期刊
NATURE CELL BIOLOGY
卷 22, 期 6, 页码 728-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41556-020-0511-2
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资金
- National Key Research and Development Program [2016YFA0502600]
- National Cancer Institute (NCI) [P01CA104838, R35CA197602, P30CA016520]
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. Li et al. show that hepatocyte-specific loss of Fbp1 in mice leads to steatosis and senescence in hepatic stellate cells, thereby disrupting metabolism and facilitating liver tumorigenesis.
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