Molecular profiling and specific targeting of gemcitabine-resistant subclones in heterogeneous pancreatic cancer cell populations

Frontiers in Oncology

Oncology

Tobias Keck¹  Benedikt Färber¹  Olga Lapshyna¹  Meike ten Winkel¹  Ulrich F. Wellner¹  Kim Honselmann¹  Benjamin Heckelmann¹  Rüdiger Braun¹  Kira Bichmann¹  Jessica Watzelt¹  Louisa Bolm¹  Hendrik Ungefroren²  Hauke Busch³  Axel Künstner³  Michael Kohl⁴  Thorben Sauer⁵  Timo Gemoll⁵ 

[1] Department of Surgery, University Medical Center Schleswig-Holstein, Lübeck, Germany;First Department of Medicine, University Medical Center Schleswig-Holstein, Lübeck, Germany;Institute of Pathology, University Medical Center Schleswig-Holstein, Kiel, Germany;Medical Systems Biology Group, Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany;Institute for Cardiogenetics, University of Lübeck, Lübeck, Germany;Medical Systems Biology Group, Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany;Section for Translational Surgical Oncology & Biobanking, Department of Surgery, University Hospital Schleswig-Holstein, University of Lübeck, Lübeck, Germany;Section for Translational Surgical Oncology & Biobanking, Department of Surgery, University Hospital Schleswig-Holstein, University of Lübeck, Lübeck, Germany;

关键词: pancreatic cancer;    intratumor heterogeneity;    treatment response;    gemcitabine;    chemotherapy;   

DOI  :  10.3389/fonc.2023.1230382

 received in 2023-05-28, accepted in 2023-08-08,  发布年份 2023

来源: Frontiers

【 摘 要 】

PurposeChemotherapy is pivotal in the multimodal treatment of pancreatic ductal adenocarcinoma (PDAC). Technical advances unveiled a high degree of inter- and intratumoral heterogeneity. We hypothesized that intratumoral heterogeneity (ITH) impacts response to gemcitabine treatment and demands specific targeting of resistant subclones.MethodsUsing single cell-derived cell lines (SCDCLs) from the classical cell line BxPC3 and the basal-like cell line Panc-1, we addressed the effect of ITH on response to gemcitabine treatment.ResultsIndividual SCDCLs of both parental tumor cell populations showed considerable heterogeneity in response to gemcitabine. Unsupervised PCA including the 1,000 most variably expressed genes showed a clustering of the SCDCLs according to their respective sensitivity to gemcitabine treatment for BxPC3, while this was less clear for Panc-1. In BxPC3 SCDCLs, enriched signaling pathways EMT, TNF signaling via NfKB, and IL2STAT5 signaling correlated with more resistant behavior to gemcitabine. In Panc-1 SCDCLs MYC targets V1 and V2 as well as E2F targets were associated with stronger resistance. We used recursive feature elimination for Feature Selection in order to compute sets of proteins that showed strong association with the response to gemcitabine. The optimal protein set calculated for Panc-1 comprised fewer proteins in comparison to the protein set determined for BxPC3. Based on molecular profiles, we could show that the gemcitabine-resistant SCDCLs of both BxPC3 and Panc-1 are more sensitive to the BET inhibitor JQ1 compared to the respective gemcitabine-sensitive SCDCLs.ConclusionOur model system of SCDCLs identified gemcitabine-resistant subclones and provides evidence for the critical role of ITH for treatment response in PDAC. We exploited molecular differences as the basis for differential response and used these for more targeted therapy of resistant subclones.

【 授权许可】

Unknown   
Copyright © 2023 Färber, Lapshyna, Künstner, Kohl, Sauer, Bichmann, Heckelmann, Watzelt, Honselmann, Bolm, ten Winkel, Busch, Ungefroren, Keck, Gemoll, Wellner and Braun