| Added by | lklinares |
|---|---|
| Group name | EquipeLL |
| Item Type | Journal Article |
| Title | FBP1 loss disrupts liver metabolism and promotes tumorigenesis through a hepatic stellate cell senescence secretome |
| Creator | Li et al. |
| Author | Fuming Li |
| Author | Peiwei Huangyang |
| Author | Michelle Burrows |
| Author | Kathy Guo |
| Author | Romain Riscal |
| Author | Jason Godfrey |
| Author | Kyoung Eun Lee |
| Author | Nan Lin |
| Author | Pearl Lee |
| Author | Ian A. Blair |
| Author | Brian Keith |
| Author | Bo Li |
| Author | M. Celeste Simon |
| Abstract | The crosstalk between deregulated hepatocyte metabolism and cells within the tumour microenvironment, as well as the consequent effects on liver tumorigenesis, are not completely understood. We show here that hepatocyte-specific loss of the gluconeogenic enzyme fructose 1,6-bisphosphatase 1 (FBP1) disrupts liver metabolic homeostasis and promotes tumour progression. FBP1 is universally silenced in both human and murine liver tumours. Hepatocyte-specific Fbp1 deletion results in steatosis, concomitant with activation and senescence of hepatic stellate cells (HSCs), exhibiting a senescence-associated secretory phenotype. Depleting senescent HSCs by 'senolytic' treatment with dasatinib/quercetin or ABT-263 inhibits tumour progression. We further demonstrate that FBP1-deficient hepatocytes promote HSC activation by releasing HMGB1; blocking its release with the small molecule inflachromene limits FBP1-dependent HSC activation, the subsequent development of the senescence-associated secretory phenotype and tumour progression. Collectively, these findings provide genetic evidence for FBP1 as a metabolic tumour suppressor in liver cancer and establish a critical crosstalk between hepatocyte metabolism and HSC senescence that promotes tumour growth. |
| Publication | Nature Cell Biology |
| Volume | 22 |
| Issue | 6 |
| Pages | 728-739 |
| Date | 2020-06 |
| Journal Abbr | Nat Cell Biol |
| Language | eng |
| DOI | 10.1038/s41556-020-0511-2 |
| ISSN | 1476-4679 |
| Library Catalog | PubMed |
| Extra | PMID: 32367049 PMCID: PMC7286794 |
| Tags | Animals, Carcinogenesis, Cell Proliferation, Female, Fructose-Bisphosphatase, Gene Expression Regulation, Neoplastic, Hepatic Stellate Cells, Humans, Liver Neoplasms, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, original, Tumor Microenvironment, Xenograft Model Antitumor Assays |
| Date Added | 2024/12/03 - 09:12:56 |
| Date Modified | 2024/12/03 - 09:12:56 |
| Notes and Attachments | PubMed entry (Attachment) Version acceptée (Attachment) |
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