Epithelial Wnt secretion drives the progression of inflammation-induced colon carcinoma in murine model

Bahar Degirmenci,Cansu Dincer,Habibe Cansu Demirel,Linda Berkova,Andreas E Moor,Abdullah Kahraman,George Hausmann,Michel Aguet,Nurcan Tuncbag,Tomas Valenta,Konrad Basler

doi:10.1016/j.isci.2021.103369

Abstract

SummaryColon cancer is initiated by stem cells that escape the strict control. This process is often driven through aberrant activation of Wnt signaling by mutations in components acting downstream of the receptor complex that unfetter tumor cells from the need for Wnts. Here we describe a class of colon cancer that does not depend on mutated core components of the Wnt pathway. Genetically blocking Wnt secretion from epithelial cells of such tumors results in apoptosis, reduced expression of colon cancer markers, followed by enhanced tumor differentiation. In contrast to the normal colonic epithelium, such tumor cells autosecrete Wnts to maintain their uncontrolled proliferative behavior. In humans, we determined certain cases of colon cancers in which the Wnt pathway is hyperactive, but not through mutations in its core components. Our findings illuminate the path in therapy to find further subtypes of Wnt-dependent colon cancer that might be responsive to Wnt secretion inhibitors.

Highlights

The human colon epithelium harbors stem cells that are responsible for its homeostasis
This process is often driven through aberrant activation of Wnt signaling by mutations in components acting downstream of the receptor complex that unfetter tumor cells from the need for Wnts
We describe a class of colon cancer that does not depend on mutated core components of the Wnt pathway

Summary

Introduction

The human colon epithelium harbors stem cells that are responsible for its homeostasis. Various studies in colorectal cancer (CRC) have demonstrated that mutations in the Wnt/b-catenin signaling pathway are the key driving force for the initiation and progression of CRC. A new class of CRCs responding to Porcn inhibitors was characterized; the response was confined to cases with mutated RSPO3 and RNF43/ZNRF3 genes (Koo et al, 2015; Madan et al, 2016). These findings serve as precedence and rationale to identify further subtypes of Wnt-dependent CRCs that might be responsive to such inhibitors

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