Abstract 3090: Targeting WNT and retinoid signaling pathways to promote differentiation of cancer stem cells along the neuroendocrine lineage in CRC

Abstract

Abstract Since APC mutations lead to overpopulation of ALDH+ stem cells (SCs) in colorectal cancers (CRCs) and that ALDH is a key component of the retinoic acid (RA) signaling pathway, the hypothesis was developed that human CRC evolves due to an imbalance between WNT and RA signaling. Indeed, we previously discovered that progressive overpopulation of ALDH+ SCs occurs in normal, mutant, adenomatous, and malignant colon crypt tissues, which coincided with the change in the APC mutation zygosity state in familial adenomatous polyposis (FAP) patients. Therefore, the SC overpopulation that drives development of CRC appears to result from dysregulated WNT signaling, of which APC is a negative regulator. Normal colonic SC differentiation is feedback regulated by neuroendocrine cells (NECs) that reside adjacent to SCs in the bottom of the colon crypt. Our goal was to determine if APC mutation and subsequent dysregulated WNT signaling contributes to the inability of SCs to differentiate into NECs, leading to overpopulation of cancer SCs (CSCs) during tumor development. Although RA signaling is altered in CRC, we still found that all- trans-retinoic acid (ATRA) could reduce the number of ALDH+ CSCs in several CRC cell lines. We also found that administering ATRA promotes differentiation of CSCs along the neuroendocrine lineage. Moreover, induction of wild-type (wt)-APC expression in HT29 CRC cells led to increased expression of several NEC markers including CGA, GLP2R, NSE, SSTR1; and decreased WNT/β-catenin signaling when tested via TCF reporter assay. Inducing wt-APC also led to reduced β-catenin and change in protein expression of several proteins known to be targeted by WNT signaling including c-MYC, c-JUN, MET, and CD44. Our preliminary results also show that inducing wt-APC expression increases the number of GLPR2+ NECs. Thus, a link between WNT and RA signaling provides a possible mechanism that might explain how mutant APC leads to decreased maturation of ALDH+ SCs along the NEC lineage and an increased the number of ALDH+ SCs. Therefore, discovering ways to increase differentiation of SCs along the NEC lineage in vivo might lead to new more effective treatment strategies for CRC patients. Citation Format: Caroline O. Facey, Victoria O. Hunsu, Brian T. Osmond, Lynn M. Opdenaker, Bruce M. Boman. Targeting WNT and retinoid signaling pathways to promote differentiation of cancer stem cells along the neuroendocrine lineage in CRC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3090.