A 11h
Invitée par Frédéric Saltel - U1053 baRITOn
Triple negative breast cancer (TNBC) is an aggressive subtype, typically associated with early metastatic recurrence, and worse patient outcomes. A deeper understanding of the cellular and molecular mechanisms of metastasis formation is essential to develop new therapy against metastatic disease. TNBC patient tumors express molecular markers of the epithelial to mesenchymal transition (EMT). However, the role of EMT during spontaneous TNBC metastasis in vivo remains unknown and the clinical relevance of EMT in TNBC patients is unclear. Using a combination of 3D organoid ex vivo cultures, and primary tumor analyses we demonstrated that spontaneous TNBC tumors from a mouse model, multiple patient-derived xenografts, and archival patient samples exhibit large populations of hybrid E/M cells in vivo, that lead invasion ex vivo. We found that the mesenchymal marker vimentin promotes invasion and represses metastatic outgrowth. Using single-cell RNA sequencing we next identified the different EMT cell states. Then, we demonstrated that TNBC metastases are heterogenous and present a complex spectrum of epithelial, hybrid EMT, and mesenchymal cell states, suggesting that there are multiple successful strategies for distant organ colonization. To decipher these different strategies, we investigated the early stages of metastasis formation. We demonstrated that cancer cell clusters more efficiently seed distant organs. We next performed a screening using CRISPR Cas9 and identified P53 as a key molecular regulator of cluster vs single-cell seeding. After seeding at the metastatic site, we showed that cancer cell clusters metastasize by dissociating into single cells, proliferating and migrating throughout the lungs, before eventually fusing to form large multiclonal metastases. Taken together, our results demonstrate an important and complex role for EMT programs during TNBC metastasis, dissect the molecular mechanisms regulating hybrid EMT, and report a novel cellular strategy for breast cancer metastasis. We speculate that this novel strategy explains both the chemotherapy responsiveness and rapid metastatic recurrence that is observed in TNBC patients.