Cell-autonomous BMP signalling plays a key role in the maintenance of tumour cell EMT and migration programs in human ovarian carcinoma

Abstract

Epithelial-mesenchymal transition (EMT) plays a key role in tumour initiation, metastasis and resistance to therapy. Cells undergoing EMT, assume multiple semi-stable transitional states along the epithelial-mesenchymal axis that necessitates tight regulatory cascades. Although more is known about pathways involved in the initial induction of EMT, cascades that mediate/maintain the transitional states and/or the final mesenchymal phenotype are yet to be elucidated. In this study, we have assessed the role of bone morphogenic protein (BMP) signalling pathway in the regulation of cancer cell EMT and migration. Mining existing data from ovarian carcinomas, we defined the BMP pathway among the key pathways enriched in tumours with elevated EMT signatures, with a significant correlation in the expression of EMT markers with BMP ligands and downstream targets of the BMP pathway. Functional inhibition of the BMP pathway in ovarian cancer cells by a small molecule inhibitor, DMH1, resulted in impaired migration and depressed EMT signatures in both in vitro and in vivo models. Finally, ectopic induction of EMT in ovarian cancer cells through activation of an independent pathway, TNF, resulted in the selective induction of Smad-mediated BMP pathway suggesting a role in maintenance of EMT, secondary to EMT induction.