Abstract 961: TCF7 promotes a mammary cancer-stem-like phenotype leading to metastasis via potentiation of a hybrid epithelial/mesenchymal (E/M) phenotype

Abstract

Abstract Cancer stem cells (CSCs) are a minor population of carcinoma cells that can self-renew and give rise to differentiated progenitors that form the bulk of the tumor. CSCs cause tumor recurrence, chemoresistance and metastasis. The epithelial-to-mesenchymal transition (EMT) promotes tumor cell migration, invasion and cancer stem cell properties. The Wnt signaling pathway is a major driver of cancer stemness and is regulated by the TCF/LEF family of transcription factors. Using loss and gain of function of TCF7 (TCF1) in mouse and human breast cancer cells, we were able to demonstrate that TCF7 promotes cancer stemness through striking regulation of the EMT process. TCF7 knockdown in PyMT mammary tumor cells induced luminal epithelial differentiation, resulting in inhibition of oncosphere formation, migration, tumor growth and lung colonization. However, in keeping with a changing view of EMT as a strictly binary process, we found that TCF7 shifts tumor cells towards a hybrid epithelial/mesenchymal state (E/M) rather than a mesenchymal (M) state. This E/M population was shown to carry stemness and metastatic properties and to be interestingly represented by a small “stem-like” subpopulation in triple negative breast cancer (TNBC) cells. Using CD44 and CD104 (integrin β4) flow cytometry to isolate E/M cells from normal MCF10A and basal-like MDA-MB-468 breast cancer cells, we show that TCF7, Snail, and GSK3β phosphorylation were all highly enriched in this population whereas Zeb-1 (a marker of mesenchymal cells), was absent from E/M cells. These data support a model whereby TCF7 potentiates Wnt signaling which in turn activates GSK3β phosphorylation, resulting in Snail upregulation and enrichment of cells in the E/M state that is conducive of stemness and metastasis. Citation Format: Huizhi Liang, Outhiriaradjou Benard, Zuen Ren, Kimita Suyama, Larry Norton, Rachel B. Hazan. TCF7 promotes a mammary cancer-stem-like phenotype leading to metastasis via potentiation of a hybrid epithelial/mesenchymal (E/M) phenotype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 961.