Functionally distinct cancer-associated fibroblast subpopulations establish a tumor promoting environment in squamous cell carcinoma

Sabrina Schütz, Llorenç Solé-Boldo, Carlota Lucena-Porcel, Jochen Hoffmann, Alexander Brobeil, Anke S. Lonsdorf, Manuel Rodríguez-Paredes () and Frank Lyko ()
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Sabrina Schütz: German Cancer Research Center
Llorenç Solé-Boldo: German Cancer Research Center
Carlota Lucena-Porcel: Ruprecht-Karls University of Heidelberg
Jochen Hoffmann: University Hospital, Ruprecht-Karls University of Heidelberg
Alexander Brobeil: Ruprecht-Karls University of Heidelberg
Anke S. Lonsdorf: University Hospital, Ruprecht-Karls University of Heidelberg
Manuel Rodríguez-Paredes: German Cancer Research Center
Frank Lyko: German Cancer Research Center

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

Abstract: Abstract Cutaneous squamous cell carcinoma (cSCC) is a serious public health problem due to its high incidence and metastatic potential. It may progress from actinic keratosis (AK), a precancerous lesion, or the in situ carcinoma, Bowen’s disease (BD). During this progression, malignant keratinocytes activate dermal fibroblasts into tumor promoting cancer-associated fibroblasts (CAFs), whose origin and emergence remain largely unknown. Here, we generate and analyze >115,000 single-cell transcriptomes from healthy skin, BD and cSCC of male donors. Our results reveal immunoregulatory and matrix-remodeling CAF subtypes that may derive from pro-inflammatory and mesenchymal fibroblasts, respectively. These CAF subtypes are largely absent in AK and interact with different cell types to establish a pro-tumorigenic microenvironment. These findings are cSCC-specific and could not be recapitulated in basal cell carcinomas. Our study provides important insights into the potential origin and functionalities of dermal CAFs that will be highly beneficial for the specific targeting of the cSCC microenvironment.

Date: 2023
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DOI: 10.1038/s41467-023-41141-9

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