Abstract B084: Trop-2 plasticity is driven by epithelial-to-mesenchymal transition in prostate cancer cells
Authors: Ján Remšík, Lucia Binó, Zuzana Kahounová, Gvantsa Kharaishvili, Sarka Simeckova, Radek Fedr, Tereza Nehybova, Eva Slabáková, Lucia Knopfová, Jan Bouchal, Milan Kral, Petr Benes, Karel Soucek
Journal: Cancer Research (2018)

Abstract Dissemination of cancer cells to distant organs has fatal consequences to most of the patients with malignant tumors. Patients with prostate and breast cancer show apparent overlap of the most common sites of cancer metastasis, suggesting that breast and prostate tumor cells share common mechanisms of dissemination and colonization. During each step of prostate and breast cancer metastasis, malignant cells display phenotypic plasticity that is associated with the manifestation of epithelial and mesenchymal properties or an epithelial-to-mesenchymal transition (EMT). One of the molecules that most likely interlink processes of pathologic plasticity of cancer cells, their dissemination capability, and response to microenvironmental factors is Tumor-Associated Calcium Signal TransDucer 2 (Trop-2, TACSTD2). Trop-2 is a type-I transmembrane glycoprotein encoded by TACSTD2 gene often associated with tumorigenesis and cancer progression, but the data remain controversial. Trop-2 deregulation has been repeatedly proposed as an event associated with cancer progression and poor patient prognosis. Instead of this simplistic view, our results showed Trop-2 level change as a context-dependent, dynamic event associated with cancer plasticity and dissemination. Using antibody-based surface profiling of selected cancer stem-like cell markers in human and mouse prostate and breast cancer cell lines, we identified subpopulation of Trop-2+ cells within culture of metastatic prostate cell line DU-145 and similarly Trop-2+ subpopulation within mouse mammary cancer cell line 4T1. Gene expression analysis of sorted subpopulations showed significant correlation of Trop-2 with epithelial phenotype, and this finding was further validated in wide panel of human and murine cell lines and independent patient datasets. We further proved that expression of Trop-2 is regulated by EMT transcription factors and DNA methylation. Moreover, immunohistochemical analysis of Trop-2 in pairs of primary prostate tumors and lymph node metastasis showed strong association with E-cadherin and epithelial-mesenchymal plasticity in patient samples. In conclusion, we showed that Trop-2 expression associates with epithelial phenotype and can be suppressed either epigenetically or through the action of EMT master regulators. Acknowledgments: This work was supported by Ministry of Health of the Czech Republic, grant no. 15-33999A and 15-28628A, and by GAČR 15-11707S, HistoPARK (CZ.1.07/2.3.00/20.0185), and by project FNUSA-ICRC (no. CZ.1.05/1.1.00/02.0123) and ICRC-ERA-HumanBridge a.k.a. REGPOT (Grant agreement no. 316 345) from the European Regional Development Fund. Citation Format: Ján Remšík, Lucia Binó, Zuzana Kahounová, Gvantsa Kharaishvili, Sarka Simeckova, Radek Fedr, Tereza Nehybova, Eva Slabáková, Lucia Knopfová, Jan Bouchal, Milan Kral, Petr Benes, Karel Soucek. Trop-2 plasticity is driven by epithelial-to-mesenchymal transition in prostate cancer cells [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B084.