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

## TL;DR

This study shows that the PAPPA gene's expression in stromal cells is linked to cancer prognosis, with mixed effects depending on cancer type.

## Contribution

The study reveals PAPPA's tumor-specific prognostic effects and its association with cancer-associated fibroblasts in the tumor microenvironment.

## Key findings

- High PAPPA expression correlates with poor survival in pancreatic and lung cancers but improved survival in some brain tumors.
- PAPPA is primarily expressed in stromal cells rather than cancer cells in most tumors.
- PAPPA remains an independent prognostic factor even when cancer-associated fibroblast infiltration is considered.

## Abstract

Pregnancy-associated plasma protein A (PAPPA) is important for normal fetal development, but its exact role in cancer has been unclear. In this study, we analyzed PAPPA across many cancer types to understand how it relates to tumor progression and patient survival. We found that in many tumors, PAPPA is produced not by the cancer cells themselves but by surrounding connective or stromal cells, which can help shape a tumor-supportive environment. PAPPA is linked to worse outcomes in most cancers, while in others it is associated with better survival. Higher PAPPA levels in cancers such as pancreatic and lung cancer were generally associated with poorer prognosis, whereas in certain brain tumors they were linked to improved survival. These findings suggest that PAPPA may serve as a useful biomarker for assessing tumor aggressiveness and highlight the importance of the tumor microenvironment. Understanding how cancers interact with nearby healthy cells may help clinicians better predict patient risk and inform strategies that target this supportive environment.

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.