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
  • 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. [email protected].
  • 13. Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, 90033, USA. [email protected].
  • 14. Department of Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, 90073, USA. [email protected].
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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