Single cell transcriptomic analysis of HPV16-infected epithelium identifies a keratinocyte subpopulation implicated in cancer

Mary C. Bedard, Tafadzwa Chihanga, Adrean Carlile, Robert Jackson, Marion G. Brusadelli, Denis Lee, Andrew VonHandorf, Mark Rochman, Phillip J. Dexheimer, Jeffrey Chalmers, Gerard Nuovo, Maria Lehn, David E. J. Williams, Aditi Kulkarni, Molly Carey, Amanda Jackson, Caroline Billingsley, Alice Tang, Chad Zender, Yash Patil, Trisha M. Wise-Draper, Thomas J. Herzog, Robert L. Ferris, Ady Kendler, Bruce J. Aronow, Matthew Kofron, Marc E. Rothenberg, Matthew T. Weirauch, Koenraad Doorslaer, Kathryn A. Wikenheiser-Brokamp, Paul F. Lambert, Mike Adam (), S. Steven Potter () and Susanne I. Wells ()
Additional contact information
Mary C. Bedard: Cincinnati Children’s Hospital Medical Center
Tafadzwa Chihanga: Cincinnati Children’s Hospital Medical Center
Adrean Carlile: Cincinnati Children’s Hospital Medical Center
Robert Jackson: University of Arizona
Marion G. Brusadelli: Division of Clinical Operations, Medpace
Denis Lee: University of Wisconsin
Andrew VonHandorf: Cincinnati Children’s Hospital Medical Center
Mark Rochman: Cincinnati Children’s Hospital Medical Center
Phillip J. Dexheimer: Cincinnati Children’s Hospital Medical Center
Jeffrey Chalmers: William G. Lowrie Department of Chemical and Biomolecular Engineering, Ohio State University
Gerard Nuovo: Ohio State University Medical Center
Maria Lehn: University of Cincinnati College of Medicine
David E. J. Williams: University of Arizona
Aditi Kulkarni: University of Pittsburgh
Molly Carey: University of Cincinnati Medical Center
Amanda Jackson: University of Cincinnati Medical Center
Caroline Billingsley: University of Cincinnati Medical Center
Alice Tang: University of Cincinnati
Chad Zender: University of Cincinnati
Yash Patil: University of Cincinnati
Trisha M. Wise-Draper: University of Cincinnati College of Medicine
Thomas J. Herzog: University of Cincinnati Medical Center
Robert L. Ferris: University of Pittsburgh
Ady Kendler: University of Cincinnati College of Medicine
Bruce J. Aronow: Cincinnati Children’s Hospital Medical Center
Matthew Kofron: Cincinnati Children’s Hospital Medical Center
Marc E. Rothenberg: Cincinnati Children’s Hospital Medical Center
Matthew T. Weirauch: Cincinnati Children’s Hospital Medical Center
Koenraad Doorslaer: University of Arizona
Kathryn A. Wikenheiser-Brokamp: University of Cincinnati College of Medicine
Paul F. Lambert: University of Wisconsin
Mike Adam: Cincinnati Children’s Hospital Medical Center
S. Steven Potter: Cincinnati Children’s Hospital Medical Center
Susanne I. Wells: Cincinnati Children’s Hospital Medical Center

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: Abstract Persistent HPV16 infection is a major cause of the global cancer burden. The viral life cycle is dependent on the differentiation program of stratified squamous epithelium, but the landscape of keratinocyte subpopulations which support distinct phases of the viral life cycle has yet to be elucidated. Here, single cell RNA sequencing of HPV16 infected compared to uninfected organoids identifies twelve distinct keratinocyte populations, with a subset mapped to reconstruct their respective 3D geography in stratified squamous epithelium. Instead of conventional terminally differentiated cells, an HPV-reprogrammed keratinocyte subpopulation (HIDDEN cells) forms the surface compartment and requires overexpression of the ELF3/ESE-1 transcription factor. HIDDEN cells are detected throughout stages of human carcinogenesis including primary human cervical intraepithelial neoplasias and HPV positive head and neck cancers, and a possible role in promoting viral carcinogenesis is supported by TCGA analyses. Single cell transcriptome information on HPV-infected versus uninfected epithelium will enable broader studies of the role of individual keratinocyte subpopulations in tumor virus infection and cancer evolution.

Date: 2023
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DOI: 10.1038/s41467-023-37377-0

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