Bcl-xL as prognostic marker and potential therapeutic target in cholangiocarcinoma

Paula Hoffmeister-Wittmann; Andreas Mock; Federico Nichetti; Felix Korell; Christoph E. Heilig; Anna Lena Scherr; Michael Günther; Thomas Albrecht; Eblina Kelmendi; Kaiyu Xu; Luisa Nader; Annika Kessler; Nathalie Schmitt; Sarah Fritzsche; Sofia Weiler; Benjamin Sobol; Albrecht Stenzinger; Stefan Boeck; Christoph B. Westphalen; Klaus Schulze-Osthoff; Jörg Trojan; Thomas Kindler; Wilko Weichert; Karsten Spiekermann; Michael Bitzer; Gunnar Folprecht; Anna L. Illert; Melanie Boerries; Frederick Klauschen; Sebastian Ochsenreither; Jens Siveke; Sebastian Bauer; Hanno Glimm; Benedikt Brors; Jennifer Hüllein; Daniel Hübschmann; Sebastian Uhrig; Peter Horak; Simon Kreutzfeldt; Jesus M. Banales; Christoph Springfeld; Dirk Jäger; Peter Schirmacher; Stephanie Roessler; Steffen Ormanns; Benjamin Goeppert; Stefan Fröhling; Bruno C. Köhler

doi:10.1111/liv.15392

Bcl-x_L as prognostic marker and potential therapeutic target in cholangiocarcinoma

Paula Hoffmeister-Wittmann, Andreas Mock, Federico Nichetti, Felix Korell, Christoph E. Heilig, Anna Lena Scherr, Michael Günther, Thomas Albrecht, Eblina Kelmendi, Kaiyu Xu, Luisa Nader, Annika Kessler, Nathalie Schmitt, Sarah Fritzsche, Sofia Weiler, Benjamin Sobol, Albrecht Stenzinger, Stefan Boeck, Christoph B. Westphalen, Klaus Schulze-OsthoffJörg Trojan, Thomas Kindler, Wilko Weichert, Karsten Spiekermann, Michael Bitzer, Gunnar Folprecht, Anna L. Illert, Melanie Boerries, Frederick Klauschen, Sebastian Ochsenreither, Jens Siveke, Sebastian Bauer, Hanno Glimm, Benedikt Brors, Jennifer Hüllein, Daniel Hübschmann, Sebastian Uhrig, Peter Horak, Simon Kreutzfeldt, Jesus M. Banales, Christoph Springfeld, Dirk Jäger, Peter Schirmacher, Stephanie Roessler, Steffen Ormanns, Benjamin Goeppert, Stefan Fröhling, Bruno C. Köhler

Chair of Pathology

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

Abstract

Intrahepatic, perihilar, and distal cholangiocarcinoma (iCCA, pCCA, dCCA) are highly malignant tumours with increasing mortality rates due to therapy resistances. Among the mechanisms mediating resistance, overexpression of anti-apoptotic Bcl-2 proteins (Bcl-2, Bcl-x_L, Mcl-1) is particularly important. In this study, we investigated whether antiapoptotic protein patterns are prognostically relevant and potential therapeutic targets in CCA. Bcl-2 proteins were analysed in a pan-cancer cohort from the NCT/DKFZ/DKTK MASTER registry trial (n = 1140, CCA n = 72) via RNA-sequencing and transcriptome-based protein activity interference revealing high ranks of CCA for Bcl-x_L and Mcl-1. Expression of Bcl-x_L, Mcl-1, and Bcl-2 was assessed in human CCA tissue and cell lines compared with cholangiocytes by immunohistochemistry, immunoblotting, and quantitative-RT-PCR. Immunohistochemistry confirmed the upregulation of Bcl-x_L and Mcl-1 in iCCA tissues. Cell death of CCA cell lines upon treatment with specific small molecule inhibitors of Bcl-x_L (Wehi-539), of Mcl-1 (S63845), and Bcl-2 (ABT-199), either alone, in combination with each other or together with chemotherapeutics was assessed by flow cytometry. Targeting Bcl-x_L induced cell death and augmented the effect of chemotherapy in CCA cells. Combined inhibition of Bcl-x_L and Mcl-1 led to a synergistic increase in cell death in CCA cell lines. Correlation between Bcl-2 protein expression and survival was analysed within three independent patient cohorts from cancer centers in Germany comprising 656 CCA cases indicating a prognostic value of Bcl-x_L in CCA depending on the CCA subtype. Collectively, these observations identify Bcl-x_L as a key protein in cell death resistance of CCA and may pave the way for clinical application.

