Epithelial-to-mesenchymal transition: lessons from development, insights into cancer and the potential of EMT-subtype based therapeutic intervention.

Epithelial-to-mesenchymal transition (EMT) is a fundamental developmental process wherein polarized epithelial cells lose their junctional architecture and apical-basal polarity to become motile mesenchymal cells, and there is emerging evidence for its role in propagating tumor dissemination. While many multifaceted nodules converge onto the EMT program, in this review we will highlight the fundamental biology of the signaling schemas that enable EMT. In many cancers, the property of tumor dissemination and metastasis is closely associated with re-enabling developmental properties such as EMT. We discuss the molecular complexity of the tumor heterogeneity in terms of EMT-based gene expression molecular subtypes, and the rewiring of critical signaling nodules in the subtypes displaying higher degrees of EMT can be therapeutically exploited. Specifically in the context of a deadly malignancy such as ovarian cancer where there are no defined mutations or limited biomarkers for developing targeted therapy or personalized medicine, we highlight the importance of identifying EMT-based subtypes that will improve therapeutic intervention. In ovarian cancer, the poor prognosis mesenchymal 'Mes' subtype presents with amplified signaling of the receptor tyrosine kinase (RTK) AXL, extensive crosstalk with other RTKs such as cMET, EGFR and HER2, and sustained temporal activation of extracellular-signal regulated kinase (ERK) leading to induction of EMT transcription factor Slug, underscoring a pathway addiction in Mes that can be therapeutically targeted. We will further examine the emergence of therapeutic modalities in these EMT subtypes and finally conclude with potential interdisciplinary biophysical methodologies to provide additional insights in deciphering the mechanistic and biochemical aspects of EMT. This review intends to provide an overview of the cellular and molecular changes accompanying epithelial-to-mesenchymal transition (EMT) in development and the requisition of this evolutionarily conserved pathway in cancer progression and metastatic disease. Specifically, in a heterogeneous disease such as ovarian cancer lacking defined targetable mutations, the identification of EMT-based subtypes has opened avenues to tailor precision personalized medicine. In particular, using the oncogenic RTK AXL as an example, we will highlight how this classification enables EMT-subtype specific identification of targets that could improve treatment options for patients and how there is a growing need for biophysical approaches to model dynamic processes such as EMT.