# Precision imaging of the spatial regulators of the hybrid epithelial/mesenchymal state in head and neck cancer

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $701,699

## Abstract

PROJECT SUMMARY
Head and neck squamous cell carcinoma (HNSCC), including oral cavity squamous cell carcinoma (OCSCC) is
the sixth leading cause of cancer-related mortality, with the majority of deaths attributable to tumor metastasis
and failures in treatment. Because most cases of OCSCC result from tobacco and alcohol exposure, these
tumors are highly heterogeneous, greatly complicating diagnosis, treatment, and investigations into the biology
of this disease. We recently performed dissociated single cell RNA-sequencing (scRNA-seq) in OCSCC and
identified a hybrid epithelial/mesenchymal state (HEM) with some features of classical EMT, yet persistent
expression of epithelial markers. Further investigation into HEM demonstrated its localization at the leading edge
of tumors where it appears to drive invasion and metastasis as well as poor outcomes in OCSCC. How does
HEM trigger worse outcomes in HNSCC patients? Based on recent multispectral, multiplexed imaging analysis,
we have found that HEM leads to exclusion of tumor infiltrating lymphocytes including T-cells. Thus,
understanding what underlying structural and biological features of a tumor dictate this phenotype of immune
exclusion and induce HEM is of critical importance to advancing diagnostic biomarkers and targeted therapeutics
for HNSCC. We hypothesize that HEM reflects the underlying tumor architecture and the complex interplay
between cells in the OCSCC ecosystem. However, due to the heterogeneity of these tumors both biologically as
well as spatially, bulk and/or dissociated transcriptomic and proteomic techniques forego this critical information.
Our goal is to utilize advanced imaging approaches to mature a set of imaging-based biomarkers based on HEM
and its interactions with the immune system, thereby creating opportunities to advance patient stratification and
treatment of OCSCC. To test our hypothesis, we will: (1) Further define the effect of HEM on immune infiltration
using MSI, especially as it relates to specific architectural features of tumor morphology. We will utilize MSI to
analyze patient tumors treated with immune checkpoint inhibitors (ICI) to identify imaging-based metrics that
predict response. Next, (2) we will combine proteomic, transcriptomic, and histopathologic approaches while
retaining spatial information to obtain a more comprehensive understanding of the spectrum of HEM states and
expression heterogeneity within the tumor environment that contributes to HEM. Finally, (3) we will establish
pathways to both train and mentor the next generation of head and neck cancer investigators, creating both
hands-on laboratory exchanges as well as portable education modules for use in community colleges. At the
research level, testing these hypotheses will provide critical insights into the relationship between tumor-
infiltrating immune cells and HEM, and the underlying expression states that direct HEM and ICI response more
broadly. From a DEIA lens, our work will aim...

## Key facts

- **NIH application ID:** 11057776
- **Project number:** 1R01DE033741-01A1
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Shannon L Stott
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $701,699
- **Award type:** 1
- **Project period:** 2024-09-02 → 2025-06-10

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11057776

## Citation

> US National Institutes of Health, RePORTER application 11057776, Precision imaging of the spatial regulators of the hybrid epithelial/mesenchymal state in head and neck cancer (1R01DE033741-01A1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/11057776. Licensed CC0.

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