FBP1 Loss Disrupts Liver Metabolism and Promotes Tumorigenesis Through a Hepatic Stellate Cell Senescence Secretome

Nat Cell Biol. 2020 May 4.

Fuming Li^1,2, Peiwei Huangyang^1,2,3, Michelle Burrows^1,2, Kathy Guo^1,2,4, Romain Riscal^1,2, Jason Godfrey^1,2, Kyoung Eun Lee^1,2,5, Nan Lin^1,2,6, Pearl Lee^1,2, Ian A Blair⁷, Brian Keith^1,2,8, Bo Li^9,10, M Celeste Simon^11,12

1. Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
2. Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
3. Helen Diller Cancer Center, UCSF, San Francisco, CA, USA.
4. Kornberg School of Dentistry, Temple University, Philadelphia, PA, USA.
5. Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA.
6. Trinity Partners, LLC, Waltham, MA, USA.
7. Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
8. The Wistar Institute, Philadelphia, PA, USA.
9. Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China. libo47@mail.sysu.edu.cn.
10. RNA Biomedical Institute, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China. libo47@mail.sysu.edu.cn.
11. Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. celeste2@pennmedicine.upenn.edu.
12. Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA. celeste2@pennmedicine.upenn.edu. 

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.

Presented by Fuming Li