Report Highlights Role of Cancer-Associated Fibroblasts in Melanoma Metastases

Cancer-associated fibroblasts (CAFs) play an important role in metastatic melanoma, and an enhanced understanding of that role could lead to important new therapeutic pathways, according to a new report. The findings were published in the journal Pigment Cell & Melanoma Research.¹

Metastasis is a critical issue in the study of melanoma, since widespread metastasis is the leading cause of death among people with melanoma, noted corresponding author Peter Angel, PhD, of the German Cancer Research Center, and colleagues. Melanoma is the most dangerous type of skin cancer, making up nearly two-thirds of skin cancer deaths despite representing less than 5% of all skin cancers.² In addition, Angel and colleagues noted that the global burden of melanoma continues to increase. The AIM at Melanoma Foundation reports that the number of new invasive melanomas diagnosed in the United States increased by nearly 50% from 2009 to 2023.³

Recent research has highlighted the important role of nonmalignant cells within the tumor microenvironment, the investigators noted, with CAFs believed to play an especially important part. In melanoma specifically, for instance, a study of 117 melanoma patients who were treated with anti-PD-1 immunotherapy found that pretreatment CAF profiles were associated with patient outcomes, both in terms of progression-free survival and overall survival.⁴

One reason CAFs are important—and difficult—to understand is that they have a high degree of heterogeneity, Angel and colleagues wrote. They said multiple potential sources of CAFs have been described, including fibroblasts, mesenchymal stem cells, and epithelial and endothelial cells.

“Thus, CAFs have been considered to rather be a dynamic cell state than a specific cell type,” they wrote.

A 2023 paper in Experimental & Molecular Medicine noted that CAFs “profoundly influence the behavior of cancer cells and other stromal cells.”⁵ Yet, that paper also noted that developing therapies based on CAFs has proven challenging. Most clinical trials involving CAFs, they noted, have ended in failure. Yet, they said technologies like single cell RNA (scRNA) sequencing could become a powerful tool in the future to develop better targeted therapies.

In the new study, Angel and colleagues used scRNA sequencing to analyze melanoma. While most previous scRNA-based CAF research has focused on primary tumors, the new report used a mouse model to sequence and then compare samples of both primary tumors and lung metastasis samples.

The investigators analyzed the transcriptional signatures of 8,400 CAFs and normal fibroblasts and then compared the genetic profiles of murine melanoma primary tumors to those of lung metastases.

“This revealed distinct subsets for primary tumor and metastasis-specific CAF populations, respectively,” they found.

Their analysis further identified tumor-dependent crosstalk between neutrophils and CAFs, which they said was mediated via SAA3 and IL1b-related signaling pathways.

Angel and colleagues said they then used human melanoma samples to confirm that the interaction was also present in human melanoma metastasis.

The investigators said their research aligns with prior studies, including reports that found levels of SAA proteins in pancreatic ductal adenocarcinoma and non-small cell lung cancer were elevated in cases of liver metastasis compared to healthy donors and those with locally advanced tumors. They added that plasma SAA has already been used as a prognostic marker in melanoma.

“Taken together, our analysis deepens the understanding of CAFs in MM metastasis and sheds light on further putative opportunities to tackle the treatment of metastasized MM by targeting metastasis CAFs and corresponding signaling pathways,” they wrote.

References

1. Tauch S, Hey J, Kast B, et al. A Unique Signature for Cancer-Associated Fibroblasts in Melanoma Metastases. Pigment Cell Melanoma Res. 2025;38(2):e70002. doi:10.1111/pcmr.70002
2. Dzwierzynski WW. Managing malignant melanoma [published correction appears in Plast Reconstr Surg. 2014 Mar;133(3):762]. Plast Reconstr Surg. 2013;132(3):446e-460e. doi:10.1097/PRS.0b013e31829ad411
3. Aim at Melanoma Foundation. Facts & Statistics. Aim at Melanoma. Published 2025. Accessed March 10, 2025.https://www.aimatmelanoma.org/facts-statistics/?gclid=Cj0KCQiAvqGcBhCJARIsAFQ5ke6ruyVmoNVxGiSS2h5-seMBK3RE9XinRSUOrOIZ5iStkv6KhQh0gXsaAr6hEALw_wcB
4. Wong PF, Wei W, Gupta S, et al. Multiplex quantitative analysis of cancer-associated fibroblasts and immunotherapy outcome in metastatic melanoma. J Immunother Cancer. 2019;7(1):194. doi:10.1186/s40425-019-0675-0
5. Yang D, Liu J, Qian H, Zhuang Q. Cancer-associated fibroblasts: from basic science to anticancer therapy. Exp Mol Med. 2023;55(7):1322-1332. doi:10.1038/s12276-023-01013-0