Key result
High ANGPTL4 expression in pancreatic ductal adenocarcinoma is linked to reduced overall survival.
Why the study?
Pancreatic ductal adenocarcinoma has poor survival rates, increased ANGPTL4 expression correlates with poor outcomes, and identifying genes contributing to chemoresistance could provide novel therapeutic targets.
Cohort (n=178)
p-value: p=0.043
ANGPTL4 overexpression promotes gemcitabine resistance and cell migration in pancreatic cancer, which can be reversed by targeting its downstream effectors ITGB4 and APOL1.
May identify chemoresistant PDAC subsets via ANGPTL4; hypothesis-generating and requires prospective validation.
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers based on five-year survival rates. Genes contributing to chemoresistance represent novel therapeutic targets that can improve treatment response. Increased expression of ANGPTL4 in tumors correlates with poor outcomes in pancreatic cancer. METHODS: We used statistical analysis of publicly available gene expression data (TCGA-PAAD) to test whether expression of ANGPTL4 and its downstream targets, ITGB4 and APOL1, were correlated with patient survival. We measured the impact of ANGPTL4 overexpression in a common pancreatic cancer cell line, MIA PaCa-2 cells, using CRISPRa for overexpression and DsiRNA for knockdown. We characterized global gene expression changes associated with high levels of ANGPTL4 and response to gemcitabine treatment using RNA-sequencing. Gemcitabine dose response curves were calculated on modified cell lines by measuring cell viability with CellTiter-Glo (Promega). Impacts on cell migration were measured using a time course scratch assay. RESULTS: We show that ANGPTL4 overexpression leads to in vitro resistance to gemcitabine and reduced survival times in patients. Overexpression of ANGPTL4 induces transcriptional signatures of tumor invasion and metastasis, proliferation and differentiation, and inhibition of apoptosis. Analyses revealed an overlapping signature of genes associated with both ANGPTL4 activation and gemcitabine response. Increased expression of the genes in this signature in patient PDAC tissues was significantly associated with shorter patient survival. We identified 42 genes that were both co-regulated with ANGPTL4 and were responsive to gemcitabine treatment. ITGB4 and APOL1 were among these genes. Knockdown of either of these genes in cell lines overexpressing ANGPTL4 reversed the observed gemcitabine resistance and inhibited cellular migration associated with epithelial to mesenchymal transition (EMT) and ANGPTL4 overexpression. CONCLUSIONS: These data suggest that ANGPTL4 promotes EMT and regulates the genes APOL1 and ITGB4. Importantly, we show that inhibition of both targets reverses chemoresistance and decreases migratory potential. Our findings have revealed a novel pathway regulating tumor response to treatment and suggest relevant therapeutic targets in pancreatic cancer.
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Gordon et al. (2023) conducted a cohort in Pancreatic ductal adenocarcinoma (n=178). High ANGPTL4 expression vs. Low ANGPTL4 expression was evaluated on Overall survival (p=0.043). High expression of ANGPTL4 in pancreatic ductal adenocarcinoma tumor tissue was significantly associated with reduced overall survival compared to low expression.
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