Clinical Evolution of Epithelial-Mesenchymal Transition in Human Carcinomas. Cancer research Navas, T., Kinders, R. J., Lawrence, S. M., Ferry-Galow, K. V., Borgel, S., Hollingshead, M. G., Srivastava, A. K., Alcoser, S. Y., Makhlouf, H. R., Chuaqui, R., Wilsker, D. F., Konaté, M. M., Miller, S. B., Voth, A. R., Chen, L., Vilimas, T., Subramanian, J., Rubinstein, L., Kummar, S., Chen, A. P., Bottaro, D. P., Doroshow, J. H., Parchment, R. E. 2019

Abstract

The significance of the phenotypic plasticity afforded by epithelial-mesenchymal transition (EMT) for cancer progression and drug resistance remains to be fully elucidated in the clinic. We evaluated epithelial-mesenchymal phenotypic characteristics across a range of tumor histologies using a validated, high resolution digital microscopic immunofluorescence assay (IFA) that incorporates ß-catenin detection and cellular morphology to delineate carcinoma cells from stromal fibroblasts and that quantitates the individual and co-localized expression of the epithelial marker E-cadherin (E) and the mesenchymal marker vimentin (V) at subcellular resolution ("EMT IFA"). We report the discovery of ß-catenin+ cancer cells that co-express E-cadherin and vimentin in core needle biopsies from patients with various advanced metastatic carcinomas wherein these cells are transitioning between strongly epithelial and strongly mesenchymal-like phenotypes. Treatment of carcinoma models with anticancer drugs that differ in their mechanism of action (the tyrosine kinase inhibitor pazopanib in MKN45 gastric carcinoma xenografts, and the combination of tubulin-targeting agent paclitaxel with the BCR-ABL inhibitor nilotinib in MDA-MB-468 breast cancer xenografts) caused changes in the tumor epithelial-mesenchymal character. Moreover, the appearance of partial-EMT or mesenchymal-like carcinoma cells in MDA-MB-468 tumors treated with the paclitaxel-nilotinib combination resulted in upregulation of cancer stem cell (CSC) markers and susceptibility to FAK inhibitor. A metastatic prostate cancer patient treated with the PARP inhibitor talazoparib exhibited similar CSC marker upregulation. Therefore, the phenotypic plasticity conferred on carcinoma cells by EMT allows for rapid adaptation to cytotoxic or molecularly-targeted therapy and could create a form of acquired drug resistance that is transient in nature.

View details for DOI 10.1158/0008-5472.CAN-18-3539

View details for PubMedID 31732654