Justin Vareecal Joseph

The cGAS-STING pathway is a therapeutic target in a preclinical model of hepatocellular carcinoma

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The cGAS-STING pathway is a therapeutic target in a preclinical model of hepatocellular carcinoma. / Thomsen, Martin K.; Skouboe, Morten K.; Boularan, Cedric; Vernejoul, Fabienne; Lioux, Thierry; Leknes, Siv L.; Berthelsen, Martin F.; Riedel, Maria; Cai, Huiqiang; Joseph, Justin V.; Perouzel, Eric; Tiraby, Michele; Vendelbo, Mikkel H.; Paludan, Søren R.

I: Oncogene, Bind 39, Nr. 8, 02.2020, s. 1652-1664.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

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Thomsen, Martin K. ; Skouboe, Morten K. ; Boularan, Cedric ; Vernejoul, Fabienne ; Lioux, Thierry ; Leknes, Siv L. ; Berthelsen, Martin F. ; Riedel, Maria ; Cai, Huiqiang ; Joseph, Justin V. ; Perouzel, Eric ; Tiraby, Michele ; Vendelbo, Mikkel H. ; Paludan, Søren R. / The cGAS-STING pathway is a therapeutic target in a preclinical model of hepatocellular carcinoma. I: Oncogene. 2020 ; Bind 39, Nr. 8. s. 1652-1664.

Bibtex

@article{8195510f029d491ba6e96432fd3c0fa4,
title = "The cGAS-STING pathway is a therapeutic target in a preclinical model of hepatocellular carcinoma",
abstract = "Hepatocellular carcinoma (HCC) is the most common primary liver cancer, and the incidence of HCC is increasing. Recently, cancer immunotherapy has emerged as an efficient treatment against some cancers. Here we have used a mouse model of mutagen-induced HCC to explore the therapeutic usefulness of targeting the DNA-activated STING pathway in HCC. STING-deficient mice exhibited unaltered initial development of HCC, but had higher number of large tumors at late stages of disease. In the liver of STING-deficient HCC mice, we observed reduced levels of phospho-STAT1, autophagy, and cleaved caspase3. These responses were activated in the liver by treatment with a cyclic dinucleotide (CDN) STING agonist. Importantly, CDN treatment of mice after HCC development efficiently reduced tumor size. Initiation of CDN treatment at an even later stage of disease to allow HCC detection by MR scanning revealed that the majority of tumors regressed in response to CDN, but new tumors were also detected, which were unresponsive to CDN treatment. Overall, the modulation of the STING pathway affects the development of HCC, and holds promise for a use as a treatment of this disease, most likely in combination with other immunomodulatory treatments such as PD1 inhibitors or with standard of care.",
keywords = "ACTIVATION, CANCER, CELLS, CONTRIBUTES, DNA, HEPATOCYTES, IMMUNITY, INFLAMMATION, INTERFERON-ALPHA, REGRESSION",
author = "Thomsen, {Martin K.} and Skouboe, {Morten K.} and Cedric Boularan and Fabienne Vernejoul and Thierry Lioux and Leknes, {Siv L.} and Berthelsen, {Martin F.} and Maria Riedel and Huiqiang Cai and Joseph, {Justin V.} and Eric Perouzel and Michele Tiraby and Vendelbo, {Mikkel H.} and Paludan, {S{\o}ren R.}",
year = "2020",
month = feb,
doi = "10.1038/s41388-019-1108-8",
language = "English",
volume = "39",
pages = "1652--1664",
journal = "Oncogene",
issn = "0950-9232",
publisher = "Nature Publishing Group",
number = "8",

}

RIS

TY - JOUR

T1 - The cGAS-STING pathway is a therapeutic target in a preclinical model of hepatocellular carcinoma

AU - Thomsen, Martin K.

AU - Skouboe, Morten K.

AU - Boularan, Cedric

AU - Vernejoul, Fabienne

AU - Lioux, Thierry

AU - Leknes, Siv L.

AU - Berthelsen, Martin F.

AU - Riedel, Maria

AU - Cai, Huiqiang

AU - Joseph, Justin V.

AU - Perouzel, Eric

AU - Tiraby, Michele

AU - Vendelbo, Mikkel H.

AU - Paludan, Søren R.

PY - 2020/2

Y1 - 2020/2

N2 - Hepatocellular carcinoma (HCC) is the most common primary liver cancer, and the incidence of HCC is increasing. Recently, cancer immunotherapy has emerged as an efficient treatment against some cancers. Here we have used a mouse model of mutagen-induced HCC to explore the therapeutic usefulness of targeting the DNA-activated STING pathway in HCC. STING-deficient mice exhibited unaltered initial development of HCC, but had higher number of large tumors at late stages of disease. In the liver of STING-deficient HCC mice, we observed reduced levels of phospho-STAT1, autophagy, and cleaved caspase3. These responses were activated in the liver by treatment with a cyclic dinucleotide (CDN) STING agonist. Importantly, CDN treatment of mice after HCC development efficiently reduced tumor size. Initiation of CDN treatment at an even later stage of disease to allow HCC detection by MR scanning revealed that the majority of tumors regressed in response to CDN, but new tumors were also detected, which were unresponsive to CDN treatment. Overall, the modulation of the STING pathway affects the development of HCC, and holds promise for a use as a treatment of this disease, most likely in combination with other immunomodulatory treatments such as PD1 inhibitors or with standard of care.

AB - Hepatocellular carcinoma (HCC) is the most common primary liver cancer, and the incidence of HCC is increasing. Recently, cancer immunotherapy has emerged as an efficient treatment against some cancers. Here we have used a mouse model of mutagen-induced HCC to explore the therapeutic usefulness of targeting the DNA-activated STING pathway in HCC. STING-deficient mice exhibited unaltered initial development of HCC, but had higher number of large tumors at late stages of disease. In the liver of STING-deficient HCC mice, we observed reduced levels of phospho-STAT1, autophagy, and cleaved caspase3. These responses were activated in the liver by treatment with a cyclic dinucleotide (CDN) STING agonist. Importantly, CDN treatment of mice after HCC development efficiently reduced tumor size. Initiation of CDN treatment at an even later stage of disease to allow HCC detection by MR scanning revealed that the majority of tumors regressed in response to CDN, but new tumors were also detected, which were unresponsive to CDN treatment. Overall, the modulation of the STING pathway affects the development of HCC, and holds promise for a use as a treatment of this disease, most likely in combination with other immunomodulatory treatments such as PD1 inhibitors or with standard of care.

KW - ACTIVATION

KW - CANCER

KW - CELLS

KW - CONTRIBUTES

KW - DNA

KW - HEPATOCYTES

KW - IMMUNITY

KW - INFLAMMATION

KW - INTERFERON-ALPHA

KW - REGRESSION

UR - http://www.scopus.com/inward/record.url?scp=85075388345&partnerID=8YFLogxK

U2 - 10.1038/s41388-019-1108-8

DO - 10.1038/s41388-019-1108-8

M3 - Journal article

C2 - 31740782

AN - SCOPUS:85075388345

VL - 39

SP - 1652

EP - 1664

JO - Oncogene

JF - Oncogene

SN - 0950-9232

IS - 8

ER -