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Identification of a dihydroartemisinin-related prognostic signature and its contribution to the tumor microenvironment of pancreatic cancer

ABSTRACT: Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by high metastatic potential and a stroma-rich tumor microenvironment (TME). Dihydroartemisinin (DHA) has shown antitumor potential in various cancers, but its therapeutic effects on the TME of PDAC are not yet understood. Methods: DHA-related differentially expressed genes (DEGs) were identified by high-throughput RNA sequencing in PDAC cells and utilized to explore the biological functions of DHA. The clinical value of DHA was examined by constructing a prognostic risk model using the TCGA dataset. We identified SERPINB5 as a downstream target of DHA involved in TME remodeling through cancer-associated fibroblast (CAF) regulation. The clinical value of SERPINB5 was validated through prognostic risk modeling and immunohistochemistry staining. Results: Our findings indicate that DHA may affect CAF-mediated TME remodeling. Prognostic risk modeling indicates that DHA was associated with PDAC prognosis, implying its clinical potential. DHA may improve the prognosis of PDAC patients by downregulating the expression of SERPINB5, which may participate in regulating CAFs. Conclusions: This study suggests that DHA might improve the prognosis of PDAC patients, and it may influence the PDAC TME by downregulating SERPINB5, offering new insights into DHA's antitumor mechanisms and its potential clinical applications in PDAC treatment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE285958 | GEO | 2026/01/31

REPOSITORIES: GEO

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Project description:Immunotherapeutics represent highly promising agents with the potential to improve patient outcomes in a variety of cancer types. Unfortunately, single-agent immunotherapy has achieved limited clinical benefit to date in patients suffering from pancreatic ductal adenocarcinoma (PDAC). This may be due to the presence of a uniquely immunosuppressive tumor microenvironment (TME) present in PDACs, which creates a barrier to effective immune surveillance. Critical obstacles to immunotherapy in PDAC tumors include the dense desmoplastic stroma that acts as a barrier to T-cell infiltration and the high numbers of tumor-associated immunosuppressive cells. We have identified hyperactivated focal adhesion kinase (FAK) activity in neoplastic PDAC cells as a significant regulator of the fibrotic and immunosuppressive TME. We found that FAK activity was elevated in human PDAC tissues and correlates with high levels of fibrosis and poor CD8+ cytotoxic T-cell infiltration. Single-agent FAK inhibition (VS-4718) dramatically limited tumor progression, resulting in a doubling of survival in the p48-Cre/LSL-KrasG12D/p53Flox/+ (KPC) mouse model of human PDAC. This alteration in tumor progression was associated with dramatically reduced tumor fibrosis, decreased numbers of tumor-infiltrating immature myeloid cells and immunosuppressive macrophages. We postulated that these desirable effects of FAK inhibition on the TME might render PDAC tumors more sensitive to immunotherapy. Accordingly, we found that VS-4718 rendered the previously unresponsive KPC mouse model responsive to anti-PD1 and anti-CTLA4 antagonists leading to a nearly tripling of survival times. These data suggest that FAK inhibition increases immune surveillance by overcoming the fibrotic and immunosuppressive PDAC TME thus rendering tumors more responsive to immunotherapy. We treated KP orthotopic tumor-bearing mice with vehicle and FAK inhibitor (FAKi) for 14 days, then extracted total RNA from tumor tissues.

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Identification of a dihydroartemisinin-related prognostic signature and its contribution to the tumor microenvironment of pancreatic cancer

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