Phase-specific signatures of wound fibroblasts and matrix patterns define cancer-associated fibroblast subtypes

Wietecha, M. S.; Lauenstein, D.; Cangkrama, M.; Seiler, S.; Jin, J.; Goppelt, A.; Claassen, M.; Levesque, M.; Dummer, R.; Werner, S.

doi:10.1101/2022.11.18.516967

bioRxiv · 10.1101/2022.11.18.516967

Phase-specific signatures of wound fibroblasts and matrix patterns define cancer-associated fibroblast subtypes

Wietecha, M. S.·Lauenstein, D.·Cangkrama, M.·Seiler, S.·Jin, J.·Goppelt, A.·Claassen, M.·Levesque, M.·Dummer, R.·Werner, S.

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Abstract

Healing wounds and cancers present remarkable cellular and molecular parallels, but the specific roles of the healing phases are largely unknown. We developed a bioinformatics pipeline to identify genes and pathways that define distinct phases across the time course of healing. Their comparison to cancer transcriptomes revealed that a resolution-phase wound signature is associated with increased severity in skin cancer and enriches for extracellular matrix-related pathways. Comparisons of transcriptomes of early- and late-phase wound fibroblasts vs skin cancer-associated fibroblasts (CAFs) identified an "early-wound" CAF subtype, which localizes to the inner tumor stroma and expresses collagen-related genes that are controlled by the RUNX2 transcription factor. A "late-wound" CAF subtype localizes to the outer tumor stroma and expresses elastin-related genes. Matrix imaging of primary melanoma tissue microarrays validated these matrix signatures and identified collagen- vs elastin-rich niches within the tumor microenvironment, whose spatial organization predicts survival and recurrence. These results identify wound-regulated genes and matrix patterns with prognostic potential in skin cancer.

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Wietecha, M. S., Lauenstein, D., Cangkrama, M., Seiler, S., Jin, J., Goppelt, A., Claassen, M., Levesque, M., Dummer, R., Werner, S.. 2022-11-20. Phase-specific signatures of wound fibroblasts and matrix patterns define cancer-associated fibroblast subtypes. https://doi.org/10.1101/2022.11.18.516967

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