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

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, Satdarshan Paul Monga, Anthoula Lazaris, Keigo Machida, Michael Karin, Ernesto Guccione and Hidekazu Tsukamoto ()
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Sonal Sinha: Keck School of Medicine of the University of Southern California
Satoka Aizawa: 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
Rajan Shrestha: Keck School of Medicine of the University of Southern California
Stephanie Q. Pan: 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
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

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-38406-8

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