Small molecule-induced simultaneous destabilization of \u03b2-catenin and RAS is an effective molecular strategy to suppress stemness of colorectal cancer cells

Yong-Hee Cho,Kang-Yell Choi,Ho-Young Lee,Eun Ji Ro,Dong Woo Kang,Dong-Kyu Kwak,Jaebeom Cho,Jeong-Su Yoon

doi:10.1186/s12964-020-0519-z

Abstract

BackgroundCancer stem cells (CSCs), the major driver of tumorigenesis, is a sub-population of tumor cells responsible for poor clinical outcomes. However, molecular mechanism to identify targets for controlling CSCs is poorly understood.MethodsGene Set Enrichment Analyses (GSEA) of Wnt/β-catenin and RAS signaling pathways in stem-like subtype of colorectal cancer (CRC) patients were performed using two gene expression data set. The therapeutic effects of destabilization of β-catenin and RAS were tested by treatment of small molecule KYA1797K using CRC patient derived cells.ResultsTreatment with KYA1797K, a small molecule that destabilizes both β-catenin and RAS via Axin binding, effectively suppresses the stemness of CSCs as shown in CRC spheroids and small intestinal tumors of ApcMin/+/K-RasG12DLA2 mice. Moreover, KYA1797K also suppresses the stemness of cells in CRC patient avatar model systems, such as patient-derived tumor organoids (PDTOs) and patient-derived tumor xenograft (PDTX).ConclusionOur results suggest that destabilization of both β-catenin and RAS is a potential therapeutic strategy for controlling stemness of CRC cells.EL4qu77E_Vg6o-DHLyPXBuVideo abstract

Highlights

Cancer stem cells (CSCs), the major driver of tumorigenesis, is a sub-population of tumor cells responsible for poor clinical outcomes
Significance was denoted as n.s. not significant, *P < 0.05, **P < 0.01, and ***P < 0.001. Both Wnt/β-catenin and RAS signaling pathways are activated in Colorectal cancer (CRC) harboring CSC properties Due to the frequent mutations in the components of Wnt/β-catenin and RAS pathways in CRC and their critical roles in the synergistic activation of CSCs [15, 16, 24], we first investigated whether activation of these pathways are correlated with stem cell activities in the CRC patients
Since simultaneous activations of Wnt/β-catenin and RAS signaling pathways is associated with stabilizations of both β-catenin and RAS proteins by Adenomatous polyposis coli (APC) loss [18, 25], we examined the expression levels of β-catenin and RAS in the CSC-like populations which have higher spheroid forming sorted by fluorescent activating cell sorting (FACS) using CSC markers including CD44, CD133, and CD166 compared with those in the non-CSC populations

Summary

Introduction

Cancer stem cells (CSCs), the major driver of tumorigenesis, is a sub-population of tumor cells responsible for poor clinical outcomes. Kras mutation alone does not induce CSC activation or the tumor formation in murine small intestine, co-occurrence of mutations in both Apc and Kras enriches and activates CSCs via synergistic activation of the Wnt/β-catenin pathway [14,15,16]. Inhibition of both pathways has been suggested as an effective strategy for suppression of CSCs as a treatment for CRC [17, 18]

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Conclusion