Pregnancy-associated plasma protein-A drives melanoma metastasis and immune evasion via IGF signaling

Background Melanoma is one of the most common cancers diagnosed during pregnancy. Pregnancy-associated plasma protein-A (PAPPA) is a secreted metalloproteinase that increases local insulin-like growth factor (IGF) bioavailability via proteolytic cleavage of IGF-binding protein 4 (IGFBP-4) to induce PI3K/AKT signaling. While the PAPPA/IGF axis has been implicated in tumor progression of several cancer types, its role in melanoma remains poorly defined. Methods We first examined PAPPA gene alterations in primary and metastatic melanomas using the cBioPortal database. We next generated PAPPA model systems using knocking out and overexpression in melanoma cells. Functional PAPPA/IGF axis were assessed via western blot and flow cytometry. Metastatic phenotypes were evaluated using MTS, wound-healing, and Transwell assays. Immune-related effects were investigated by analyzing tumoural expression of human leukocyte antigen (HLA)-ABC and assessing IGF-induced proliferation of patient-derived regulatory T cells (Tregs) using flow cytometry. Results Gain-of-function variants in PAPPA were enriched in metastatic melanoma relative to primary tumors. Functional analyses confirmed active PAPPA/IGF signaling in melanoma, with pathway disruption leading to reduced proliferation, migration, and invasion capacity. Moreover, PAPPA/IGF signaling was revealed to exert immunosuppressive effects including HLA-ABC downregulation and increased Treg proliferation. Conclusion These findings identify a functional PAPPA/IGF axis in melanoma that supports both metastatic progression and immune evasion, highlighting PAPPA as a potential therapeutic target.