaires. Ainsi, la MMP-11 est un facteur paracrine majeur pour le développement de la glande mammaire. Enfin, pour poursuivre ces travaux, j'ai établi des souris transgéniques conditionnelles ciblant l'expression de la MMP-11 dans les adipocytes.