# Regulation of Colon Cancer by AIM2

> **NIH NIH K22** · UNIVERSITY OF ARIZONA · 2020 · $159,549

## Abstract

DESCRIPTION (provided by the applicant) Colorectal cancer is second leading cause of cancer-related deaths
among men and women in the United States, with metastasis to secondary organs (e.g., liver) playing a major
role in patient mortality. Patients with metastatic, or stage IV, colon cancer display a 5 year survival rate of only
11%. Recent clinical and gene profiling studies indicate that a loss of Absent in Melanoma 2 (AIM2) expression
in colon tumors is highly correlated with stage IV colon cancer and reduced patient survival. AIM2 is a cytosolic
innate immune sensor that forms a multi-protein complex termed the inflammasome following binding of
double-stranded DNA. I have recently reported that AIM2 suppresses colon cancer development independently
of its inflammasome function by limiting the uncontrolled replication of colonic epithelial cells by acting as a
checkpoint of Akt-mediated survival. Mechanistically, AIM2 suppresses Akt activity by targeting the PI3K family
member DNA-dependent protein kinase (DNA-PK). Although DNA-PK activation and expression is reportedly
elevated in colon tumors, and DNA-PK promotes Akt activation, cell survival and metastatic gene profiles, the
function of DNA-PK during colon cancer pathogenesis is largely understudied. In addition, AIM2 has been
suggested to limit tumorigenesis by regulating the composition of the intestinal microbiota, yet there is no direct
evidence for this, and it is unknown if microbiota-derived DNA facilitates AIM2's tumor suppressor function or
what AIM2-related factors are responsible for limiting tumorigenesis. In this proposal, I will test the
hypothesis that AIM2 restricts cancer initiation and metastasis by limiting Akt and DNA-PK activation
in response to the microbiota using the following specific aims: 1) Determine the functional requirement of
DNA binding to AIM2 during the suppression of cancer-relevant pathways in vitro; 2) Assess the ability of AIM2
to limit DNA-PK-mediated colon cancer development and metastasis in vivo; and 3) Elucidate the mechanism
by which AIM2 responds to and regulates the intestinal microbiota to limit colon cancer. This proposal builds
upon my prior work that includes a strong background in cell signal transduction, intestinal microbiome profiling
and animal models of colon cancer initiation while working in the laboratory of Jenny P-Y Ting at the
Lineberger Comprehensive Cancer Center at the University of North Carolina at Chapel Hill. With additional
technical assistance and core facility support from my collaborators, this K22 award will provide critical training
in in vitro primary colon organoid culture systems, Crispr/Cas9 gene editing, mouse models of spontaneous
tumorigenesis and metastasis, gene expression and signal transduction profiling of human cancer tissue and
manipulation of the microbiome to target cancer, which are required to achieve my long-term goal of becoming
an established tenured-track principle investigator in the area of...

## Key facts

- **NIH application ID:** 9985753
- **Project number:** 5K22CA212030-03
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Justin Ethan Wilson
- **Activity code:** K22 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $159,549
- **Award type:** 5
- **Project period:** 2018-08-01 → 2021-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9985753

## Citation

> US National Institutes of Health, RePORTER application 9985753, Regulation of Colon Cancer by AIM2 (5K22CA212030-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9985753. Licensed CC0.

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