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; Hidekazu Tsukamoto

doi:10.1038/s41467-023-38406-8

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.

Authors

Sonal Sinha^{1

2}, Satoka Aizawa^{1

2}, Yasuhiro Nakano³, Alexander Rialdi⁴, Hye Yeon Choi^{1

2}, Rajan Shrestha^{1

2}, Stephanie Q Pan^{1

2}, Yibu Chen⁵, Meng Li⁵, Audrey Kapelanski-Lamoureux⁶, Gregory Yochum⁷, Linda Sher⁸, Satdarshan Paul Monga⁹, Anthoula Lazaris⁶, Keigo Machida^{1

10}, Michael Karin¹¹, Ernesto Guccione⁴, 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].

Abstract

Hepatocellular carcinoma (HCC) is the 3^rd 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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural

MeSH terms

Animals
Carcinogenesis / genetics
Carcinogenesis / metabolism
Carcinoma, Hepatocellular* / metabolism
Fatty Acid Desaturases
Hepatic Stellate Cells / metabolism
Liver Neoplasms* / metabolism
Male
Mice
Receptors, Leukotriene B4 / genetics
Receptors, Leukotriene B4 / metabolism
Tumor Microenvironment
beta Catenin / metabolism

Substances

beta Catenin
Fatty Acid Desaturases
Receptors, Leukotriene B4
Scd2 protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding