New Research in The American Journal of Pathology identifies the protein-linked receptor C5aR1 as a novel prognostic biomarker and potential therapeutic target to help patients with cutaneous squamous cell carcinoma

Philadelphia, May 29, 2025 – Researchers have identified C5aR1 as a novel biomarker for metastasis risk and poor prognosis in patients with cutaneous squamous cell carcinoma (cSCC), the most common type of metastatic skin cancer. The new study's findings in The American Journal of Pathology, published by Elsevier, found that C5aR1 promotes the invasion of cSCC tumor cells. Its elevated presence suggests that C5aR1 might serve as a useful prognostic marker for metastatic disease and, potentially, a target for future therapies in advanced cSCC.

The incidence of cSCC is increasing. Exposure to solar UV radiation is the predominant risk factor for cSCC. Approximately 3% to 5% of primary cSCCs metastasize, and the prognosis for patients with metastatic cSCC is poor. Although most cases are curable by excision of the primary tumor, a subset of patients develop aggressive and metastatic disease with few treatment options. It is estimated that cSCC accounts for nearly 25% of annual skin cancer deaths.

Lead investigator Veli-Matti Kähäri, MD, PhD, Department of Dermatology, and FICAN West Cancer Research Laboratory University of Turku and Turku University Hospital, Turku, Finland, explains, "Currently, there are no established molecular markers in clinical practice for predicting the metastasis risk of primary cSCCs. There is an urgent need for predictive biomarkers for the prognosis of cSCC and for new therapeutic targets for metastatic cSCC."

Studies in multiple cancers have indicated that the complement system, which is a part of the human innate immune system and is a tumor-suppressing cytolytic mechanism, can also contribute to tumor progression and metastasis by inducing inflammation or causing immunosuppression. This prompted researchers conducting the current study to investigate the interaction between C5a (which acts as a signaling molecule in cancer) and its protein receptor C5aR1 (which is found on the surface of cells) in cSCC.

Investigators noted that when C5a binds to C5aR1, it activates signaling pathways within the cell, leading to changes in cell behavior. They examined C5aR1 in the context of cSCC progression and metastasis by combining in vitro 3D spheroid co-culture of cSCC cells and skin fibroblasts, human cSCC xenograft tumors grown in SCID (Severe Combined Immunodeficiency) mice, and a large panel of patient-derived tumor samples of non-metastatic cSCC, metastatic cSCCs and cSCC metastases.

First author Lauri Heiskanen, MD, Department of Dermatology, and FICAN West Cancer Research Laboratory University of Turku and Turku University Hospital, Turku, Finland, elaborates, "We observed that fibroblasts in the tumor microenvironment induced C5aR1 expression in cSCC cells. Exposure to recombinant C5a further increased the invasiveness of cSCC cells. In patient-derived cSCC samples, high C5aR1 expression — both in tumor cells and in stromal fibroblasts — was linked to metastasis risk and poor survival."

Researchers were surprised to find that fibroblasts influenced C5aR1 expression in cancer cells, and that the C5aR1 expression in stromal fibroblasts also had a role in metastasis and poor prognosis in cSCC. They also had not anticipated that C5aR1 expression would correlate with patient outcomes across a large clinical sample set.

Co-investigators Pilvi Riihilä, MD, PhD, and Liisa Nissinen, PhD, Department of Dermatology, and FICAN West Cancer Research Laboratory University of Turku and Turku University Hospital, Turku, Finland, conclude, "What is particularly interesting in the results of our study is how the tumor microenvironment — especially fibroblasts in this study — affects progression of cSCC through C5aR1. It emphasizes the idea that the interplay between tumor cells and stromal cells plays an important role in cancer progression. Our findings suggest that C5aR1 is a potential metastatic risk marker, a novel prognostic biomarker, and promising therapeutic target for cSCC."