Kupffer Cell-Derived Tnf Triggers Cholangiocellular Tumorigenesis through JNK due to Chronic Mitochondrial Dysfunction and ROS

Detian Yuan; Shan Huang; Emanuel Berger; Lei Liu; Nina Gross; Florian Heinzmann; Marc Ringelhan; Tracy O. Connor; Mira Stadler; Michael Meister; Julia Weber; Rupert Öllinger; Nicole Simonavicius; Florian Reisinger; Daniel Hartmann; Rüdiger Meyer; Maria Reich; Marco Seehawer; Valentina Leone; Bastian Höchst; Dirk Wohlleber; Simone Jörs; Marco Prinz; Duncan Spalding; Ulrike Protzer; Tom Luedde; Luigi Terracciano; Matthias Matter; Thomas Longerich; Percy Knolle; Thomas Ried; Verena Keitel; Fabian Geisler; Kristian Unger; Einat Cinnamon; Eli Pikarsky; Norbert Hüser; Roger J. Davis; Darjus F. Tschaharganeh; Roland Rad; Achim Weber; Lars Zender; Dirk Haller; Mathias Heikenwalder

doi:10.1016/j.ccell.2017.05.006

Kupffer Cell-Derived Tnf Triggers Cholangiocellular Tumorigenesis through JNK due to Chronic Mitochondrial Dysfunction and ROS

Detian Yuan, Shan Huang, Emanuel Berger, Lei Liu, Nina Gross, Florian Heinzmann, Marc Ringelhan, Tracy O. Connor, Mira Stadler, Michael Meister, Julia Weber, Rupert Öllinger, Nicole Simonavicius, Florian Reisinger, Daniel Hartmann, Rüdiger Meyer, Maria Reich, Marco Seehawer, Valentina Leone, Bastian HöchstDirk Wohlleber, Simone Jörs, Marco Prinz, Duncan Spalding, Ulrike Protzer, Tom Luedde, Luigi Terracciano, Matthias Matter, Thomas Longerich, Percy Knolle, Thomas Ried, Verena Keitel, Fabian Geisler, Kristian Unger, Einat Cinnamon, Eli Pikarsky, Norbert Hüser, Roger J. Davis, Darjus F. Tschaharganeh, Roland Rad, Achim Weber, Lars Zender, Dirk Haller^*, Mathias Heikenwalder

^*Corresponding author for this work

Department of Immunology and Cancer Research

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

150 Scopus citations

Abstract

Intrahepatic cholangiocarcinoma (ICC) is a highly malignant, heterogeneous cancer with poor treatment options. We found that mitochondrial dysfunction and oxidative stress trigger a niche favoring cholangiocellular overgrowth and tumorigenesis. Liver damage, reactive oxygen species (ROS) and paracrine tumor necrosis factor (Tnf) from Kupffer cells caused JNK-mediated cholangiocellular proliferation and oncogenic transformation. Anti-oxidant treatment, Kupffer cell depletion, Tnfr1 deletion, or JNK inhibition reduced cholangiocellular pre-neoplastic lesions. Liver-specific JNK1/2 deletion led to tumor reduction and enhanced survival in Akt/Notch- or p53/Kras-induced ICC models. In human ICC, high Tnf expression near ICC lesions, cholangiocellular JNK-phosphorylation, and ROS accumulation in surrounding hepatocytes are present. Thus, Kupffer cell-derived Tnf favors cholangiocellular proliferation/differentiation and carcinogenesis. Targeting the ROS/Tnf/JNK axis may provide opportunities for ICC therapy.

Original language	English
Pages (from-to)	771-789.e6
Journal	Cancer Cell
Volume	31
Issue number	6
DOIs	https://doi.org/10.1016/j.ccell.2017.05.006
State	Published - 12 Jun 2017

Bibliographical note

Publisher Copyright:
© 2017 Elsevier Inc.

