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| Status |
Public on Mar 13, 2023 |
| Title |
Hepatic stellate cell-derived oxylipin activates leukotrine B4 receptor 2-β-catenin-YAP1 cascade to promote liver tumorigenesis |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Hepatocellular carcinoma (HCC) is the 3rd most deadly malignancy due to limited therapeutic options. Activated hepatic stellate cells (aHSC) give rise to major cancer-associated myofibroblasts in HCC and considered a potential therapeutic target. Here we report that selective ablation of stearoyl CoA desaturase (Scd) in aHSC globally suppressed nuclear β-catenin (CTNNB1) and YAP1 in the tumor microenvironment and prevented liver tumorigenesis in mice. Tumor suppression was associated with reduced leukotriene B4 receptor 2 (LTB4R2) and its high affinity oxylipin ligand, 12-hydroxyheptadecatrienoic acid (12-HHTrE). LTB4R2 ablation and pharmacological inhibition, recapitulated CTNNB1 and YAP1 inactivation and tumor suppression in vivo and in culture. Single cell RNA sequencing identified a unique subset of tumor-associated aHSC expressing Cyp1b1 but no other 12-HHTrE biosynthetic genes. aHSC released 12-HHTrE in a manner dependent on SCD and their conditioned medium reproduced the LTB4R2-mediated tumor-promoting effects of 12-HHTrE in HCC cells. CYP1B1-expressing aHSC were detected in proximity of LTB4R2-positive cancer cells in human HCC and the growth of patient HCC organoids was blunted by LTB4R2 antagonism or knockdown. Collectively, our research identified a novel aHSC-initiated 12-HHTrE-LTB4R2-CTNNB-YAP1 pathway as a potential HCC therapeutic target.
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| Overall design |
Scd2f/f;Col1a1-Cre vs. Scd2f/f mice subjected to the hepatic carcinogen DEN and fed Western alcohol diet
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| Contributor(s) |
Tsukamoto H, Sinha S, Aizawa S, Chen Y, Li M, Karin M |
| Citation missing |
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| |
| Submission date |
Jan 19, 2022 |
| Last update date |
Mar 13, 2023 |
| Contact name |
Hidekazu Tsukamoto |
| E-mail(s) |
htsukamo@med.usc.edu
|
| Organization name |
University of Southern California
|
| Department |
Pathology
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| Lab |
Southern California Research Center for ALPD & Cirrhosis
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| Street address |
1333 San Pablo Street MMR414
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| City |
Los Angeles |
| State/province |
CA |
| ZIP/Postal code |
90089 |
| Country |
USA |
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| Platforms (1) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
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| Samples (9)
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| Relations |
| BioProject |
PRJNA798682 |
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