Urokinase-type plasminogen activator receptor contributes to chemosensitivity and epithelial-to-mesenchymal transition in PDAC

uPAR and p38 regulate autophagy dependent gemcitabine resistance in AsPC1: autophagy inhibitors and gemcitabine as a potential combined therapy for a subgroup of pancreastic cancers

by Luogen Peng
Doctoral thesis
Date of Examination:2020-11-11
Date of issue:2020-10-26
Advisor:Prof. Dr. Volker Ellenrieder
Referee:Prof. Dr. Philipp Ströbel
Referee:Prof. Dr. Wolfgang Brück
Persistent Address: http://dx.doi.org/10.53846/goediss-8274

 

 

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Abstract

English

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is the most frequent maliganancy of the pancreas and the fourth most lethal cancer with a 5-year overall survival rate of < 5 %. Patients with a gene amplification in the urokinase plasminogen activator receptor (uPAR) gene have a particularly poor prognosis. uPAR signaling has been associated with migration, metastasis and cell proliferation mediated through Ras-ERK signaling. However, in several tumor entities uPAR regulation has been shown to induce cellular dormancy and chemoresistance by altering the ERK and p38MAPK equilibrium. Experimental Design: We created two functionally homozygous uPAR knock out clones of the PDAC cell line AsPC-1 by CRISPR/Cas9 to evaluate the critical function of uPAR in the tumor progression and resistance against chemotherapy. Results: Here we show that in the KRAS mutated cell line ASPC-1 the ablation of uPAR induces a switch from the ERK driven proliferative to a p38MAPK induced cellular dormancy and an autophagy mediated chemoresistance against gemcitabine. Genetic and pharmacological inhibition of FAK, CDC42, p38MAPK and autophagy reversed gemcitabine resistance only in uPAR knock out cells leaving wild type AsPC-1 cells unaffected. Clinical samples with low levels of uPAR and activated p38MAPK correlated with a better prognosis even though activated p38MAPK corresponded to increased autophagy and gemcitabine resistance in vitro. Conclusions: We propose that KRAS mutated PDAC patients with low uPAR and high p38MAPK activity levels represent a subgroup with an improved response to a combination treatment including gemcitabine and autophagy inhibitors.
Keywords: PDAC, uPAR, p38MAPK, autophagy, gemcitabine resistance
 
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