Original language	English
Pages (from-to)	2855-2870
Number of pages	16
Journal	Liver International
Volume	42
Issue number	12
DOIs	https://doi.org/10.1111/liv.15392
State	Published - Dec 2022

Keywords

Bcl-2
Bcl-x
Mcl-1
apoptosis
chemotherapy
cholangiocarcinoma

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10.1111/liv.15392

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Hoffmeister-Wittmann, P., Mock, A., Nichetti, F., Korell, F., Heilig, C. E., Scherr, A. L., Günther, M., Albrecht, T., Kelmendi, E., Xu, K., Nader, L., Kessler, A., Schmitt, N., Fritzsche, S., Weiler, S., Sobol, B., Stenzinger, A., Boeck, S., Westphalen, C. B., ... Köhler, B. C. (2022). Bcl-x_L as prognostic marker and potential therapeutic target in cholangiocarcinoma. Liver International, 42(12), 2855-2870. https://doi.org/10.1111/liv.15392

@article{3112b00ead08417483f6f2b8ce16bf01,

title = "Bcl-xL as prognostic marker and potential therapeutic target in cholangiocarcinoma",

abstract = "Intrahepatic, perihilar, and distal cholangiocarcinoma (iCCA, pCCA, dCCA) are highly malignant tumours with increasing mortality rates due to therapy resistances. Among the mechanisms mediating resistance, overexpression of anti-apoptotic Bcl-2 proteins (Bcl-2, Bcl-xL, Mcl-1) is particularly important. In this study, we investigated whether antiapoptotic protein patterns are prognostically relevant and potential therapeutic targets in CCA. Bcl-2 proteins were analysed in a pan-cancer cohort from the NCT/DKFZ/DKTK MASTER registry trial (n = 1140, CCA n = 72) via RNA-sequencing and transcriptome-based protein activity interference revealing high ranks of CCA for Bcl-xL and Mcl-1. Expression of Bcl-xL, Mcl-1, and Bcl-2 was assessed in human CCA tissue and cell lines compared with cholangiocytes by immunohistochemistry, immunoblotting, and quantitative-RT-PCR. Immunohistochemistry confirmed the upregulation of Bcl-xL and Mcl-1 in iCCA tissues. Cell death of CCA cell lines upon treatment with specific small molecule inhibitors of Bcl-xL (Wehi-539), of Mcl-1 (S63845), and Bcl-2 (ABT-199), either alone, in combination with each other or together with chemotherapeutics was assessed by flow cytometry. Targeting Bcl-xL induced cell death and augmented the effect of chemotherapy in CCA cells. Combined inhibition of Bcl-xL and Mcl-1 led to a synergistic increase in cell death in CCA cell lines. Correlation between Bcl-2 protein expression and survival was analysed within three independent patient cohorts from cancer centers in Germany comprising 656 CCA cases indicating a prognostic value of Bcl-xL in CCA depending on the CCA subtype. Collectively, these observations identify Bcl-xL as a key protein in cell death resistance of CCA and may pave the way for clinical application.",

keywords = "Bcl-2, Bcl-x, Mcl-1, apoptosis, chemotherapy, cholangiocarcinoma",

author = "Paula Hoffmeister-Wittmann and Andreas Mock and Federico Nichetti and Felix Korell and Heilig, {Christoph E.} and Scherr, {Anna Lena} and Michael G{\"u}nther and Thomas Albrecht and Eblina Kelmendi and Kaiyu Xu and Luisa Nader and Annika Kessler and Nathalie Schmitt and Sarah Fritzsche and Sofia Weiler and Benjamin Sobol and Albrecht Stenzinger and Stefan Boeck and Westphalen, {Christoph B.} and Klaus Schulze-Osthoff and J{\"o}rg Trojan and Thomas Kindler and Wilko Weichert and Karsten Spiekermann and Michael Bitzer and Gunnar Folprecht and Illert, {Anna L.} and Melanie Boerries and Frederick Klauschen and Sebastian Ochsenreither and Jens Siveke and Sebastian Bauer and Hanno Glimm and Benedikt Brors and Jennifer H{\"u}llein and Daniel H{\"u}bschmann and Sebastian Uhrig and Peter Horak and Simon Kreutzfeldt and Banales, {Jesus M.} and Christoph Springfeld and Dirk J{\"a}ger and Peter Schirmacher and Stephanie Roessler and Steffen Ormanns and Benjamin Goeppert and Stefan Fr{\"o}hling and K{\"o}hler, {Bruno C.}",

