Abstract LB179: <i>TCF7</i> deletion accelerates intestinal adenoma development by unleashing the proliferation of slow-cycling tumor stem cells

Abstract Somatic loss of function of APC tumor suppressor gene and aberrant activation of WNT signaling are key initiation events in colorectal cancers (CRCs). TCF/LEF transcription factors are mediators of the Wnt signaling pathway. Although their collective role in CRC is well established, the contribution of individual TCF/LEF factors and their isoforms to CRC tumorigenesis is not completely understood. Here, we discovered that in the ApcMin/+ mouse model of CRC development, 90% of Tcf7+ cells were slow-cycling tumor stem/progenitor cells, which also co-expressed the tumor stem/progenitor cell marker Prox1. Furthermore, TCF7+ cells in CRC patient samples also express CRC stem cell markers. The Tcf7/Lef1 double-positive tumor stem/progenitor cells from Apc mutant mice expressed lower levels of Myc targets, cell cycle regulator E2F, and overall G2M signaling than double-negative cells. Both constitutive deletion of the long isoforms of Tcf7 and conditional inactivation of Tcf7 in Lgr5+ or Prox1+ tumor stem/progenitor cells in Apcfl/fl or ApcMin/+ mice increased Myc expression and cell proliferation, leading to a robust increase in intestinal tumorigenesis. Deletion of either Tcf7 or Lef1 in Apcfl/fl mice increased the expression of inhibitors of differentiation 1-3 (Id1-3) and Fosl1, a downstream target of both Tcf7 and Id1, that is mitotic machinery controller and driver of CRC metastasis, and decreased the proportion of tumor enterocytes. These findings revealed that Tcf7 and Lef1 act to restrain the proliferation of slow-cycling tumor stem/progenitor cells. Our findings could lead to the discovery of additional therapeutic vulnerabilities during CRC development. Citation Format: Marika Jenna Lassila, Cinzia Bessone, Fatemeh Seyednasrollah, Johanna Aspholm, Tatiana V. Petrova, Tuomas Kaprio, Caj Haglund, Pauliina Kallio, Kari Alitalo. TCF7 deletion accelerates intestinal adenoma development by unleashing the proliferation of slow-cycling tumor stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB179.