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Soo Park, MD
Soo Park, MD
Posted: Wednesday, January 15, 2025
According to Beate M. Lichtenberger, PhD, of the Medical University of Vienna, and colleagues, cancer-associated fibroblasts (CAFs) seem to play a key role in cancer progression and prognosis; however, they present with remarkable functional heterogeneity and plasticity and therefore modulate multiple processes. With their study published in Nature Communications, these investigators aimed to explore the intratumoral diversity of these fibroblasts in squamous cell carcinoma, melanoma, and basal cell carcinoma through molecular and spatial single-cell analysis.
“In summary, our work provides a cellular and molecular atlas of the three most frequent skin cancer types, comprising neoplastic epithelial, mesenchymal, and immune cells,” the study authors concluded. “Therefore, determining the predominant cancer-associated fibroblast subset within tumor samples may improve future diagnostic strategies and thereby open new avenues for better personalized therapies.”
The researchers obtained fresh 4-mm punch biopsies from central tumors, as well as unaffected skin adjacent to these tumors. Healthy 10 × 10–cm skin samples were obtained from abdominal plastic surgeries and subsequently used in a cell isolation procedure. Immunohistochemistry was performed on human formalin-fixed paraffin-embedded skin sections, and the HALO image analysis platform was used to quantify and assess various cancer-associated fibroblast populations.
These analyses led to the identification of three specific cancer-associated fibroblast subtypes: matrix, immunomodulatory, and myofibroblast-like RGS5-positive cancer-associated fibroblasts. According to a large cohort tissue analysis, there appeared to be notable shifts in the patterns of cancer-associated fibroblast subtypes with increasing malignancy. In fact, two subtypes—matrix and immunomodulatory—exhibited different immunomodulatory mechanisms.
Immunomodulatory fibroblasts were abundant in late-stage tumors and expressed high levels of chemokines and cytokines to facilitate the recruitment and activation of immune cells. Matrix cancer-associated fibroblasts, however, were found to restrict T-cell invasion in low-grade tumors via ensheathing tumor nests, and they also synthesized the extracellular matrix. This finding, supported by the induction of an immunomodulatory fibroblast phenotype, suggests that targeting these fibroblast variants may enhance the efficacy of immunotherapy in skin cancers.
Disclosure: The study authors reported no conflicts of interest.
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