# Elucidating IL-6/STAT3-mediated Phenotypic Changes in Head and Neck Cancer Stem Cells

> **NIH NIH F30** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $51,320

## Abstract

ABSTRACT
Head and neck squamous cell carcinoma (HNSCC) is a frequent and deadly malignancy. Despite significant
advances in the understanding of the pathobiology of HNSCC, the substantial patient morbidity associated with
treatment and the high frequency of tumor recurrence/metastasis result in an unacceptably low patient survival
and poor quality of life. The cancer stem cell (CSC) hypothesis attempts to explain the observed heterogeneity
of cancer cells within a tumor, with many malignant features of a cancer cell deriving from a shift towards stem-
like features. CSCs function as drivers of tumor initiation, therapeutic evasion, and recurrence in HNSCC.
Platinum-based agents such as Cisplatin have been shown to enhance the CSC fraction and self-renewal, as
determined by Bmi-1 expression. Head and neck CSCs rely on cellular crosstalk within the perivascular niche,
particularly on endothelial cell-secreted IL-6. Our preliminary data showed that IL-6/STAT3 inhibition prevents
Cisplatin-induced CSC self-renewal. But the mechanism through which inhibition of IL-6 signaling asserts this
function and its implications on therapeutic resistance and tumor recurrence remain unclear. The long-term
objective of this project is to study molecular mechanisms underlying the acquisition and maintenance of the
stem-like cancer cell phenotype. The overall hypothesis of this work is that therapeutic blockade of the IL-
6/STAT3 pathway suppresses the Bmi-1-mediated CSC self-renewal and inhibits HNSCC recurrence. To
test this hypothesis, we propose the following specific aims: 1) to elucidate mechanisms underlying IL-6/STAT3-
mediated phenotypic changes in the cancer cell population, 2) to describe the real-time effect of IL-6/STAT3
inhibition and Cisplatin therapy on CSC proliferation patterns, and 3) to determine the effect of inhibiting CSC
self-renewal on resistance to conventional Cisplatin therapy and recurrence in HNSCC. To accomplish these
aims, both genetic and pharmacologic approaches will be used in CSC assays in vitro and in vivo to test the
hypothesis that the CSC phenotype is regulated by Bmi-1 via IL-6/STAT3 signaling. We will investigate the real-
time phenotypic changes within the CSC population using a CRISPR/Cas9 reporter system to test the hypothesis
that IL-6/STAT3 inhibition promotes asymmetric cell division of CSC by decreasing their self-renewal. Cisplatin-
resistant cell lines and patient-derived xenograft mouse models will be used to test the hypothesis that inhibiting
IL-6/STAT3 signaling will overcome evasive resistance to Cisplatin and prevent tumor recurrence. Elucidating
crucial mechanisms that define the fate of head and neck cancer stem cells will inform mechanism-based
therapies that have the potential to enhance the survival and quality of life of patients with head and neck cancer.

## Key facts

- **NIH application ID:** 9944310
- **Project number:** 5F30DE029097-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Alexandra Eileen Herzog
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $51,320
- **Award type:** 5
- **Project period:** 2019-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9944310

## Citation

> US National Institutes of Health, RePORTER application 9944310, Elucidating IL-6/STAT3-mediated Phenotypic Changes in Head and Neck Cancer Stem Cells (5F30DE029097-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9944310. Licensed CC0.

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