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

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

  • Sci Adv. 2022 Jun 10;8(23):eabm7981. doi: 10.1126/sciadv.abm7981.
Christian F Guerrero-Juarez 1 2 3 4,  Gun Ho Lee 5,  Yingzi Liu 1 3,  Shuxiong Wang 2 3,  Matthew Karikomi 2,  Yutong Sha 2,  Rachel Y Chow 1,  Tuyen T L Nguyen 1,  Venus Sosa Iglesias 1,  Sumaira Aasi 5,  Michael L Drummond 1,  Qing Nie 1 2 3 4,  Kavita Sarin 5,  Scott X Atwood 1 3 4 6 7
Affiliations

Affiliations

  • 1 Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA 92697, USA.
  • 2 Department of Mathematics, University of California, Irvine, Irvine, CA 92697, USA.
  • 3 NSF-Simons Center for Multiscale Cell Fate Research, University of California, Irvine, Irvine, CA 92697, USA.
  • 4 Center for Complex Biological Systems, University of California, Irvine, Irvine, CA 92697, USA.
  • 5 Department of Dermatology, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • 6 Department of Dermatology, University of California, Irvine, Irvine, CA 92697, USA.
  • 7 Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, CA 92697, USA.
PMID: 35687691 DOI: 10.1126/sciadv.abm7981
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.

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