note = "Publisher Copyright: {\textcopyright} 2022 The Authors. Liver International published by John Wiley & Sons Ltd.",

year = "2022",

month = dec,

doi = "10.1111/liv.15392",

language = "English",

volume = "42",

pages = "2855--2870",

journal = "Liver International",

issn = "1478-3223",

publisher = "Wiley-Blackwell Publishing Ltd",

number = "12",

}

Hoffmeister-Wittmann, P, Mock, A, Nichetti, F, Korell, F, Heilig, CE, Scherr, AL, Günther, M, Albrecht, T, Kelmendi, E, Xu, K, Nader, L, Kessler, A, Schmitt, N, Fritzsche, S, Weiler, S, Sobol, B, Stenzinger, A, Boeck, S, Westphalen, CB, Schulze-Osthoff, K, Trojan, J, Kindler, T, Weichert, W, Spiekermann, K, Bitzer, M, Folprecht, G, Illert, AL, Boerries, M, Klauschen, F, Ochsenreither, S, Siveke, J, Bauer, S, Glimm, H, Brors, B, Hüllein, J, Hübschmann, D, Uhrig, S, Horak, P, Kreutzfeldt, S, Banales, JM, Springfeld, C, Jäger, D, Schirmacher, P, Roessler, S, Ormanns, S, Goeppert, B, Fröhling, S & Köhler, BC 2022, 'Bcl-x_L as prognostic marker and potential therapeutic target in cholangiocarcinoma', Liver International, vol. 42, no. 12, pp. 2855-2870. https://doi.org/10.1111/liv.15392

TY - JOUR

T1 - Bcl-xL as prognostic marker and potential therapeutic target in cholangiocarcinoma

AU - Hoffmeister-Wittmann, Paula

AU - Mock, Andreas

AU - Nichetti, Federico

AU - Korell, Felix

AU - Heilig, Christoph E.

AU - Scherr, Anna Lena

AU - Günther, Michael

AU - Albrecht, Thomas

AU - Kelmendi, Eblina

AU - Xu, Kaiyu

AU - Nader, Luisa

AU - Kessler, Annika

AU - Schmitt, Nathalie

AU - Fritzsche, Sarah

AU - Weiler, Sofia

AU - Sobol, Benjamin

AU - Stenzinger, Albrecht

AU - Boeck, Stefan

AU - Westphalen, Christoph B.

AU - Schulze-Osthoff, Klaus

AU - Trojan, Jörg

AU - Kindler, Thomas

AU - Weichert, Wilko

AU - Spiekermann, Karsten

AU - Bitzer, Michael

AU - Folprecht, Gunnar

AU - Illert, Anna L.

AU - Boerries, Melanie

AU - Klauschen, Frederick

AU - Ochsenreither, Sebastian

AU - Siveke, Jens

AU - Bauer, Sebastian

AU - Glimm, Hanno

AU - Brors, Benedikt

AU - Hüllein, Jennifer

AU - Hübschmann, Daniel

AU - Uhrig, Sebastian

AU - Horak, Peter

AU - Kreutzfeldt, Simon

AU - Banales, Jesus M.

AU - Springfeld, Christoph

AU - Jäger, Dirk

AU - Schirmacher, Peter

AU - Roessler, Stephanie

AU - Ormanns, Steffen

AU - Goeppert, Benjamin

AU - Fröhling, Stefan

AU - Köhler, Bruno C.

