Pan-Cancer Analysis of PAPPA Gene Reveals Tumor-Specific Prognostic Effects

Pregnancy-associated plasma protein A (PAPPA) is a metalloproteinase that regulates insulin-like growth factor availability via cleavage of IGF-binding proteins, yet its role in cancer remains incompletely understood. Using integrated public datasets, we systematically examined PAPPA expression, prognostic relevance, cellular localization, and stromal associations across multiple tumor types. PAPPA was reduced in several cancers and primarily localized to stromal cells, whereas in cholangiocarcinoma and thyroid carcinoma it was elevated and also detected in malignant cells. High PAPPA expression was associated with poorer overall survival in bladder, cervical, lung squamous, mesothelioma, pancreatic, and gastric cancers, but exhibited a protective effect in lower-grade glioma. In tumors with adverse prognosis, PAPPA strongly correlated with cancer-associated fibroblast (CAF) infiltration and CAF marker genes; however, multivariable Cox analyses indicated that PAPPA generally retained an independent prognostic factor, whereas CAF infiltration was mostly not independently associated with overall survival. Interestingly, in LGG, despite negative PAPPA–CAF correlations, multivariable analysis showed that PAPPA remained protective while CAF infiltration was associated with worse survival. Pathway analyses linked PAPPA-associated genes to proteoglycans in cancer and PI3K–AKT and RAS signaling. Collectively, these findings establish PAPPA as an independent prognostic factor across most cancers, while its expression frequently coincides with high CAF infiltration in select tumor types, highlighting the need for further investigation. © 2026 by the authors.