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

Benedikt Färber; Olga Lapshyna; Axel Künstner; Michael Kohl; Thorben Sauer; Kira Bichmann; Benjamin Heckelmann; Jessica Watzelt; Kim Honselmann; Louisa Bolm; Meike ten Winkel; Hauke Busch; Hendrik Ungefroren; Tobias Keck; Timo Gemoll; Ulrich F. Wellner; Rüdiger Braun

doi:10.3389/fonc.2023.1230382

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

Benedikt Färber, Olga Lapshyna, Axel Künstner, Michael Kohl, Thorben Sauer, Kira Bichmann, Benjamin Heckelmann, Jessica Watzelt, Kim Honselmann, Louisa Bolm, Meike ten Winkel, Hauke Busch, Hendrik Ungefroren, Tobias Keck, Timo Gemoll, Ulrich F. Wellner, Rüdiger Braun^*

^*Corresponding author for this work

University of Kiel

3 Citations (Scopus)

Abstract

Purpose: Chemotherapy 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. Methods: Using 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. Results: Individual 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. Conclusion: Our 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.

Original language	English
Article number	1230382
Journal	Frontiers in Oncology
Volume	13
Pages (from-to)	1230382
ISSN	2234-943X
DOIs	https://doi.org/10.3389/fonc.2023.1230382
Publication status	Published - 2023

Funding

This work was supported in part by grants from the German Research Foundation (DFG) through the Clinician Scientist School Lübeck (DFG #413535489), the Junior Funding Program of the University of Lübeck, and the Brigitte and Dr. Konstanze Wegener Foundation (project # 81). AK acknowledges computational support from the OMICS compute cluster at the University of Lübeck. BF is grateful for the support from the doctoral scholarship "Lübeck Medicine of Excellence" and TS for the support from the Ad Infinitum Foundation. We acknowledge financial support by Land Schleswig-Holstein within the funding program Open Access Publikationsfonds. Acknowledgments

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Research Areas and Centers

Research Area: Luebeck Integrated Oncology Network (LION)
Centers: University Cancer Center Schleswig-Holstein (UCCSH)

DFG Research Classification Scheme

2.22-14 Hematology, Oncology

Access to Document

10.3389/fonc.2023.1230382

Cite this

Färber, B., Lapshyna, O., Künstner, A., Kohl, M., Sauer, T., Bichmann, K., Heckelmann, B., Watzelt, J., Honselmann, K., Bolm, L., ten Winkel, M., Busch, H., Ungefroren, H., Keck, T., Gemoll, T., Wellner, U. F., & Braun, R. (2023). Molecular profiling and specific targeting of gemcitabine-resistant subclones in heterogeneous pancreatic cancer cell populations. Frontiers in Oncology, 13, 1230382. Article 1230382. https://doi.org/10.3389/fonc.2023.1230382

@article{112c0f82bb904c24a23c990977c24917,

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

abstract = "Purpose: Chemotherapy 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. Methods: Using 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. Results: Individual 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. Conclusion: Our 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.",

author = "Benedikt F{\"a}rber and Olga Lapshyna and Axel K{\"u}nstner and Michael Kohl and Thorben Sauer and Kira Bichmann and Benjamin Heckelmann and Jessica Watzelt and Kim Honselmann and Louisa Bolm and \{ten Winkel\}, Meike and Hauke Busch and Hendrik Ungefroren and Tobias Keck and Timo Gemoll and Wellner, \{Ulrich F.\} and R{\"u}diger Braun",

note = "Publisher Copyright: Copyright {\textcopyright} 2023 F{\"a}rber, Lapshyna, K{\"u}nstner, Kohl, Sauer, Bichmann, Heckelmann, Watzelt, Honselmann, Bolm, ten Winkel, Busch, Ungefroren, Keck, Gemoll, Wellner and Braun.",

year = "2023",

doi = "10.3389/fonc.2023.1230382",

language = "English",

volume = "13",

pages = "1230382",

journal = "Frontiers in Oncology",

issn = "2234-943X",

}

Färber, B, Lapshyna, O, Künstner, A, Kohl, M, Sauer, T , Bichmann, K, Heckelmann, B, Watzelt, J, Honselmann, K, Bolm, L , ten Winkel, M , Busch, H, Ungefroren, H, Keck, T , Gemoll, T , Wellner, UF & Braun, R 2023, 'Molecular profiling and specific targeting of gemcitabine-resistant subclones in heterogeneous pancreatic cancer cell populations', Frontiers in Oncology, vol. 13, 1230382, pp. 1230382. https://doi.org/10.3389/fonc.2023.1230382

TY - JOUR

T1 - Molecular profiling and specific targeting of gemcitabine-resistant subclones in heterogeneous pancreatic cancer cell populations

AU - Färber, Benedikt

AU - Lapshyna, Olga

AU - Künstner, Axel

AU - Kohl, Michael

AU - Sauer, Thorben

AU - Bichmann, Kira

AU - Heckelmann, Benjamin

AU - Watzelt, Jessica

AU - Honselmann, Kim

AU - Bolm, Louisa

AU - ten Winkel, Meike

AU - Busch, Hauke

AU - Ungefroren, Hendrik

AU - Keck, Tobias

AU - Gemoll, Timo

AU - Wellner, Ulrich F.

AU - Braun, Rüdiger

PY - 2023

Y1 - 2023

N2 - Purpose: Chemotherapy 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. Methods: Using 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. Results: Individual 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. Conclusion: Our 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.

AB - Purpose: Chemotherapy 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. Methods: Using 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. Results: Individual 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. Conclusion: Our 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.

UR - https://www.scopus.com/pages/publications/85171266467

U2 - 10.3389/fonc.2023.1230382

DO - 10.3389/fonc.2023.1230382

M3 - Journal articles

C2 - 37719017

AN - SCOPUS:85171266467

SN - 2234-943X

VL - 13

SP - 1230382

JO - Frontiers in Oncology

JF - Frontiers in Oncology

M1 - 1230382

ER -

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

Abstract

Funding

UN SDGs

Research Areas and Centers

DFG Research Classification Scheme

Access to Document

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