6 2022
Science Advances published our work on single cell analysis of human basal cell carcinomas
How basal cell carcinoma (BCC) interacts with its tumor microenvironment to promote growth is unclear. Here we use singe-cell RNA sequencing to define the human BCC ecosystem and discriminate between
normal and malignant epithelial cells. We identify spatial biomarkers of both tumors and their surrounding stroma that reinforce the heterogeneity of each tissue type. Combining pseudotime, RNA velocity-PAGA, cellular entropy, and regulon analysis in stromal cells reveal a
cancer-specific rewiring of fibroblasts where STAT1, TGF-β, and inflammatory signals induce a non-canonical WNT5A program that maintains the stromal inflammatory state. Cell-cell communication modeling suggests that tumors respond to the sudden burst of fibroblast-specific
inflammatory signaling pathways by producing heat shock proteins, whose expression we validated in situ. Finally, dose-dependent treatment with an HSP70 inhibitor suppresses in vitro vismodegib-resistant BCC cell growth, Hedgehog signaling, and in vivo tumor growth in a BCC
mouse model, validating HSP70’s essential role in tumor growth and reinforcing the critical nature of tumor microenvironment crosstalk in BCC progression.
