Tuesday, April 1, 2025
4/1/2025
Tissue Damage-Driven Squamous Cell Carcinoma - 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 Our unpublished research into HNSCC has demonstrated that this similarity extends beyond genetics and has identified the composition of the extracellular matrix (ECM) within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. Together, our integrated in vitro and in vivo studies will provide the rationale and platform to develop clinically relevant strategies for improved SCC treatment and prevention.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).