# The role of the senescent microenvironment on cancer initiating cells in the colon.

> **NIH NIH U01** · FRED HUTCHINSON CANCER RESEARCH CENTER · 2021 · $451,960

## Abstract

PROJECT SUMMARY/ABSTRACT
 Advanced age is the single most significant risk factor for cancer. Although there are many
plausible age-related mechanisms that mediate the increased risk for cancer in the elderly,
functional evidence is lacking for the majority of these mechanisms. This proposal will focus on
the role of the aged microenvironment, particularly senescence, in promoting the formation of
colorectal cancer (CRC), which is a common age-related cancer in the U.S. It is well established
that the majority of CRCs arise through the serial accumulation of mutations and epigenetic
alterations in oncogenes and tumor suppressor genes in colon epithelial stem cells. However,
our group and others have found cells with cancer-causing DNA alterations (e.g. oncogenic KRAS
and TP53) in the histologically normal colon mucosa of people, which suggests that the DNA
alterations alone are not sufficient to drive the complete CRC formation process.
 Our group has recently shown that a senescent normal colon tissue microenvironment can
promote the neoplastic behavior of colon epithelial cells ex vivo. We found increased senescent
fibroblasts in the colons of the elderly and of people at high risk for CRC. We found that certain
senescence associated secretory phenotype (SASP) factors produced by senescent fibroblasts
can induce cancer hallmark behaviors through the activation of oncogenic signaling pathways.
Based on our preliminary data we hypothesize that senescent fibroblasts in older people and the
accompanying specific Senescence Associated Secretory Phenotype (SASP) secreted proteins
promote the tumorigenesis of colon epithelial cells that have acquired age-related oncogenic
mutations, which we have defined as cancer-initiating cells. To provide direct functional evidence
to test this hypothesis, we propose the following Specific Aims:
AIM 1A. To determine whether senescent fibroblasts can promote the survival and/or
transformation of colon cancer initiating cells in ex vivo and in vivo organoid model systems.
AIM 1B. To determine the necessary and sufficient role of specific cancer-associated SASP
factors produced by the senescent fibroblasts in cancer formation.
AIM 2. To determine whether a senescent tissue microenvironment is necessary for the survival
and clonal expansion of mutant APC and mutant KRAS cancer-initiating cells using a well
characterized CRC mouse model, the inducible Villin-Cre;Apcflx/flx; KrasLSL-G12D (AK) mice, with two
approaches: AIM 2A: a pharmacological approach using the senomorphic drug rapamycin and
the senolytic drug treatment DNQ (dasatinib and quercetin) AIM 2B: a genetic approach using
the p16-3MR transgenic model, which allows the inducible ablation of senescent cells.

## Key facts

- **NIH application ID:** 10355956
- **Project number:** 1U01AG077920-01
- **Recipient organization:** FRED HUTCHINSON CANCER RESEARCH CENTER
- **Principal Investigator:** William Mallory Grady
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $451,960
- **Award type:** 1
- **Project period:** 2021-09-30 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10355956

## Citation

> US National Institutes of Health, RePORTER application 10355956, The role of the senescent microenvironment on cancer initiating cells in the colon. (1U01AG077920-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10355956. Licensed CC0.

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