# Mechanisms of stem cell aging that contribute to clonal outgrowth in head and neck tissues

> **NIH NIH F32** · HARVARD UNIVERSITY · 2021 · $65,994

## Abstract

Project Summary/Abstract
 By the year 2050, it is projected that over 72 million people will be 65 years or older in the United
States, representing 20% of the population. This rapid, worldwide, demographic shift in age has many societal,
economic, and public health implications. One of the most common chronic illnesses and pathological
conditions experienced with increasing age is cancer. Head and neck cancer (HNC), in particular, is the
seventh most common cancer worldwide and accounts for more than 500,000 deaths annually. Incidence of
HNC significantly increases in individuals over the age of 40 and is more common in men. Further, individuals
with a prior hematologic cancer diagnosis who have undergone hematopoietic stem cell (HSCT) treatments
have an elevated risk for the development of HNC. Primary treatments for HNC are surgery and/or radiation
therapy, but these treatments have devastating effects on swallowing function and speech. Multiple causal
pathways likely exist for the development of HNC in aged individuals and following HSCT. One likely
mechanism promoting both aging and cancer is the acquisition and accumulation of epigenetic modifications
and genetic alterations within resident tissue stem cells in the head and neck. Clonal expansion of these
mutated stem cells may accelerate the incidence of HNC in the aging population and in those who have
undergone HSCT.
 The purpose of this proposal is to identify underlying cellular and systemic mechanisms contributing to
the development of cancer in head and neck tissues (oral cavity, tongue, pharynx, esophagus, neck) with
aging and following HSCT, and determine whether somatic mutations in relevant tissue stem cells drive clonal
expansion, HNC initiation, and tumor development. Our hypotheses are that frequency of head and neck
tissue stem cells will be significantly reduced with increasing age and following HSCT treatment and that
epigenetic and genetic modifications of head and neck tissue stem cells will be 1) significantly increased
in frequency with age and following HSCT, 2) differentially represented in male and female mice, and 3)
capable of driving clonal outgrowth/HNC emergence when introduced into relevant tissue stem cell
populations. To address these hypotheses, this proposal has 3 specific aims: 1) determine cell-intrinsic
mechanisms of clonal evolution in head and neck somatic tissue stem cells in aged male and female mice, 2)
examine effects of environment on epigenetic and genetic profiles of somatic tissue stem cells, and 3) examine
whether in vivo introduction of somatic mutations in head and neck tissues are capable of driving clonal
outgrowth of tissue stem cells and HNC initiation. Altogether, this study will provide significant new knowledge
regarding mechanisms contributing to HNC with age and following HSCT, and enable development of targeted
and effective therapies.

## Key facts

- **NIH application ID:** 10141922
- **Project number:** 1F32AG071208-01
- **Recipient organization:** HARVARD UNIVERSITY
- **Principal Investigator:** Heidi Kletzien
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $65,994
- **Award type:** 1
- **Project period:** 2021-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10141922

## Citation

> US National Institutes of Health, RePORTER application 10141922, Mechanisms of stem cell aging that contribute to clonal outgrowth in head and neck tissues (1F32AG071208-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10141922. Licensed CC0.

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