Interplay between tumor microenvironment and partial EMT as the driver of tumor progression

Epithelial-to-mesenchymal transition (EMT), an evolutionary conserved phenomenon, has been extensively studied to address the unresolved variable treatment response across therapeutic regimes in cancer subtypes. EMT has long been envisaged to regulate tumor invasion, migration, and therapeutic resistance during tumorigenesis. However, recently it has been highlighted that EMT involves an intermediate partial EMT (pEMT) phenotype, defined by incomplete loss of epithelial markers and incomplete gain of mesenchymal markers. It has been further emphasized that pEMT transition involves a spectrum of intermediate hybrid states on either side of pEMT spectrum. Emerging evidence underlines bi-directional crosstalk between tumor cells and surrounding microenvironment in acquisition of pEMT phenotype. Although much work is still ongoing to gain mechanistic insights into regulation of pEMT phenotype, it is evident that pEMT plays a critical role in tumor aggressiveness, invasion, migration, and metastasis along with therapeutic resistance. In this review, we focus on important role of tumor-intrinsic factors and tumor microenvironment in driving pEMT and emphasize that engineered controlled microenvironments are instrumental to provide mechanistic insights into pEMT biology. We also discuss the significance of pEMT in regulating hallmarks of tumor progression i.e. cell cycle regulation, collective migration, and therapeutic resistance. Although constantly evolving, current progress and momentum in the pEMT field holds promise to unravel new therapeutic targets to halt tumor progression at early stages as well as tackle the complex therapeutic resistance observed across many cancer types.