Role of TGFβ-induced EMT in tumor stemness and treatment-resistance

Epithelial-mesenchymal transition (EMT) generates cell fates important for cancer metastasis. Transforming growth factor β (TGFβ) is secreted by cancer cells and stimulates EMT.

TGFβ-EMT cooperatively form cancer stem cells (CSCs), heterogenous tumor cells, metastatic and treatment-resistant cells. Such cells are rare and difficult to detect in tumors.

A fundamental problem in cancer biology is the elucidation of molecular mechanisms that explain which, among many alternative phenotypes generate CSCs and treatment-resistant cells. Our hypothesis claims that cell division is important for the above. We aim at demonstrating how TGFβ and EMT generate chemoresistance by stimulating CSC development.

We will characterize cell division mechanisms and associated genes that mediate pro-stemness actions of TGFβ in breast cancer cells, by using 3D oncosphere cultures and single cell technology. We will develop diagnostic analysis of human tumor tissue and will screen for drugs that target cell division.

During 5-years we aim at delivering: a) transcriptional and epigenetic mechanisms of EMT phenotypes and CSCs; b) mechanisms of cell division regulation in EMT, CSCs; c) EMT, CSC and TGFβ signaling co-identification in tumor tissue; d) evidence on whether chemical inhibitors can block CSC chemoresistance.

The project operates within modern cancer research and has potential for application to diagnostic oncology and preclinical drug development.