ROS Production and NF-κB Activation Triggered by RAC1 Facilitate WNT-Driven Intestinal Stem Cell Proliferation and Colorectal Cancer Initiation

Summary

The Adenomatous Polyposis Coli ( APC) gene is mutated in the majority of colorectal cancers (CRCs). Loss of APC leads to constitutively active WNT signaling, hyperproliferation, and tumorigenesis. Identification of pathways that facilitate tumorigenesis after APC loss is important for therapeutic development. Here, we show that RAC1 is a critical mediator of tumorigenesis after APC loss. We find that RAC1 is required for expansion of the LGR5 intestinal stem cell (ISC) signature, progenitor hyperproliferation, and transformation. Mechanistically, RAC1-driven ROS and NF-κB signaling mediate these processes. Together, these data highlight that ROS production and NF-κB activation triggered by RAC1 are critical events in CRC initiation.

Graphical Abstract

Highlights

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  RAC1 is required for tumorigenesis after APC loss

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  LGR5 ISC transformation requires RAC1

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  RAC1-driven ROS production and NF-κB activation are required for CRC initiation

Abstract

This study demonstrates that RAC1-mediated ROS production and NF-KB activation is required for LGR5 stem cell expansion and colorectal cancer initiation after loss of the APC gene.