Hepatic stellate cell stearoyl co-A desaturase activates leukotriene B4 receptor 2 - β-catenin cascade to promote liver tumorigenesis
© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:14 |
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| Enthalten in: |
Nature communications - 14(2023), 1 vom: 08. Mai, Seite 2651 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Sinha, Sonal [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 12.05.2023 Date Revised 25.01.2024 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s41467-023-38406-8 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM356598977 |
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| 245 | 1 | 0 | |a Hepatic stellate cell stearoyl co-A desaturase activates leukotriene B4 receptor 2 - β-catenin cascade to promote liver tumorigenesis |
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| 500 | |a Date Revised 25.01.2024 | ||
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| 520 | |a © 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, U.S. Gov't, Non-P.H.S. | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
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| 700 | 1 | |a Nakano, Yasuhiro |e verfasserin |4 aut | |
| 700 | 1 | |a Rialdi, Alexander |e verfasserin |4 aut | |
| 700 | 1 | |a Choi, Hye Yeon |e verfasserin |4 aut | |
| 700 | 1 | |a Shrestha, Rajan |e verfasserin |4 aut | |
| 700 | 1 | |a Pan, Stephanie Q |e verfasserin |4 aut | |
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| 700 | 1 | |a Li, Meng |e verfasserin |4 aut | |
| 700 | 1 | |a Kapelanski-Lamoureux, Audrey |e verfasserin |4 aut | |
| 700 | 1 | |a Yochum, Gregory |e verfasserin |4 aut | |
| 700 | 1 | |a Sher, Linda |e verfasserin |4 aut | |
| 700 | 1 | |a Monga, Satdarshan Paul |e verfasserin |4 aut | |
| 700 | 1 | |a Lazaris, Anthoula |e verfasserin |4 aut | |
| 700 | 1 | |a Machida, Keigo |e verfasserin |4 aut | |
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| 700 | 1 | |a Guccione, Ernesto |e verfasserin |4 aut | |
| 700 | 1 | |a Tsukamoto, Hidekazu |e verfasserin |4 aut | |
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