The DNAJB1-PRKACA Oncogenic Fusion Drives Stepwise Biliary and Pancreatic Carcinogenesis from Intraductal Precursor Lesions
Carney, P. R.; Nukaya, M.; Carter, J. A.; Veltri, A. J.; Matkowskyj, K. A.; Stram, A.; Rubinstein, C. D.; Veith, A. C.; Pillarisetty, V. G.; Bradfield, C. A.; Bradfield, C.; Ronnekleiv-Kelly, S.
Show abstract
Intraductal oncocytic papillary neoplasms (IOPNs) are rare tumors that develop from biliary and pancreatic ductal epithelium and progress to lethal cancers. Human IOPNs and IOPN-associated carcinomas are known to harbor the DNAJB1-PRKACA gene fusion, however the role of the oncogenic fusion in carcinogenesis is poorly understood. We developed a Cre-inducible mouse model of human DNAJB1-PRKACA expression and substantiated that the DNAJB1-PRKACA fusion gene is a bona fide driver of IOPN-associated biliary and pancreatic carcinoma. By analyzing the unique histopathologic and transcriptional changes that occur at each stage of tumor development, we found that these murine tumors closely mimic human DNAJB1-PRKACA driven tumors. Furthermore, we identified that many of the salient features of invasive carcinoma are established at the pre-invasive stage, including evidence of tumor cell metabolic dysregulation, immunosuppressive tumor stroma and expression of genes strongly associated with invasive DNAJB1-PRKACA driven cancer in humans. Finally, we found that Slc16a14, a characteristic DNAJB1-PRKACA regulated super-enhancer associated gene, serves as a robust biomarker of malignant transformation from IOPN to invasive carcinoma.
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