# Tissue Damage-Driven Squamous Cell Carcinoma

> **NIH NIH R01** · THOMAS JEFFERSON UNIVERSITY · 2022 · $349,713

## Abstract

Squamous cell carcinoma (SCC) is responsible for ~10% of total cancer mortality worldwide. SCC prognosis is
context-dependent and does not seem to be determined by driver gene somatic mutations, which are similar
across different body sites and pathological grades. Our study of SCC arising in the rare genetic skin disease
Recessive Dystrophic Epidermolysis Bullosa (RDEB) has identified genetic similarities between this deadly,
tissue damage-driven cancer, and a related cancer arising in the oral cavity, termed head and neck SCC
(HNSCC). Our unpublished research into HNSCC has demonstrated that this similarity extends beyond genetics
and has identified the composition of the extracellular matrix (ECM) within the tumor microenvironment as a
potential predictor of poor outcome. Our current proposal leverages the similarities between RDEB and certain
sub-types of HNSCC to explore initiation and progression events that are likely driven by different environmental
stimuli but which result in the same outcome; SCC with poor prognosis. In RDEB, ~90% of patients develop
cutaneous SCC by age 55 and 5-year survival is close to 0%. SCC in the skin of RDEB patients arise within
chronic wounds, an environment quite different to most head and neck cancers. Nevertheless, analysis of
mutations in these tumors suggests that similar mechanisms are driving tumor initiation, and analysis of gene
expression and ECM proteins suggests that similar mechanisms also drive tumor progression. We have
developed a novel assay of mutation in cultured keratinocytes which will determine the extent of existing mutation
in single cells isolated from peri-tumoral, normal-appearing tissue, a tissue region that is prone to cancer
development (a phenomenon known as ‘field cancerization’). Using this approach, we will also determine the
relationship between elements associated with risk factors in HNSCC, and mutagenesis driven by endogenous
deaminases of the AID (activation-induced cytidine deaminase) and APOBEC (apolipoprotein B mRNA editing
enzyme, catalytic polypeptide) family, which have been shown to be active in all SCC genomes. To address the
role of ECM in progression of SCC, we will utilize a novel assay of tissue fibrosis that recapitulates the continual
collagen remodeling observed in SCC fibroblasts (in both RDEB and HNSCC) when compared with normal
fibroblasts isolated from the same patient which do not exhibit such collagen remodeling. We will interrogate the
role of thrombospondin-1 (TSP1) in driving tumor cell invasion through two separate but related mechanisms,
activation of transforming growth factor-beta signaling and regulation of ECM secretion. In parallel, we will
determine the timing of mutational processes resulting from tissue damage by assessing mutation acquisition in
APOBEC transgenic animals. Importantly, these studies will also enable us to evaluate APOBEC inhibition as
a potential preventative or treatment intervention for SCC in a pre-clinical setting. T...

## Key facts

- **NIH application ID:** 10322172
- **Project number:** 5R01CA244522-02
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** Andrew South
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $349,713
- **Award type:** 5
- **Project period:** 2021-01-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10322172

## Citation

> US National Institutes of Health, RePORTER application 10322172, Tissue Damage-Driven Squamous Cell Carcinoma (5R01CA244522-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10322172. Licensed CC0.

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