Track

Basic Science

Abstract

Cutaneous squamous cell carcinoma (cSCC) is the second most common human cancer, with estimates of approximately 1.8 million new cases annually in the US. In organ transplant patients, cSCC has a 65- to 250-fold higher incidence and behaves more aggressively with a higher risk of invasion, metastasis, and death. Progression from cSCC in situ (SCCIS) to invasive and metastatic cSCC is not yet well-understood. In this study, we performed spatial transcriptomic analysis at single-cell resolution using the Xenium 10x Genomics platform and acquired the transcriptomes of >700,000 cells from 34 specimens (20 immunocompetent, 14 transplant) across 8 patients (6 immunocompetent, 2 transplant) to uncover biomarkers that predict invasion. This approach allowed us to discover new cell subtypes and differentially expressed genes for SCCIS and explore the molecular differences between transplant and non-transplant SCCIS to identify biomarkers involved in the progression towards invasive carcinoma. We identified diverse cell types, including three distinct keratinocyte subtypes and three distinct SCCIS subtypes with different gene expression profiles and functions. In SCCIS, we discovered an invasive subtype with differential proliferative and migration potential. We then performed differential gene expression analysis and identified biomarkers of SCCIS predictive of immunosuppression and immunocompetence. Specifically, desmocollin-2 (DSC2, p-value 8.57E^-59) and gap junction beta-2 (GJB2, p-value 2.25E^-28) had increased expression in SCCIS while ARG1 and IL33 (p-value 0.00371) were associated with SCCIS in transplant patients. Additional studies will be performed to further validate these results and determine the underlying mechanism of how these biological pathways regulate lesion growth.