Interplay between Desmoglein2 and hypoxia controls intravasation and circulating tumor cell clustering in breast cancer metastasis

Abstract

Abstract Interaction between tumor cells and their microenvironment plays a critical role in tumorigenesis and metastasis. Disseminated tumor cells in the blood (circulating tumor cells (CTCs)), particularly CTC clusters, are positively correlated with metastatic potential and poor prognosis. However, the key factors required for tumor cell dissemination and CTC clustering remain elusive. We found that Desmoglein2 (DSG2), a key cell adhesion molecule participated in desmosome mediated intercellular adhesion, and its regulation by hypoxia, a potent microenvironmental factor linked to cancer progression, were critical for breast tumorigenesis, CTC clustering and metastasis. Expression of DSG2 was positively correlated with poor prognosis and recurrence risk in breast cancer patients. High DSG2 expression promoted tumor growth, CTC clustering and distant organ colonization. Conversely, epithelial-to-mesenchymal transition (EMT), invasion and intravasation were able to occur when DSG2 was suppressed under hypoxia. In hypoxic cancer cells, HIF1α directly bound and recruited polycomb repressive complex 2 components to the DSG2 proximal promoter, thus allowing cells to detach from the primary tumor. Once hypoxic stress was released in the vascular system, DSG2 de-repression allowed CTCs to form clusters and colonize in distant organs. Together, our results demonstrated the role of DSG2 expression in breast tumor progression and cancer metastasis. These data also revealed a new molecular mechanism by which hypoxia drives metastasis. Significant Statement During metastasis, a hypoxic microenvironment is a major force driving primary tumor cells to disseminate into the circulatory system. The majority of these circulating tumor cells (CTCs) cannot survive when traveling alone. However, collective movement as CTC clusters enables them to avoid immune surveillance and increases the probability that they will successfully metastasize to distal organs. Dynamic down regulation of DSG2 in hypoxic tumor tissue and reactivation of expression in CTCs allowed high rates of tumor cell dissemination, CTC cluster formation and metastasis that are characteristics of the most aggressive breast cancers. The findings highlight both the potential, and potential pitfalls, of using DSG2 as a therapeutic target.