Keywords

JNK
Kupffer cell
Tnf
cholastasis
intrahepatic cholangiocarcinoma
mitochondrial dysfunction
pro-inflammatory niche
reactive oxygen species
unfolded protein response

UN SDGs

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10.1016/j.ccell.2017.05.006

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Yuan, D., Huang, S., Berger, E., Liu, L., Gross, N., Heinzmann, F., Ringelhan, M., Connor, T. O., Stadler, M., Meister, M., Weber, J., Öllinger, R., Simonavicius, N., Reisinger, F., Hartmann, D., Meyer, R., Reich, M., Seehawer, M., Leone, V., ... Heikenwalder, M. (2017). Kupffer Cell-Derived Tnf Triggers Cholangiocellular Tumorigenesis through JNK due to Chronic Mitochondrial Dysfunction and ROS. Cancer Cell, 31(6), 771-789.e6. https://doi.org/10.1016/j.ccell.2017.05.006

@article{5fb4aba6cbf944ffafd7f0d4ee3e5e32,

title = "Kupffer Cell-Derived Tnf Triggers Cholangiocellular Tumorigenesis through JNK due to Chronic Mitochondrial Dysfunction and ROS",

abstract = "Intrahepatic cholangiocarcinoma (ICC) is a highly malignant, heterogeneous cancer with poor treatment options. We found that mitochondrial dysfunction and oxidative stress trigger a niche favoring cholangiocellular overgrowth and tumorigenesis. Liver damage, reactive oxygen species (ROS) and paracrine tumor necrosis factor (Tnf) from Kupffer cells caused JNK-mediated cholangiocellular proliferation and oncogenic transformation. Anti-oxidant treatment, Kupffer cell depletion, Tnfr1 deletion, or JNK inhibition reduced cholangiocellular pre-neoplastic lesions. Liver-specific JNK1/2 deletion led to tumor reduction and enhanced survival in Akt/Notch- or p53/Kras-induced ICC models. In human ICC, high Tnf expression near ICC lesions, cholangiocellular JNK-phosphorylation, and ROS accumulation in surrounding hepatocytes are present. Thus, Kupffer cell-derived Tnf favors cholangiocellular proliferation/differentiation and carcinogenesis. Targeting the ROS/Tnf/JNK axis may provide opportunities for ICC therapy.",

keywords = "JNK, Kupffer cell, Tnf, cholastasis, intrahepatic cholangiocarcinoma, mitochondrial dysfunction, pro-inflammatory niche, reactive oxygen species, unfolded protein response",

author = "Detian Yuan and Shan Huang and Emanuel Berger and Lei Liu and Nina Gross and Florian Heinzmann and Marc Ringelhan and Connor, {Tracy O.} and Mira Stadler and Michael Meister and Julia Weber and Rupert {\"O}llinger and Nicole Simonavicius and Florian Reisinger and Daniel Hartmann and R{\"u}diger Meyer and Maria Reich and Marco Seehawer and Valentina Leone and Bastian H{\"o}chst and Dirk Wohlleber and Simone J{\"o}rs and Marco Prinz and Duncan Spalding and Ulrike Protzer and Tom Luedde and Luigi Terracciano and Matthias Matter and Thomas Longerich and Percy Knolle and Thomas Ried and Verena Keitel and Fabian Geisler and Kristian Unger and Einat Cinnamon and Eli Pikarsky and Norbert H{\"u}ser and Davis, {Roger J.} and Tschaharganeh, {Darjus F.} and Roland Rad and Achim Weber and Lars Zender and Dirk Haller and Mathias Heikenwalder",

note = "Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",

year = "2017",

month = jun,

day = "12",

doi = "10.1016/j.ccell.2017.05.006",

language = "אנגלית",

volume = "31",

pages = "771--789.e6",

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Yuan, D, Huang, S, Berger, E, Liu, L, Gross, N, Heinzmann, F, Ringelhan, M, Connor, TO, Stadler, M, Meister, M, Weber, J, Öllinger, R, Simonavicius, N, Reisinger, F, Hartmann, D, Meyer, R, Reich, M, Seehawer, M, Leone, V, Höchst, B, Wohlleber, D, Jörs, S, Prinz, M, Spalding, D, Protzer, U, Luedde, T, Terracciano, L, Matter, M, Longerich, T, Knolle, P, Ried, T, Keitel, V, Geisler, F, Unger, K, Cinnamon, E , Pikarsky, E, Hüser, N, Davis, RJ, Tschaharganeh, DF, Rad, R, Weber, A, Zender, L, Haller, D & Heikenwalder, M 2017, 'Kupffer Cell-Derived Tnf Triggers Cholangiocellular Tumorigenesis through JNK due to Chronic Mitochondrial Dysfunction and ROS', Cancer Cell, vol. 31, no. 6, pp. 771-789.e6. https://doi.org/10.1016/j.ccell.2017.05.006

TY - JOUR

T1 - Kupffer Cell-Derived Tnf Triggers Cholangiocellular Tumorigenesis through JNK due to Chronic Mitochondrial Dysfunction and ROS

AU - Yuan, Detian

AU - Huang, Shan

AU - Berger, Emanuel

AU - Liu, Lei

AU - Gross, Nina

AU - Heinzmann, Florian

AU - Ringelhan, Marc

AU - Connor, Tracy O.

