Soutenance de thèse de GUO GUO

Résumé de la thèse

Breast cancer is a heterogeneous disease that can be classified into different molecular subtypes based on gene expression profiles, specifically hormone receptor status (estrogen and progesterone receptors) and HER2 expression (human epidermal growth factor receptor 2). Through the continuous refinement of the molecular subtypes of breast cancer, the understanding of the disease and the accuracy of its treatment have been improved. The main molecular subtypes of breast cancer include five types: luminal A breast cancer, luminal B breast cancer, HER2-enriched breast cancer, triple-negative/basal-like breast cancer, and normal-like breast cancer. Triple-negative breast cancer (TNBC) is known for its high aggressiveness and poor clinical prognosis, due to the lack of expression of estrogen receptors (ER), progesterone receptors (PR) and human epidermal growth factor receptor 2 (HER2), and there is still no effective treatment.
Tumor-associated macrophages (TAMs) are known to play an important role in the tumor environment. MATs can promote tumor cell proliferation, immunosuppression, and support tumor growth and metastasis. MATs are also usually associated with poor clinical outcomes. Colony-stimulating factor 1 (CSF1) and its receptor CSF1R regulate macrophage differentiation and survival, and numerous studies have shown that CSF1/CSF1R expression can predict progression and mortality in breast cancer patients. Targeting the CSF1-CSF1R axis to deplete or reprogram macrophages has shown promise in preclinical models, although clinical efficacy has been limited. Recent studies of spatial and single-cell transcriptomics, conducted in both human cancer models and preclinical models, have revealed the existence of multiple subsets of MATs with distinct gene expression profiles, metabolic programs, spatial localization, and functions, ranging from tumor restriction to high tumor proliferation. New evidence indicates that niches of specialized stromal cells within tumors promote macrophage survival and functional specialization. In TNBC, stromal localization of TAMs, rather than their total abundance, is strongly correlated with poor prognosis, indicating that the tumor stroma provides a selective niche for pro-tumor TAMs.
We have developed a new mouse model of TNBC based on orthotopic transplantation of organoids deficient in Brca1 and p53, two key oncogenic mutations in human TNBC. Our single-cell RNA sequencing experiments conducted on tumors derived from Brca1/p53 (B487) organoids revealed that CSF1 is selectively expressed by cancer-associated fibroblasts (CAFs) located in the tumor stroma. We hypothesized that CAF-derived CSF1 formed a selective niche for pro-tumora TAMsux. Therefore, my thesis aimed to systematically investigate the niches of MATs in this TNBC model and their role in tumor progression. My initial goal was to isolate myeloid cells and stromal cells from normal mammary glands and B487 tumors for single-cell RNA sequencing to characterize the heterogeneity of TAMs and stromal cells. Bioinformatics analyses were then used to predict molecular interactions in silico using CellChat. I then developed conditional genetic targeting strategies to disrupt the TAM niche and assess the impact on tumor progression.