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Chromatin Landscape Analysis of Patient PDAC

ABSTRACT: We established a human pluripotent stem cell (hPSC)-derived pancreatic progenitor organoid (PO) culture that provides the cellular plasticity for PDAC modeling and supports robust gene editing. Through the combinatorial expression of oncogenic KRAS and deletion of multiple tumor suppressor genes (TSGs)，we successfully recapitulated the transcriptional hallmarks of initial malignant transformation and progression of PDAC in POs in vitro. Moreover, these POs exhibited distinct histopathology from preneoplastic pancreatic intraepithelial neoplasia (PanIN) and moderately differentiated to poorly differentiated PDAC upon orthotopic transplantation. Further chromatin accessibility profiling unveiled 1) a progressive loss of pancreatic lineage program during disease development, accompanied by repression of TET1, 5hmc marking and hypermethylation of essential pancreatic lineage transcription factors and 2) an emergence of trans-lineage/malignant feature, associated with the opening of AP-1 motif enriched chromatin regions. Gene perturbation screening identified FOSL2, FOS, and JUNB as pro-malignancy AP-1 factors during malignant transformation of POs. Notably, inhibition of ERK, a regulator of AP-1, not only reversed AP-1 levels and malignant feature in transformed POs, but also derepressed TET1 and its associated chromatin regions. Thus, our de novo PDAC POs faithfully model the disease development and reveal distinct but concerted mechanisms that drive the cellular plasticity in PDAC. The comprehensive validation of this model against clinical datasets approves its potential for discovery of therapeutic targets and biomarkers for preventive screening in the future.

ORGANISM(S): Homo sapiens

PROVIDER: GSE272463 | GEO | 2026/04/24

REPOSITORIES: GEO

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Project description:Pancreatic ductal adenocarcinoma (PDAC) is a high lethal cancer with poor prognosis and lack of effective therapeutic options. Chronic metabolic disorders, including obesity and type 2 diabetes, are established risk factors for PDAC and contribute to its unfavorable prognosis. Prolonged exposure to altered metabolic states induces aberrant fluctuations in specific metabolites, which can impact the epigenetic landscape and facilitate the acquisition of neoplastic lesions. Indeed, certain metabolites function as cofactors for epigenetic enzymes, modulating their activity. In this study, we explored the interplay between metabolism and epigenetics in PDAC tumorigenesis under dysmetabolic conditions, aiming to uncover novel vulnerabilities in pancreatic cancer. The link between dysmetabolism and PDAC was examined in LSL-KrasG12D; PDX-1-Cre mice (KC mice) exposed to high-fat diet (HFD). Untargeted metabolomic analysis of pancreatic tissue revealed altered free fatty acid levels and elevated S-adenosyl methionine (SAM) during tumor development in HFD-fed mice. Targeted metabolomics further showed increased succinate (SA) levels alongside reduced α-ketoglutarate (αKG) levels, indicating dysregulation of the DNA methylation pathway. Given these findings, the DNA demethylation complex of ten-to-eleven-translocation methylcytosine 1 (TET1) and thymine DNA glycosylase (TDG) was further investigated in human pancreatic ductal epithelial cells bearing KRAS mutation exposed to dysmetabolic mimicking culture conditions. We demonstrated that dysmetabolic stress disrupts quickly TET1/TDG function, leading to accumulation of iterative cytosine modifications, including 5-formylcytosine (5fC), and increased apurinic/apyrimidinic (AP) sites. Specifically, AP site accumulation was a consequence of TDG hyperactivation induced by direct binding of SA on its arginine residue 275. This TDG alteration, together with the methylation-prone metabolic environment, impairs the base excision repair (BER) pathway by hypermethylation of the promoters of DNA ligases 1 (LIG1) and 3 (LIG3) and thus inducing their downregulation. The resulting inhibition of single-strand break repair predisposes to genomic instability and promotes pancreatic preneoplastic lesion development. Our results reveal an unprecedented role of metabolic-epigenetic crosstalk in dysmetabolism-driven PDAC tumorigenesis. These findings highlight TDG as a novel therapeutic target and propose 5fC and AP sites as potential biomarkers for pancreatic cancer.

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Chromatin Landscape Analysis of Patient PDAC

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