Proteome Profiling of Primary Pancreatic Ductal Adenocarcinomas Undergoing Additive Chemoradiation Link ALDH1A1 to Early Local Recurrence and Chemoradiation Resistance |
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Authors: | VO Oria P Bronsert AR Thomsen MC Föll C Zamboglou L Hannibal S Behringer ML Biniossek C Schreiber AL Grosu L Bolm D Rades T Keck M Werner UF Wellner O Schilling |
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Institution: | 2. Faculty of Biology, University of Freiburg, Freiburg, Germany;3. Spemann Graduate School of Biology and Medicine, Freiburg, Germany;4. Institute of Surgical Pathology, University Medical Center, Freiburg, Germany;5. German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) Heidelberg, Germany;11. Department of Radiation Oncology, Medical Center – University of Freiburg, Germany;12. Laboratory of Clinical Biochemistry and Metabolism, Department for Pediatrics, Medical Center, University of Freiburg, Freiburg, Germany;8. Institute of Pathology, UKSH Campus Lübeck, Lübeck, Germany;9. Department of Radiation Oncology, UKSH Campus Lübeck, Lübeck, Germany |
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Abstract: | Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis with frequent post-surgical local recurrence. The combination of adjuvant chemotherapy with radiotherapy is under consideration to achieve a prolonged progression-free survival (PFS). To date, few studies have determined the proteome profiles associated with response to adjuvant chemoradiation. We herein analyzed the proteomes of primary PDAC tumors subjected to additive chemoradiation after surgical resection and achieving short PFS (median 6 months) versus prolonged PFS (median 28 months). Proteomic analysis revealed the overexpression of Aldehyde Dehydrogenase 1 Family Member A1 (ALDH1A1) and Monoamine Oxidase A (MAOA) in the short PFS cohort, which were corroborated by immunohistochemistry. In vitro, specific inhibition of ALDH1A1 by A37 in combination with gemcitabine, radiation, and chemoradiation lowered cell viability and augmented cell death in MiaPaCa-2 and Panc 05.04 cells. ALDH1A1 silencing in both cell lines dampened cell proliferation, cell metabolism, and colony formation. In MiaPaCa-2 cells, ALDH1A1 silencing sensitized cells towards treatment with gemcitabine, radiation or chemoradiation. In Panc 05.04, increased cell death was observed upon gemcitabine treatment only. These findings are in line with previous studies that have suggested a role of ALDH1A1 chemoradiation resistance, e.g., in esophageal cancer. In summary, we present one of the first proteome studies to investigate the responsiveness of PDAC to chemoradiation and provide further evidence for a role of ALDH1A1 in therapy resistance. |
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Keywords: | Address all correspondence to: Dr Oliver Schilling Institute of Molecular Medicine and Cell Research Stefan Meier Strasse 17 Freiburg 79104 Germany |
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