# Mechanisms and Therapeutic Targets of SCC Metastasis

> **NIH VA I01** · VA NORTHERN CALIFORNIA HEALTH CARE SYS · 2024 · —

## Abstract

Squamous cell carcinomas (SCCs) arise from stratified epithelia, the most relevant organ sites in the veteran
population 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 the civilian population. SCC’s worst outcome is death
through metastasis, most commonly in the lung. SCC deaths exceed melanoma deaths due to the high
number of SCC cases. The lack of spontaneous SCC lung metastasis models has hindered identification of
SCC lung metastasis mechanisms and therapeutic targets. We developed several genetically engineered
mouse models that target driver mutations frequently found in human SCCs to keratin K15+ stem cells. These
models develop spontaneous lung SCC metastasis with different frequencies. Together with their derived cell
lines, they are unique tools to study mechanisms of SCC lung metastasis in different immune tumor
microenvironments (TME). We have shown that a subpopulation of cancer stem cells (CSCs), i.e., the Hoechst
dye excluding side population (SP), have the ability to metastasize, suggesting that CSC properties dictate the
lung metastasis route. Our preliminary data revealed that cancer associated fibroblasts (CAFs) derived from
metastatic SCCs enhanced CSC expansion and invasion in vitro and seeding to the lung in vivo. Further, CAFs
undergo unique changes in gene expression of extracellular matrix (ECM) proteins, and candidate markers for
SCC CAFs are distinctive from other metastatic cancers. Lastly, targeting myeloid cells reduced SCC
metastasis. Taken together, we hypothesize that CSC properties predispose them to travel via blood vessels
and survive in the lung. Additionally, SCC-CAF crosstalk has local and systemic effects preparing the
metastatic TME and premetastatic (prior to metastasis)/metastatic (after SCC cell seeding) niche. Using our
mouse models as well as patients’ SCC specimens, the proposed studies will identify prognostic markers and
therapeutic targets for high risk metastatic SCCs and develop interventional therapies that will be brought into
clinic in the near future. Aim 1 will assess if molecules associated with multipotent CSC properties contribute
to CSCs invasion and intravasation to blood vessels. Aim 2 will identify metastatic SCC-specific CAF ECM
signatures and molecular markers that enhance metastatic CSC properties. Aim 3 will identify systemic effects
of CAF-SCC interactions that establish a metastatic TME in primary SCC and pre-metastatic/metastatic niche
in the lung. Our unique mouse model systems and cross-species comparisons with human SCCs, multiple high
throughput assays and innovative approaches will significantly accelerate discovery of SCC metastasis
mechanisms and simultaneously test therapeutic interventions.

## Key facts

- **NIH application ID:** 10844420
- **Project number:** 5I01BX003232-08
- **Recipient organization:** VA NORTHERN CALIFORNIA HEALTH CARE SYS
- **Principal Investigator:** Xiao-Jing Wang
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2016-10-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10844420

## Citation

> US National Institutes of Health, RePORTER application 10844420, Mechanisms and Therapeutic Targets of SCC Metastasis (5I01BX003232-08). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10844420. Licensed CC0.

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