Study identifies how obesity-related liver cancer becomes more aggressive and resistant to treatment

A research team affiliated with National Institute of Standards and Technology has made a significant discovery explaining why liver cancers associated with obesity and metabolic disorders tend to be more aggressive and less responsive to conventional treatments. The study reveals that a specific signalling pathway involving endotrophin - a protein secreted during liver fibrosis - and the receptor protein CD44 promotes tumour malignancy and drug resistance.

Led by Professor Jiyoung Park of the Department of Biological Sciences at UNIST, the research team demonstrated, for the first time, how endotrophin binds to CD44 on cancer cells, activating a cascade that accelerates tumour growth and invasion. This interaction also confers resistance to sorafenib, a common targeted therapy for liver cancer.

Liver cancer linked to obesity and metabolic dysfunction develops rapidly and poses significant treatment challenges due to its aggressive nature and poor response to existing drugs. Although elevated endotrophin levels have been observed in patients with liver cancer, the precise molecular mechanisms remained unclear until now.

The team found that in obese liver tissue, excess endotrophin interacts with CD44 on hepatocellular carcinoma (HCC) cells, triggering the STAT3 signalling pathway. This activation results in rapid tumour proliferation and increased invasive behaviour.

Animal studies validated these findings: mice treated with inhibitors targeting both endotrophin and CD44 exhibited markedly reduced tumour formation and size. Importantly, blocking this pathway also restored sensitivity to sorafenib and alleviated liver fibrosis and inflammation.

"Our research shows that the interaction between endotrophin and CD44 is a key driver of liver cancer progression in obesity-related cases,” explained Professor Park. “Developing drugs to disrupt this interaction could weaken tumour aggressiveness and help overcome resistance to current therapies."

The findings were reported in the paper, ‘Endotrophin and CD44-Mediated Heterotypic Signaling Mediates Tumor-Stroma Crosstalk and Facilitates Malignant Progression in Hepatocellular Carcinoma’, published in Cancer Research. To access this paper, please click here (log-in maybe required)