Abstract
Abstract In this study, we aimed to find genes with a key function in the development of molecular subtypes in pancreatic ductal adenocarcinoma (PDAC). Through transcriptome analysis, we discovered that the endogenous serine/cysteine proteinase inhibitor SERPINB3 (squamous cell carcinoma antigen 1, SCCA1) was distinctively upregulated in the basal-like/squamous subtype, known as an aggressive subtype, and this upregulation associated with decreased patient survival in both a test (N=123) and a validation cohort (N=84). In additional investigations of the tumor metabolome and transcriptome using PDAC patient tumors and cell lines, SERPINB3 and the basal-like/squamous subtype showed a robust relationship with upregulated levels of amino acids (e.g., hydroxyproline) whereas SERPINB3 promoted a gene signature indicative of the basal-like/squamous subtype. Additional mechanistic studies revealed that SERPINB3 and hydroxyproline promoted the migration/invasion of PDAC cells. Moreover, SERPINB3 also promoted metastasis in an orthotopic mouse model of PDAC through stromal factors that increased tumor microvessel density. To conclude, inhibiting SERPINB3 function may attenuate disease progression of the basal-like/squamous subtype in PDAC through changes to the tumor stroma and tumor metabolism. Citation Format: Yuuki Ohara, Wei Tang, Liu Huaitian, Shouhui Yang, Peijun He, Helen Cawley, Paloma Valenzuela, Lin Zhang, Jochen Gaedcke, B. Michael Ghadimi, Matthias M. Gaida, Frank Bergmann, H. Richard Alexander, Nader Hanna, Stefan Ambs, S. Perwez Hussain. SERPINB3 promotes the aggressive basal-like/squamous subtype and correlates with poor prognosis in pancreatic ductal adenocarcinoma through metabolic reprogramming [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6225.
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