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Abstract The epithelial to mesenchymal transition (EMT) is a dynamic process underlying metastasis. Here we show that TCF1, a TCF7 gene product, promotes a hybrid epithelial/mesenchymal (E/M) phenotype in basal breast cancer cells that was enriched in stemness and metastasis as compared to cells residing in the M-like state. E/M cells (CD104highCD44high) were enriched in canonical Wnt signaling, thereby upregulating FOXC2 which was turn able of converting M into E/M cells. Consistent with the E/M state, FOXC2 upregulated TA and ΔNp63 isoforms which control epithelial differentiation and Wnt signaling via β4 integrin/CD104 and Frizzled 7 upregulation respectively. Importantly, Wnt3a was able of stimulating ERK phosphorylation in E/M cells leading to FOXC2 and p63 upregulation thereby preventing E/M to M differentiation. These findings were further corroborated by ATAC-sequencing pointing predominantly to FOXC2 as a master regulator of the E/M state that was suppressed by ERK inhibition. Together, these results demonstrate that TCF7 stimulates Wnt3a/ERK activation which in turn activates the FOXC2/p63 axis, thereby promoting the hybrid EMT state underlying stemness and metastasis. Citation Format: Huizhi Liang, Outhiriaradjou Benard, Zuen Ren, Kimita Suyama, Jingli Wang, Anthony Griffen, Hao Wang, Lindsay LeFave, Larry Norton, Rachel B. Hazan. An intricate connection between canonical Wnt and MAPK/ERK signaling drives the partial hybrid EMT state involving FOXC2/p63 activation leading to cancer stemness and metastasis abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (7Suppl): Abstract nr LB208.
Liang et al. (Fri,) studied this question.