Maintenance of epithelial traits and resistance to mesenchymal reprogramming promote proliferation in metastatic breast cancer

Abstract

Despite important advances in the treatment of breast cancer, the 5-year survival rate for patients with distant metastasis remains less than 30%. Metastasis is a complex, multi-step process beginning with local invasion and ending with the outgrowth of systemically disseminated cells into actively proliferating metastases that ultimately cause the destruction of vital organs. It is this last step that limits patient survival and, at the same time, remains the least understood mechanistically. Here, we focus on understanding determinants of metastatic outgrowth using metastatic effusion biopsies from stage IV breast cancer patients. By modelling metastatic outgrowth through xenograft transplantation, we show that tumour initiation potential of patient-derived metastatic breast cancer cells across breast cancer subtypes is strongly linked to high levels of EPCAM expression. Breast cancer cells with high EPCAM levels are highly plastic and, upon induction of epithelial-mesenchymal transition (EMT), readily adopt mesenchymal traits while maintaining epithelial identity. In contrast, low EPCAM levels are caused by the irreversible reprogramming to a mesenchymal state with concomitant suppression of metastatic outgrowth. The ability of breast cancer cells to retain epithelial traits is tied to a global epigenetic program that limits the actions of EMT-transcription factor ZEB1, a suppressor of epithelial genes. Our results provide direct evidence that maintenance of epithelial identity is required for metastatic outgrowth while concomitant expression of mesenchymal markers enables plasticity. In contrast, loss of epithelial traits is characteristic of an irreversible mesenchymal reprogramming associated to a deficiency for metastatic outgrowth. Collectively, our data provide a framework for the intricate intercalation of mesenchymal and epithelial traits in metastatic growth.