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Hepatic stellate cell stearoyl co-A desaturase activates leukotriene B4 receptor 2 - β-catenin cascade to promote liver tumorigenesis

Author

Listed:
  • Sonal Sinha

    (Keck School of Medicine of the University of Southern California
    Keck School of Medicine of the University of Southern California)

  • Satoka Aizawa

    (Keck School of Medicine of the University of Southern California
    Keck School of Medicine of the University of Southern California)

  • Yasuhiro Nakano

    (The University of Tokyo)

  • Alexander Rialdi

    (Icahn School of Medicine at Mount Sinai Hess Center for Science and Medicine)

  • Hye Yeon Choi

    (Keck School of Medicine of the University of Southern California
    Keck School of Medicine of the University of Southern California)

  • Rajan Shrestha

    (Keck School of Medicine of the University of Southern California
    Keck School of Medicine of the University of Southern California)

  • Stephanie Q. Pan

    (Keck School of Medicine of the University of Southern California
    Keck School of Medicine of the University of Southern California)

  • Yibu Chen

    (USC Libraries Bioinformatics Services of the University of Southern California)

  • Meng Li

    (USC Libraries Bioinformatics Services of the University of Southern California)

  • Audrey Kapelanski-Lamoureux

    (Research Institute of the McGill University Health Centre)

  • Gregory Yochum

    (Pennsylvania State University)

  • Linda Sher

    (Keck School of Medicine of the University of Southern California)

  • Satdarshan Paul Monga

    (University of Pittsburg School of Medicine)

  • Anthoula Lazaris

    (Research Institute of the McGill University Health Centre)

  • Keigo Machida

    (Keck School of Medicine of the University of Southern California
    Keck School of Medicine of the University of Southern California)

  • Michael Karin

    (University of California San Diego)

  • Ernesto Guccione

    (Icahn School of Medicine at Mount Sinai Hess Center for Science and Medicine)

  • Hidekazu Tsukamoto

    (Keck School of Medicine of the University of Southern California
    Keck School of Medicine of the University of Southern California
    Department of Veterans Affairs Greater Los Angeles Healthcare System)

Abstract

Hepatocellular carcinoma (HCC) is the 3rd most deadly malignancy. Activated hepatic stellate cells (aHSC) give rise to cancer-associated fibroblasts in HCC and are considered a potential therapeutic target. Here we report that selective ablation of stearoyl CoA desaturase-2 (Scd2) in aHSC globally suppresses nuclear CTNNB1 and YAP1 in tumors and tumor microenvironment and prevents liver tumorigenesis in male mice. Tumor suppression is associated with reduced leukotriene B4 receptor 2 (LTB4R2) and its high affinity oxylipin ligand, 12-hydroxyheptadecatrienoic acid (12-HHTrE). Genetic or pharmacological inhibition of LTB4R2 recapitulates CTNNB1 and YAP1 inactivation and tumor suppression in culture and in vivo. Single cell RNA sequencing identifies a subset of tumor-associated aHSC expressing Cyp1b1 but no other 12-HHTrE biosynthetic genes. aHSC release 12-HHTrE in a manner dependent on SCD and CYP1B1 and their conditioned medium reproduces the LTB4R2-mediated tumor-promoting effects of 12-HHTrE in HCC cells. CYP1B1-expressing aHSC are detected in proximity of LTB4R2-positive HCC cells and the growth of patient HCC organoids is blunted by LTB4R2 antagonism or knockdown. Collectively, our findings suggest aHSC-initiated 12-HHTrE-LTB4R2-CTNNB1-YAP1 pathway as a potential HCC therapeutic target.

Suggested Citation

  • Sonal Sinha & Satoka Aizawa & Yasuhiro Nakano & Alexander Rialdi & Hye Yeon Choi & Rajan Shrestha & Stephanie Q. Pan & Yibu Chen & Meng Li & Audrey Kapelanski-Lamoureux & Gregory Yochum & Linda Sher &, 2023. "Hepatic stellate cell stearoyl co-A desaturase activates leukotriene B4 receptor 2 - β-catenin cascade to promote liver tumorigenesis," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38406-8
    DOI: 10.1038/s41467-023-38406-8
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    References listed on IDEAS

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    1. Aveline Filliol & Yoshinobu Saito & Ajay Nair & Dianne H. Dapito & Le-Xing Yu & Aashreya Ravichandra & Sonakshi Bhattacharjee & Silvia Affo & Naoto Fujiwara & Hua Su & Qiuyan Sun & Thomas M. Savage & , 2022. "Opposing roles of hepatic stellate cell subpopulations in hepatocarcinogenesis," Nature, Nature, vol. 610(7931), pages 356-365, October.
    2. Ingmar Mederacke & Christine C. Hsu & Juliane S. Troeger & Peter Huebener & Xueru Mu & Dianne H. Dapito & Jean-Philippe Pradere & Robert F. Schwabe, 2013. "Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology," Nature Communications, Nature, vol. 4(1), pages 1-11, December.
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