AU - Stadler, Mira

AU - Meister, Michael

AU - Weber, Julia

AU - Öllinger, Rupert

AU - Simonavicius, Nicole

AU - Reisinger, Florian

AU - Hartmann, Daniel

AU - Meyer, Rüdiger

AU - Reich, Maria

AU - Seehawer, Marco

AU - Leone, Valentina

AU - Höchst, Bastian

AU - Wohlleber, Dirk

AU - Jörs, Simone

AU - Prinz, Marco

AU - Spalding, Duncan

AU - Protzer, Ulrike

AU - Luedde, Tom

AU - Terracciano, Luigi

AU - Matter, Matthias

AU - Longerich, Thomas

AU - Knolle, Percy

AU - Ried, Thomas

AU - Keitel, Verena

AU - Geisler, Fabian

AU - Unger, Kristian

AU - Cinnamon, Einat

AU - Pikarsky, Eli

AU - Hüser, Norbert

AU - Davis, Roger J.

AU - Tschaharganeh, Darjus F.

AU - Rad, Roland

AU - Weber, Achim

AU - Zender, Lars

AU - Haller, Dirk

AU - Heikenwalder, Mathias

PY - 2017/6/12

Y1 - 2017/6/12

N2 - Intrahepatic cholangiocarcinoma (ICC) is a highly malignant, heterogeneous cancer with poor treatment options. We found that mitochondrial dysfunction and oxidative stress trigger a niche favoring cholangiocellular overgrowth and tumorigenesis. Liver damage, reactive oxygen species (ROS) and paracrine tumor necrosis factor (Tnf) from Kupffer cells caused JNK-mediated cholangiocellular proliferation and oncogenic transformation. Anti-oxidant treatment, Kupffer cell depletion, Tnfr1 deletion, or JNK inhibition reduced cholangiocellular pre-neoplastic lesions. Liver-specific JNK1/2 deletion led to tumor reduction and enhanced survival in Akt/Notch- or p53/Kras-induced ICC models. In human ICC, high Tnf expression near ICC lesions, cholangiocellular JNK-phosphorylation, and ROS accumulation in surrounding hepatocytes are present. Thus, Kupffer cell-derived Tnf favors cholangiocellular proliferation/differentiation and carcinogenesis. Targeting the ROS/Tnf/JNK axis may provide opportunities for ICC therapy.

AB - Intrahepatic cholangiocarcinoma (ICC) is a highly malignant, heterogeneous cancer with poor treatment options. We found that mitochondrial dysfunction and oxidative stress trigger a niche favoring cholangiocellular overgrowth and tumorigenesis. Liver damage, reactive oxygen species (ROS) and paracrine tumor necrosis factor (Tnf) from Kupffer cells caused JNK-mediated cholangiocellular proliferation and oncogenic transformation. Anti-oxidant treatment, Kupffer cell depletion, Tnfr1 deletion, or JNK inhibition reduced cholangiocellular pre-neoplastic lesions. Liver-specific JNK1/2 deletion led to tumor reduction and enhanced survival in Akt/Notch- or p53/Kras-induced ICC models. In human ICC, high Tnf expression near ICC lesions, cholangiocellular JNK-phosphorylation, and ROS accumulation in surrounding hepatocytes are present. Thus, Kupffer cell-derived Tnf favors cholangiocellular proliferation/differentiation and carcinogenesis. Targeting the ROS/Tnf/JNK axis may provide opportunities for ICC therapy.

KW - JNK

KW - Kupffer cell

KW - Tnf

KW - cholastasis

KW - intrahepatic cholangiocarcinoma

KW - mitochondrial dysfunction

KW - pro-inflammatory niche

KW - reactive oxygen species

KW - unfolded protein response

UR - http://www.scopus.com/inward/record.url?scp=85020666393&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2017.05.006

DO - 10.1016/j.ccell.2017.05.006

M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???

C2 - 28609656

AN - SCOPUS:85020666393

SN - 1535-6108

VL - 31

SP - 771-789.e6

JO - Cancer Cell

JF - Cancer Cell

IS - 6

ER -

Kupffer Cell-Derived Tnf Triggers Cholangiocellular Tumorigenesis through JNK due to Chronic Mitochondrial Dysfunction and ROS

Abstract

Bibliographical note

Keywords

UN SDGs

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