Urokinase-Type Plasminogen Activator Receptor (uPAR) Cooperates with Mutated KRAS in Regulating Cellular Plasticity and Gemcitabine Response in Pancreatic Adenocarcinomas

Luogen Peng; Yuchan Li; Sha Yao; Jochen Gaedcke; Victor M Baart; Cornelis F M Sier; Albrecht Neesse; Volker Ellenrieder; Hanibal Bohnenberger; Frieder Fuchs; Julia Kitz; Philipp Ströbel; Stefan Küffer

doi:10.3390/cancers15051587

Urokinase-Type Plasminogen Activator Receptor (uPAR) Cooperates with Mutated KRAS in Regulating Cellular Plasticity and Gemcitabine Response in Pancreatic Adenocarcinomas

Cancers (Basel). 2023 Mar 3;15(5):1587. doi: 10.3390/cancers15051587.

Authors

Luogen Peng^{1

2}, Yuchan Li¹, Sha Yao^{1

3}, Jochen Gaedcke⁴, Victor M Baart⁵, Cornelis F M Sier⁵, Albrecht Neesse^{6

7}, Volker Ellenrieder⁶, Hanibal Bohnenberger¹, Frieder Fuchs^{1

8

9}, Julia Kitz¹, Philipp Ströbel¹, Stefan Küffer¹

Affiliations

¹ Institute of Pathology, University Medical Center Göttingen, University of Göttingen, 37075 Göttingen, Germany.
² Department of Oncology, Changsha Central Hospital, University of South China, Changsha 410004, China.
³ Department of Pathology, The 3rd Xiangya Hospital, Central South University, Changsha 410013, China.
⁴ Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, 37075 Göttingen, Germany.
⁵ Department of Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
⁶ Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen, 37075 Göttingen, Germany.
⁷ Department of Medicine, Israelitisches Krankenhaus, 22297 Hamburg, Germany.
⁸ Department of Microbiology and Hospital Hygiene, Bundeswehr Central Hospital Koblenz, 56070 Koblenz, Germany.
⁹ Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Medical Faculty and University Hospital of Cologne, 50931 Cologne, Germany.

Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal cancers. Given the currently limited therapeutic options, the definition of molecular subgroups with the development of tailored therapies remains the most promising strategy. Patients with high-level gene amplification of urokinase plasminogen activator receptor (uPAR/PLAUR) have an inferior prognosis. We analyzed the uPAR function in PDAC to understand this understudied PDAC subgroup's biology better.

Methods: A total of 67 PDAC samples with clinical follow-up and TCGA gene expression data from 316 patients were used for prognostic correlations. Gene silencing by CRISPR/Cas9, as well as transfection of uPAR and mutated KRAS, were used in PDAC cell lines (AsPC-1, PANC-1, BxPC3) treated with gemcitabine to study the impact of these two molecules on cellular function and chemoresponse. HNF1A and KRT81 were surrogate markers for the exocrine-like and quasi-mesenchymal subgroup of PDAC, respectively.

Results: High levels of uPAR were correlated with significantly shorter survival in PDAC, especially in the subgroup of HNF1A-positive exocrine-like tumors. uPAR knockout by CRISPR/Cas9 resulted in activation of FAK, CDC42, and p38, upregulation of epithelial makers, decreased cell growth and motility, and resistance against gemcitabine that could be reversed by re-expression of uPAR. Silencing of KRAS in AsPC1 using siRNAs reduced uPAR levels significantly, and transfection of mutated KRAS in BxPC-3 cells rendered the cell more mesenchymal and increased sensitivity towards gemcitabine.

Conclusions: Activation of uPAR is a potent negative prognostic factor in PDAC. uPAR and KRAS cooperate in switching the tumor from a dormant epithelial to an active mesenchymal state, which likely explains the poor prognosis of PDAC with high uPAR. At the same time, the active mesenchymal state is more vulnerable to gemcitabine. Strategies targeting either KRAS or uPAR should consider this potential tumor-escape mechanism.

Keywords: ERK; FAK; KRAS; MEK; dormancy; gemcitabine; pancreatic cancer; uPAR.

Abstract

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