Kynureninase Is a Prognostic Biomarker of Poor Survival and Gemcitabine Resistance in Pancreatic Ductal Adenocarcinoma
8 affiliations
- 1Department of General, Visceral, Transplant and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
- 2Institute of Pathology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
- 3Section of Molecular Immunology und Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
- 4Department of Surgery, Division of General Surgery, University of British Columbia, Vancouver, BC V5Z 1M9, Canada
- 5Department of Urologic Sciences, University of British Columbia, Vancouver, BC V5Z 1M9, Canada
- 6Department of Biomedicine, University of Bergen, 5020 Bergen, Norway
- 7Mass Spectrometric Proteomics—Institute for Clinical Chemistry & Laboratory Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
- 8Department of General and Visceral Surgery, University Medical Center Oldenburg, 26133 Oldenburg, Germany
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies, largely due to intrinsic or acquired resistance to systemic therapy. In addition to dysregulated glucose metabolism, emerging evidence implicates amino acid metabolism as a key determinant of tumor growth and treatment adaptation. To identify biomarkers associated with chemoresistance, we performed SILAC-based mass spectrometry secretome profiling of gemcitabine-resistant and chemosensitive PDAC cell models, followed by qRT-PCR and immunoblot validation. Functional relevance was assessed by stable shRNA-mediated KYNU knockdown, proliferation assays, and Transwell migration assays. Clinical significance was evaluated by immunohistochemical analysis of KYNU expression in a PDAC tissue microarray (n = 368) and correlation with overall survival. Transcriptomic and pathway enrichment analyses were used to characterize resistance-associated programs. Kynureninase (KYNU), a tryptophan-catabolic enzyme, was upregulated and preferentially secreted by gemcitabine-resistant cells and induced by gemcitabine, interferon-γ, and hypoxia. KYNU knockdown significantly reduced proliferation without affecting migration. Resistant cells displayed higher KYNU expression and a broader therapy-adapted cellular state. In patient samples, high KYNU expression was associated with significantly shorter overall survival (p = 0.0198). These findings identify KYNU as a marker of a therapy-adapted PDAC phenotype and support its potential as a prognostic and treatment-response biomarker.
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BibTeX
@article{mercanoglu2026kynureninase,
title = {{Kynureninase Is a Prognostic Biomarker of Poor Survival and Gemcitabine Resistance in Pancreatic Ductal Adenocarcinoma}},
author = {Baris Mercanoglu and Nina Schraps and Anastasios D. Giannou and Siwen Zhang and Eleftherios D. Papazoglou and Cornelia Schroeder and Ziyang Hong and Marcel Kwiatkowski and Hartmut Schlüter and Faik Güntac Uzunoglu and Rainer Grotelüschen and Nathaniel Melling and Maximilian Bockhorn and Thilo Hackert and Gerrit Wolters-Eisfeld and Cenap Güngör},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = nov,
doi = {10.3390/ijms27219820},
url = {https://www.mdpi.com/1422-0067/27/21/9820},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Kynureninase Is a Prognostic Biomarker of Poor Survival and Gemcitabine Resistance in Pancreatic Ductal Adenocarcinoma
AU - Baris Mercanoglu
AU - Nina Schraps
AU - Anastasios D. Giannou
AU - Siwen Zhang
AU - Eleftherios D. Papazoglou
AU - Cornelia Schroeder
AU - Ziyang Hong
AU - Marcel Kwiatkowski
AU - Hartmut Schlüter
AU - Faik Güntac Uzunoglu
AU - Rainer Grotelüschen
AU - Nathaniel Melling
AU - Maximilian Bockhorn
AU - Thilo Hackert
AU - Gerrit Wolters-Eisfeld
AU - Cenap Güngör
PY - 2026
DA - 2026/11/01
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27219820
UR - https://www.mdpi.com/1422-0067/27/21/9820
AB - Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies, largely due to intrinsic or acquired resistance to systemic therapy. In addition to dysregulated glucose metabolism, emerging evidence implicates amino acid metabolism as a key determinant of tumor growth and treatment adaptation. To identify biomarkers associated with chemoresistance, we performed SILAC-based mass spectrometry secretome profiling of gemcitabine-resistant and chemosensitive PDAC cell models, followed by qRT-PCR and immunoblot validation. Functional relevance was assessed by stable shRNA-mediated KYNU knockdown, proliferation assays, and Transwell migration assays. Clinical significance was evaluated by immunohistochemical analysis of KYNU expression in a PDAC tissue microarray (n = 368) and correlation with overall survival. Transcriptomic and pathway enrichment analyses were used to characterize resistance-associated programs. Kynureninase (KYNU), a tryptophan-catabolic enzyme, was upregulated and preferentially secreted by gemcitabine-resistant cells and induced by gemcitabine, interferon-γ, and hypoxia. KYNU knockdown significantly reduced proliferation without affecting migration. Resistant cells displayed higher KYNU expression and a broader therapy-adapted cellular state. In patient samples, high KYNU expression was associated with significantly shorter overall survival (p = 0.0198). These findings identify KYNU as a marker of a therapy-adapted PDAC phenotype and support its potential as a prognostic and treatment-response biomarker.
SN - 1422-0067
ER -