Etude des fibroblastes sous-épithéliaux dans l'adénocarcinome pulmonaire et de leur interaction avec les cellules tumorales

Despite advances in lung cancer research, non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related death. While cancer-associated fibroblasts (CAFs) are key stromal cells influencing tumor behavior, their functional diversity remains incompletely understood. During my PhD, I characterized a distinct subepithelial CAF population (SE-CAFs), previously identified by our team, spatially distributed as one layer beneath tumor cells in NSCLC. Using RNA-sequencing, spatial transcriptomics, and multiplex immunohistochemistry, I showed that SE-CAFs exhibit a conserved transcriptional signature, closely resembling subepithelial fibroblasts found in healthy tissues and shown in the literature to support epithelium development and differentiation. Analysis of a 78 non-small cell lung carcinoma cohort revealed that SE-CAF abundance strongly correlates with well-differentiated tumor histology and a less aggressive clinical profile. In contrast, their absence is associated with tumor proliferation, an immune-rich environment, mutations such as TP53, and solid tumor histology, the latter being linked to poor prognosis. Spatial transcriptomics further showed that SE-CAFrich tumor regions contain differentiated, low-proliferating tumor cells, which could point towards a SE-CAF role in maintaining epithelial integrity and differentiation. Extending these findings, we identified SE-CAFs’ counterparts in human bladder cancer, that share key molecular features, including expression of basement membrane components, Shh-responsive genes, and non-canonical WNT ligands. Overall, my results provide descriptive insights into SE-CAFs and could suggest an anti- tumoral role through promotion of cancer differentiation. My work paves the way for functional studies of SE-CAFs, as understanding their tumor-limiting potential could lead to novel therapeutic strategies to modulate tumor differentiation and improve patient outcomes in NSCLC and potentially other epithelial cancers.