Single-cell analysis of human basal cell carcinoma reveals novel regulators of tumor growth and the tumor microenvironment

Abstract

How basal cell carcinoma (BCC) interacts with its tumor microenvironment to promote growth is unclear. 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 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 reveals a cancer-specific rewiring of fibroblasts, where STAT1, TGF-β, and inflammatory signals induce a noncanonical 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. Last, 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 cross-talk in BCC progression.

Deeper insights into transcriptional features of cancer-associated fibroblasts: An integrated meta-analysis of single-cell and bulk RNA-sequencing data

“…However, other researchers do not classify mural cells into a separate cluster, but annotate several different fibroblast populations, for example, inflammatory CAFs and myofibroblast-like CAFs, CAF-A and CAF-B, fibroblasts and fibroblast-like cells, etc. ( Li et al, 2017 ; Guerrero-Juarez et al, 2022 ; Kim et al, 2022 ). In this case, we noticed that the cell clusters we identified are similar to the various fibroblast populations described in these studies, respectively.…”

Unravelling the landscape of skin cancer through single-cell transcriptomics

“…Guerrero-Juarez et al. used CellChat to investigate tumor-stromal interactions in BCC and identified that the nearby fibroblasts act as an inflammatory hub regulating BCC growth through induction of heat shock proteins [47] . Knowledge of ligand-receptor pairing was also essential to work performed by Miao and colleagues, who performed adoptive cytotoxic T-cell transfer (ACT)-based immunotherapy in a mouse model of cSCC to investigate mechanisms of immune evasion [48] .…”

HSP70 Family in Cancer: Signaling Mechanisms and Therapeutic Advances

“…Through interacting with the ATP binding site, HSP70 inhibits ATPase activity of all isoforms of HSP70 [ 127 , 128 , 132 , 133 , 134 ]. Though this lacking isoform specificity, VER-155008 was identified to exert strong anti-tumor activity in a variety of cancers through affecting a wide range of cancer-related signaling pathways [ 59 , 88 , 89 , 90 , 91 , 92 , 93 , 94 ]. VER-155008 inhibited proliferation, suppressed invasion and migration, and induced apoptosis of pheochromocytoma cells through down-regulating phosphorylation of the PI3K/AKT/mTOR and MEK/ERK signaling pathways [ 59 ].…”