PY - 2022/12

Y1 - 2022/12

N2 - Intrahepatic, perihilar, and distal cholangiocarcinoma (iCCA, pCCA, dCCA) are highly malignant tumours with increasing mortality rates due to therapy resistances. Among the mechanisms mediating resistance, overexpression of anti-apoptotic Bcl-2 proteins (Bcl-2, Bcl-xL, Mcl-1) is particularly important. In this study, we investigated whether antiapoptotic protein patterns are prognostically relevant and potential therapeutic targets in CCA. Bcl-2 proteins were analysed in a pan-cancer cohort from the NCT/DKFZ/DKTK MASTER registry trial (n = 1140, CCA n = 72) via RNA-sequencing and transcriptome-based protein activity interference revealing high ranks of CCA for Bcl-xL and Mcl-1. Expression of Bcl-xL, Mcl-1, and Bcl-2 was assessed in human CCA tissue and cell lines compared with cholangiocytes by immunohistochemistry, immunoblotting, and quantitative-RT-PCR. Immunohistochemistry confirmed the upregulation of Bcl-xL and Mcl-1 in iCCA tissues. Cell death of CCA cell lines upon treatment with specific small molecule inhibitors of Bcl-xL (Wehi-539), of Mcl-1 (S63845), and Bcl-2 (ABT-199), either alone, in combination with each other or together with chemotherapeutics was assessed by flow cytometry. Targeting Bcl-xL induced cell death and augmented the effect of chemotherapy in CCA cells. Combined inhibition of Bcl-xL and Mcl-1 led to a synergistic increase in cell death in CCA cell lines. Correlation between Bcl-2 protein expression and survival was analysed within three independent patient cohorts from cancer centers in Germany comprising 656 CCA cases indicating a prognostic value of Bcl-xL in CCA depending on the CCA subtype. Collectively, these observations identify Bcl-xL as a key protein in cell death resistance of CCA and may pave the way for clinical application.

AB - Intrahepatic, perihilar, and distal cholangiocarcinoma (iCCA, pCCA, dCCA) are highly malignant tumours with increasing mortality rates due to therapy resistances. Among the mechanisms mediating resistance, overexpression of anti-apoptotic Bcl-2 proteins (Bcl-2, Bcl-xL, Mcl-1) is particularly important. In this study, we investigated whether antiapoptotic protein patterns are prognostically relevant and potential therapeutic targets in CCA. Bcl-2 proteins were analysed in a pan-cancer cohort from the NCT/DKFZ/DKTK MASTER registry trial (n = 1140, CCA n = 72) via RNA-sequencing and transcriptome-based protein activity interference revealing high ranks of CCA for Bcl-xL and Mcl-1. Expression of Bcl-xL, Mcl-1, and Bcl-2 was assessed in human CCA tissue and cell lines compared with cholangiocytes by immunohistochemistry, immunoblotting, and quantitative-RT-PCR. Immunohistochemistry confirmed the upregulation of Bcl-xL and Mcl-1 in iCCA tissues. Cell death of CCA cell lines upon treatment with specific small molecule inhibitors of Bcl-xL (Wehi-539), of Mcl-1 (S63845), and Bcl-2 (ABT-199), either alone, in combination with each other or together with chemotherapeutics was assessed by flow cytometry. Targeting Bcl-xL induced cell death and augmented the effect of chemotherapy in CCA cells. Combined inhibition of Bcl-xL and Mcl-1 led to a synergistic increase in cell death in CCA cell lines. Correlation between Bcl-2 protein expression and survival was analysed within three independent patient cohorts from cancer centers in Germany comprising 656 CCA cases indicating a prognostic value of Bcl-xL in CCA depending on the CCA subtype. Collectively, these observations identify Bcl-xL as a key protein in cell death resistance of CCA and may pave the way for clinical application.

KW - Bcl-2

KW - Bcl-x

KW - Mcl-1

KW - apoptosis

KW - chemotherapy

KW - cholangiocarcinoma

UR - http://www.scopus.com/inward/record.url?scp=85137860255&partnerID=8YFLogxK

U2 - 10.1111/liv.15392

DO - 10.1111/liv.15392

M3 - Article

C2 - 35983950

AN - SCOPUS:85137860255

SN - 1478-3223

VL - 42

SP - 2855

EP - 2870

JO - Liver International

JF - Liver International

IS - 12

ER -

Bcl-x_L as prognostic marker and potential therapeutic target in cholangiocarcinoma

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