MassIVE MSV000085045

Partial Public PXD017831

FBP1 loss disrupts liver metabolism and promotes tumourigenesis through a hepatic stellate cell senescence secretome

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Description

Crosstalk between deregulated hepatocyte metabolism and cells within the tumour microenvironment, and consequent effects on liver tumourigenesis, are incompletely 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, and hepatocyte-specific Fbp1 deletion results in steatosis, concomitant with activation and senescence of hepatic stellate cells (HSCs), exhibiting a senescence-associated secretory phenotype (SASP). 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, subsequent SASP development, and tumour progression. Collectively, these findings provide genetic evidence for FBP1 as a metabolic tumour suppressor in liver cancer and establish a critical link between hepatocyte metabolism and HSC senescence that promotes tumour growth. [doi:10.25345/C5NT3T] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: TMT-10plex ; FBP1 ; cell senescence secretome ; liver metabolism

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Principal Investigators:
(in alphabetical order) 		M. Celeste Simon, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, United States
Submitting User: tangh
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