Clinical and Functional Impact of CHMP3 in Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with limited treatment options. Charged multivesicular body protein 3 (CHMP3), a core component of ESCRT-III, is involved in membrane remodeling. However, its clinical and biological relevance in PDAC remained unclear. This study evaluated the prognostic association and functional relevance of CHMP3 in PDAC.

CHMP3 expression and clinical outcomes were analyzed using TCGA and CPTAC3 datasets. Protein expression was assessed by immunohistochemistry in a retrospective cohort of resected PDAC. Additional prognostic information was evaluated using concordance indices. Functional analyses were performed using siRNA-mediated CHMP3 knockdown in MIAPaCa-2 and PANC-1 cells. Single-cell RNA sequencing data assessed cell type-specific expression.

CHMP3 expression was elevated in PDAC and associated with worse overall and disease-free survival in the TCGA and IHC cohorts. In the immunohistochemical cohort, higher CHMP3 expression was associated with poorer outcomes and modestly improved clinicopathologic prediction models. However, CHMP3-high status was substantially imbalanced with nonreceipt of adjuvant chemotherapy, limiting separation of CHMP3-related prognostic effects from treatment-related confounding. In vitro, CHMP3 knockdown suppressed cell proliferation, colony formation, and migration, and increased gemcitabine sensitivity. Single-cell RNA-seq showed CHMP3 enrichment in tumor epithelial and stromal/CAF populations relative to immune cells.

CHMP3 expression is associated with poor outcomes in PDAC and may provide modest additional prognostic information when combined with conventional factors, although residual confounding by adjuvant therapy cannot be excluded. These findings support the biological relevance of CHMP3 and suggest that CHMP3 may represent a prognosis-associated marker requiring external validation.