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Forsthuber, A.

Publications and source records attributed to Forsthuber, A..

3 recordsLinked to original sources
bioRxiv2026

Spatially organized cancer-associated fibroblast subtypes partition cutaneous carcinomas into immune-active and contracted, immune-repressed niches

Basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (SCC) are the most common keratinocyte-derived malignancies, yet they differ markedly in invasiveness, metastatic potential, and immune contexture. Although cancer-associated fibroblasts (CAFs) are increasingly recognized as key regulators of tumor architecture and tumor immunity, the spatial organization of distinct CAF subtypes in cutaneous carcinomas and their functional relationship with immune cells remains incompletely understood. Using a 33-plex imaging mass cytometry (IMC) panel, we profiled 28 regions of interest (ROIs) from 17 human BCC and SCC specimens, encompassing more than 739,000 single cells, and integrated these data with RNA fluorescence in situ hybridization (RNA-FISH), immunohistochemistry (IHC), multiplex immunofluorescence, and in vitro functional assays. We identified four fibroblast populations, including immunomodulatory CAFs (iCAFs), matrix CAFs (mCAFs), myofibroblast-like CAFs (myoCAFs), and reticular fibroblasts (retFIBs), and found that aggressive tumor subtypes were characterized by increased stromal area, extracellular matrix deposition, and altered CAF composition. CAF composition differed most prominently across BCC subtypes, with nodular BCC enriched for mCAFs and infiltrative BCC showing increased myoCAF density, consistent with a shift toward a contractile stromal program. Spatial analyses revealed distinct CAF-immune niches: iCAFs localized to immune-cell-rich, inflamed niches enriched for activated and/or exhaustion-associated immune-cell marker programs, whereas myoCAFs occupied fibroblast-dense, immune-poor niches with globally reduced immune activation. mCAFs were preferentially associated with immune cell accumulation in the stroma and spatial immune compartmentalization, with limited immune cell presence within tumor nests. At the invasive front, CAF-immune coupling was highly subset-dependent, with iCAFs linked to antigen-experienced T-cell states and myoCAFs linked to immune exclusion. In vitro, patient-derived CAF cultures from myoCAF-rich biopsies showed enhanced collagen-gel contraction, with cultures enriched for MCAM+ CAFs displaying increased contractile capacity. Aggressive tumor variants displayed increased stromal nuclear YAP/TAZ, while complementary single-cell pathway analysis supported a mechanically remodeled stromal microenvironment in which mCAFs contribute ECM/matrix-remodeling programs and RGS5/myoCAF-like populations show enhanced mechanotransduction-associated signaling, rather than a uniform CAF-wide increase in canonical YAP/TAZ transcriptional output. Together, these findings define spatially organized CAF programs in cutaneous carcinomas and identify myoCAF-rich stromal niches as a recurrent feature of aggressive, immune-repressed tumor architecture. These results nominate CAF composition as a biomarker of immune architecture and a potential determinant of therapeutic response.

cancer biology↗
bioRxiv2024

A single cell and spatial genomics atlas of human skin fibroblasts in health and disease

Fibroblasts are critical cells that shape the architecture and cellular ecosystems in multiple tissues. Understanding fibroblast heterogeneity and their spatial context in health and disease has enormous clinical relevance. In this study, we constructed a spatially-resolved atlas of human skin fibroblasts from healthy skin and 23 skin disorders. We define 6 major skin fibroblast populations in health and a further three skin disease-specific fibroblast subtypes, and demonstrate the fibroblast composition in different types of skin disease. We characterise a human-specific fibroblastic reticular cell (FRC)-like subtype in the skin perivascular niche and postulate their origin from prenatal skin lymphoid tissue organiser (LTo)-like cells. We also show that inflammatory myofibroblasts (IL11+MMP1+CXCL5+IL7R+) are a conserved fibroblast subtype in inflammatory disorders and cancers across multiple human tissues. We provide a harmonised nomenclature for skin fibroblasts that integrates previous findings from human skin and other tissues.

cell biology↗
bioRxiv2023

CAF variants control the tumor-immune microenvironment and predict skin cancer malignancy

Cancer-associated fibroblasts (CAFs) play a key role in cancer progression and treatment outcome. This study dissects the yet unresolved intra-tumoral variety of CAFs in three skin cancer types -- Basal Cell Carcinoma, Squamous Cell Carcinoma, and Melanoma -- at molecular and spatial single-cell resolution. By integral analysis of the fibroblasts with the tumor microenvironment, including epithelial, mesenchymal, and immune cells, we characterize three distinct CAF subtypes: myofibroblast-like RGS5+ CAFs, matrix CAFs (mCAFs), and immunomodulatory CAFs (iCAFs). Notably, large cohort tissue analysis reveals marked shifts in CAF subtype patterns with increasing malignancy. Two CAF types exhibit immunomodulatory capabilities via distinct mechanisms. mCAFs synthesize extracellular matrix and have the ability to ensheath tumor nests, potentially limiting T cell invasion in low-grade tumors. In contrast, iCAFs are enriched in late-stage tumors, especially infiltrative BCC and high-grade melanoma, and express unexpectedly high mRNA and protein levels of cytokines and chemokines, pointing to their integral role in immune cell recruitment and activation. This finding is further supported by our observation that in vitro exposure of primary healthy fibroblasts to skin cancer cell secretomes induces an iCAF-like phenotype with immunomodulatory functions. Thus, targeting CAF variants, particularly the immunomodulatory iCAF subtype, holds promise for improved efficacy of immunotherapy in skin cancers.

cancer biology↗