# BLRD Research Career Scientist Award Application

> **NIH VA IK6** · VA NORTHERN CALIFORNIA HEALTH CARE SYS · 2023 · —

## Abstract

The overarching objective of my research program is to identify markers for prognosis and therapeutic
interventions for squamous cell carcinomas (SCCs), hence improving health outcomes for veterans. SCCs arise
from stratified epithelia; the most relevant organ sites in veterans are the skin and oral cavity where high
exposure to UV irradiation and tobacco carcinogens make the total and high-risk SCCs significantly higher than
in the civilian population. The worst outcome of SCC is death caused by distant metastasis. Skin SCC deaths
exceed melanoma deaths and SCC deaths in the head and neck are 3-4 times higher than skin SCC deaths.
The long-term goal of my VA research program is to identify markers for prognosis and therapeutic interventions
for SCCs, hence improving health outcomes for veterans. Since being funded in 2016 by a VA Merit Award, my
laboratory has been studying mechanisms related to SCC progression and therapeutic interventions. These
studies continuously translate into clinical diagnosis and therapeutic interventions directly impacting veterans’
healthcare outcomes. My laboratory pioneered inducible and epithelial-specific genetic engineered mouse
models (GEMMs) that develop SCCs and metastasis in the natural microenvironment and immune system.
These models provide unique resources for cross-species comparisons with human SCCs and performing
experimental therapeutics, including immunotherapy, in my past and ongoing Merit Award research. SCCs are
often indolent for decades. In the previous funding period, we focused on studying how SCCs break indolence
to become aggressive and metastatic cancers. We found that the properties of a subset of cancer stem cells
(CSCs) are responsible for breaking indolence through both clonogenicity and invasion. We found that
“heterozygous loss” of SMAD4, a tumor suppressor, in 30-50% of head and neck SCCs in humans, is a result of
significant inter- and intra-tumor heterogeneity at the single cell level, and that SMAD4 mutant cells have a
growth/survival advantage allowing them to take over the entire population of tumor cells. These findings
provide critical prognostic value for examining SMAD4 genomic status at the single cell level. Further, SMAD4-
deficient SCC cells have “Brca-like” defects in DNA damage repair that are susceptible to cancer
therapies that target DNA repair pathways. This finding provides an important link for a therapeutic marker
and strategy, and instigated an investigator-initiated clinical trial to treat locally advanced head and neck SCC
with radiotherapy (RT) in combination with Olaparib, which included recruiting VA patients. In tumor stroma, we
found that SMAD4 genomic loss triggers overproduction of TGFβ1, an immune suppressor and promoter for
cancer progression. In addition, cancer associated fibroblasts (CAFs) secret more TGFβ than cancer cells
and provide a CSC niche at the distant metastasis site for CSC clonal expansion. We also found that
tumor-associated macrophag...

## Key facts

- **NIH application ID:** 10594019
- **Project number:** 5IK6BX006039-03
- **Recipient organization:** VA NORTHERN CALIFORNIA HEALTH CARE SYS
- **Principal Investigator:** Xiao-Jing Wang
- **Activity code:** IK6 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2023
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2022-04-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10594019

## Citation

> US National Institutes of Health, RePORTER application 10594019, BLRD Research Career Scientist Award Application (5IK6BX006039-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10594019. Licensed CC0.

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