Analyse de l'implication des fibroblastes associés au cancer dans la vascularisation spécifique du carcinome rénal à cellules claires et la réponse aux traitements

Deciphering the involvement of the cancer-associated fibroblasts in the specific vascularization of the clear cell renal cell carcinoma and in the response to treatments

• Auteur / Autrice : Victoire Rousseau
• Direction : Catherine Monnot
• Type : Projet de thèse
• Discipline(s) : Biologie intégrée
• Date : Inscription en doctorat le 30/09/2024
• Etablissement(s) : Sorbonne université
• Ecole(s) doctorale(s) : Physiologie, physiopathologie et thérapeutique
• Partenaire(s) de recherche : Laboratoire : Centre de Recherche des Cordeliers
• Partenaire(s) de recherche : Equipe de recherche : Inflammation, Complement and Cancer

Mots clés

Mots clés libres

Microenvironnement tumoral

Angiogenèse

Analyse transcriptomique spatiale

Résistance aux traitement

Modèles in vitro tridimensionnels

Fibroblastes associés au cancer

Cancer-associated fibroblasts

Tumor microenvironment

Tridimensional in vitro models

Angiogenesis

Resistance to treatments

Spatial transcriptomic analysis

Résumé

Voir résumé anglais

The hypoxic microenvironment of solid tumors is composed of a remodeled extracellular matrix containing a dense and chaotic vascularization, cancer associated fibroblasts (CAF) and immune cells. Clear cell renal cell carcinoma (ccRCC), the most frequent renal carcinoma, is very aggressive and metastatic through hematogenous way. In more than 75% of ccRCC, mutation of the tumor suppressor protein Von Hippel-Lindau (VHL) leads to a pseudo-hypoxic context promoting tumor invasion, vascularization and extracellular matrix remodelling. Accordingly, ccRCC vasculature displays a higher degree of complexity than the vascular network reported in other solid tumors. Our team recently characterized the ccRCC vascularization composed of aberrant endothelial structures presenting specific features of dimensions and shapes, either perfused or collapsed. Although the first line treatments of ccRCC consist in anti-angiogenic treatments, either alone or combined with immunotherapy, approximatively 60% of the ccRCC patients display spontaneous or acquired resistance to these therapies. We suggest that the architectural complexity of the vasculature may be involved in the resistance mechanisms and the ccRCC clinical outcome. It is therefore of major interest to deeply characterize the formation process and the functions of the ccRCC vasculature depending on the specific tumor microenvironment. The present doctoral project aims to analyze the involvement of the CAF in the ccRCC progression, vascularization and response to treatments by deciphering their cross-talk with tumor cells and endothelial cells. The analyses will be performed by considering the spatial features of the tumor by using both in vivo and in vitro innovative approaches. The doctoral project will be based on the 1/ assessment of the CAF localization and proximity to the aberrant structures on ccRCC patient's cohorts using multiplex immunofluorescence and AI analysis softwares; 2/ Analysis of the role of CAF on ccRCC tumor invasiveness/angiogenesis capacities and on the formation and stabilization of the aberrant vascular structures, using in vitro tridimensional vascularized microtumors (VMT). Indeed, we previously developed VMT models recapitulating a ccRCC-specific aberrant endothelial structure. Paracrine and direct effects of CAF will be studied in these complex in vitro models, compatible with confocal microscopy and 3D imaging reconstruction; 3/ Analysis of the CAF involvement on the resistance mechanism to anti-angiogenic treatments both in in vitro VMT and ccRCC patient's cohorts. This study is part of a more general research axis aiming to understand the biological mechanisms of the ccRCC progression and responses to combined therapies involving anti-angiogenic and immune treatments.