Analysis of the ccRCC vasculature by engineering 3D invasive micro-tumors ; Étude de la vascularisation aberrante du ccRCC par le développement de micro-tumeurs 3D invasives

Clear cell renal cell carcinoma (ccRCC) is mainly caused by the alteration of Von Hippel-Lindau (VHL) gene expression, leading to a pseudo-hypoxic context involving a hypervascularization, tumor cell invasion and extracellular matrix remodeling. Some publications report a complex and aberrant vascular architecture. The anti-angiogenic treatments constitute a main part of the ccRCC clinical care although resistances are frequently observed. The lack of 3D pre-clinical models reproducing the ccRCC specific vascularization limit the understanding of this cancer. In this context, I studied: - the aberrant vascularization of ccRCC in interaction with invasive tumor cells, - the role of mechanical properties of tumor microenvironment on invasive strategies of tumor cells and on the formation of the aberrant vasculature. I characterized the architectural specificity of the aberrant vasculature, surrounding the ccRCC tumor mass, in close contact with a dense collagen I matrix, in a in vivo model and further developed vascularized 3D microtumors mimicking this aberrant vasculature. This model highlights the resistance of the aberrant vasculature to anti-angiogenic treatments. Moreover, I revealed a functional reciprocal relationship between endothelial and tumor invasive cells. The latter remodeled a favorable niche for the aberrant vasculature formation whereas in return, endothelial cells contribute to the tumor cell malignancy by stimulating their invasive capacities. ; Le carcinome du rein à cellules claires (ccRCC) est associé à une altération du gène Von Hippel-Lindau (VHL), responsable d’un état de pseudo-hypoxie, conduisant à une hypervascularisation, l’invasion des cellules tumorales et au remodelage matriciel. Quelques travaux rapportent une architecture vasculaire complexe et aberrante. Les traitements anti-angiogéniques constituent un pilier de la prise en charge du ccRCC, bien que de nombreuses résistances aux traitements soient décrites. L’absence de modèles in vitro 3D pertinents reconstituant la ...