Oncogenic KRAS activates an embryonic stem cell-like program in human colon cancer initiation

Anne-France Le Rolle,Philip B Paty,Zhaoshi Zeng,Jinru Shia,Thang K Chiu,Vi K Chiu,Martin R Weiser

doi:10.18632/oncotarget.6818

Abstract

Colorectal cancer is the third most frequently diagnosed cancer worldwide. Prevention of colorectal cancer initiation represents the most effective overall strategy to reduce its associated morbidity and mortality. Activating KRAS mutation (KRASmut) is the most prevalent oncogenic driver in colorectal cancer development, and KRASmut inhibition represents an unmet clinical need. We apply a systems-level approach to study the impact of KRASmut on stem cell signaling during human colon cancer initiation by performing gene set enrichment analysis on gene expression from human colon tissues. We find that KRASmut imposes the embryonic stem cell-like program during human colon cancer initiation from colon adenoma to stage I carcinoma. Expression of miR145, an embryonic SC program inhibitor, promotes cell lineage differentiation marker expression in KRASmut colon cancer cells and significantly suppresses their tumorigenicity. Our data support an in vivo plasticity model of human colon cancer initiation that merges the intrinsic stem cell properties of aberrant colon stem cells with the embryonic stem cell-like program induced by KRASmut to optimize malignant transformation. Inhibition of the embryonic SC-like program in KRASmut colon cancer cells reveals a novel therapeutic strategy to programmatically inhibit KRASmut tumors and prevent colon cancer.

Highlights

Colorectal cancer is the third most frequently diagnosed cancer worldwide and leads to death in onethird of afflicted adults
To identify biologically meaningful gene expression patterns associated with the transition from colon adenoma to stage I colon carcinoma, we performed gene set enrichment analysis (GSEA) on human colon tissues using 3995 signatures of chemical and genetic pathways
These findings suggest that the activation of the embryonic stem cells (SC)-like signature underlying the transition from colon adenoma to stage I colon carcinoma is correlated with KRAS mutation (KRASmut) expression and independent of tumor grade

Summary

Introduction

Colorectal cancer is the third most frequently diagnosed cancer worldwide and leads to death in onethird of afflicted adults. Colorectal carcinomas arise from adenomas, which are found in >25% of adults undergoing initial screening colonoscopies at age 50 [1]. While it is known that APC or CTNNB1 mutation activates aberrant WNT signaling to give rise to colon adenomas, the programs that promote their transformation to carcinomas are not well characterized. Additional driver mutations such as oncogenic KRAS occur in the context of enlarging colon adenomas to enhance colon cancer initiation [2]. The current model suggests that oncogenic KRAS promotes the malignant transformation of colon adenoma to carcinoma through further hyperactivation of WNT signaling [3, 4]

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