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

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

  • Nat Commun. 2023 May 8;14(1):2651. doi: 10.1038/s41467-023-38406-8.
Sonal Sinha 1 2,  Satoka Aizawa 1 2,  Yasuhiro Nakano 3,  Alexander Rialdi 4,  Hye Yeon Choi 1 2,  Rajan Shrestha 1 2,  Stephanie Q Pan 1 2,  Yibu Chen 5,  Meng Li 5,  Audrey Kapelanski-Lamoureux 6,  Gregory Yochum 7,  Linda Sher 8,  Satdarshan Paul Monga 9,  Anthoula Lazaris 6,  Keigo Machida 1 10,  Michael Karin 11,  Ernesto Guccione 4,  Hidekazu Tsukamoto 12 13 14
Affiliations

Affiliations

  • 1 Southern California Research Center for ALPD and Cirrhosis, Keck School of Medicine of the University of Southern California, Los Angeles, CA, 90033, USA.
  • 2 Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, 90033, USA.
  • 3 Laboratory of Cell Growth and Differentiation, Institute for Quantitative Biosciences, The University of Tokyo, Tokyo, 113-0022, Japan.
  • 4 Icahn School of Medicine at Mount Sinai Hess Center for Science and Medicine, New York, NY, 10029, USA.
  • 5 USC Libraries Bioinformatics Services of the University of Southern California, Los Angeles, CA, 90089, USA.
  • 6 Research Institute of the McGill University Health Centre, Montreal, QC, H3A 0G4, Canada.
  • 7 Department of Surgery, Pennsylvania State University, Hershey, PA, 17033, USA.
  • 8 Department of Surgery, Keck School of Medicine of the University of Southern California, Los Angeles, CA, 90033, USA.
  • 9 Department of Pathology, University of Pittsburg School of Medicine, Pittsburg, PA, 15213, USA.
  • 10 Department of Molecular Microbiology and Immunology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, 90033, USA.
  • 11 Department of Pharmacology, University of California San Diego, La Jolla, CA, 92093, USA.
  • 12 Southern California Research Center for ALPD and Cirrhosis, Keck School of Medicine of the University of Southern California, Los Angeles, CA, 90033, USA. htsukamo@med.usc.edu.
  • 13 Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, 90033, USA. htsukamo@med.usc.edu.
  • 14 Department of Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, 90073, USA. htsukamo@med.usc.edu.
PMID: 37156770 DOI: 10.1038/s41467-023-38406-8
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.

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