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

•Wound healing phase-specific genes enrich for extracellular matrix (ECM) signatures that are prognostic in tumors.•Wound fibroblasts and cancer-associated fibroblasts (CAFs) share signatures that enrich for divergent ECM repertoires: collagen vs elastin.•An early wound CAF subtype signature localizes to the inner tumor stroma and expresses collagen-related ECM genes that are controlled by RUNX2.•A late wound CAF subtype signature localizes to the outer tumor stroma and expresses elastin-related ECM genes.•Collagen- and elastin-rich ECM niches with distinct matrix architectures predict survival and recurrence in primary melanoma. 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.