What question did this study set out to answer?

The study aims to understand how C3a-C3aR1 signaling influences invasion in cutaneous squamous cell carcinoma (cSCC).

April 19, 2026

Abstract LB303: C3a-C3aR1 signaling promotes invasion of cutaneous squamous cell carcinoma

Key Points

The study aims to understand how C3a-C3aR1 signaling influences invasion in cutaneous squamous cell carcinoma (cSCC).
Investigated C3aR1 expression levels in cSCC tumors vs normal skin using Nanostring analysis.
Utilized single cell RNA-seq to examine C3aR1 in immune cells within cSCC tumors.
Performed Western blot analysis and qPCR in 3D spheroid co-cultures of cSCC cells with fibroblasts and macrophages.
Employed immunohistochemical staining on over 400 clinical tissue samples to assess C3aR1 expression.
Found increased C3aR1 mRNA levels in cSCC compared to normal skin.
Identified significant expression of C3aR1 in monocytes and macrophages in cSCC tumors.
Demonstrated that C3a enhanced cSCC cell invasion while its inhibitor reduced invasion.
C3aR1 was expressed predominantly in the most invasive cSCC tumors, classified as Clark level V and AJCC stages III or IV.

Abstract

Abstract Cutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer. The prognosis of metastatic cSCC is poor, highlighting the need for novel molecular markers and therapeutical targets for advanced cSCC. We investigated the role of complement component C3a and its receptor, C3aR1, in cSCC progression. Nanostring analysis showed elevated C3aR1 mRNA levels in cSCC tumors in vivo compared with normal skin. Single cell RNA-seq revealed significant expression of C3aR1 mRNA in monocytes, macrophages and tissue stem cells in cSCC tumors. Western blot analysis, RNA-seq and qPCR of 3D spheroid co-cultures of cSCC cells, fibroblasts and macrophages in a collagen I matrix revealed increased expression of C3aR1 protein and mRNA in the presence of M2-like macrophages. Immunofluorescence staining with a C3aR1-antibody localized C3aR1-positive cSCC cells predominantly to the invasive edges of spheroids. Treatment with recombinant C3a enhanced cSCC cell invasion, whereas the C3aR1 inhibitor SB290157 reduced invasion of cSCC cells in the spheroid co-culture model. Immunohistochemical staining of over 400 clinical tissue samples including normal skin, premalignant lesions (actinic keratoses), cSCC in situ, non-metastatic and metastatic primary cSCC, and metastases, showed C3aR1 expression on tumor cell surfaces in metastatic primary tumors and metastases. All C3aR1-positive primary tumors were classified as Clark level V and AJCC stage III or IV. These results provide evidence for the role of C3a-C3aR1 signaling in cSCC invasion and identify C3aR1 as a potential therapeutic target for locally advanced and metastatic cSCC. Citation Format: Lauri Heiskanen, Liisa Nissinen, Elina Siljamäki, Pekka Rappu, Ujjwal Suwal, Jaakko S. Knuutila, Jutta Huvila, Jyrki Heino, Veli-Matti Kahari, Pilvi Riihilä. C3a-C3aR1 signaling promotes invasion of cutaneous squamous cell carcinoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr LB303.

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