β-catenin-activated hepatocellular carcinomas are addicted to fatty acids

Abstract

FAO induced by β-catenin oncogenic activation in the liver is the driving force of the β-catenin-induced HCC. Inhibiting FAO by genetic and pharmacological approaches blocks HCC development, showing that inhibition of FAO is a suitable therapeutic approach for -mutated HCC.

Aberrant lipid metabolism in hepatocellular carcinoma cells as well as immune microenvironment: A review

“…Typically, the β‐catenin‐activated HCCs carry an activating mutation in the CTNNB1 , a gene that encodes β‐catenin in the Wnt pathway, whose mutation is not uncommon (19.5%) in human HCC . Inhibiting FAO by genetic and pharmacological approaches blocks the HCC development, which suggests that inhibiting FAO is a suitable therapeutic approach for the β‐catenin‐mutated HCC . In addition, Iwamoto et al recently reported that HCC cells would rather utilize FAO for their survival under the hypoxic conditions induced by the antiangiogenic drugs.…”

β-catenin oncogenic activation rewires fatty acid catabolism to fuel hepatocellular carcinoma

“…Beyond glycolysis, it is now well established that other pathways are hijacked in cancer cells to promote their growth 8. In their study, Senni et al 1 show that β-catenin-activated HCCs are not glycolytic because tumours induced by APC deletion do not display altered lactate production compared with adjacent non-tumour tissue. In line with this observation, they found that β-catenin overactivation in hepatocytes does not alter their glycolytic rate, nor does it change glutaminolysis.…”

“…Various pathways are dysregulated in HCC, including p53 and other cell cycle regulators, chromatin modifiers, oxidative stress, insulin and growth factor signalling, and Wnt/β-catenin signalling. In this issue, Senni and colleagues1 demonstrate the role of fatty acid oxidation as a source of energy in the metabolic adaptation triggered by β-catenin oncogenic activation in hepatocytes. This work describes an atypical cancer cell addiction to fatty acids and represents an important discovery that may pave the way for novel therapeutics.…”

“…This class of tumours is due to mutations in the gene encoding β-catenin ( CTNNB1 ) that promote its constitutive nuclear translocation and tumourigenesis due to activation of the β-catenin-dependent transcription programme. In their study, Senni et al 1 took advantage of a mouse model of HCC mimicking CTNNB1- activated human tumours through hepatocyte-specific deletion of APC 7. They used this model to characterise the impact of such oncogenic activation on cell metabolism with the aim of identifying specific metabolic pathways that could be targeted to treat such classes of HCCs.…”

“…Senni et al 1 show that human CTNNB1 -mutated HCCs have a specific pattern of gene expression related to fatty acid oxidation. They confirmed their observation using different human hepatocyte cell lines and postulated that PPARα may be involved in the dependence of β-catenin-activated HCCs on fatty acids.…”