Targeting macropinocytosis may be an effective therapeutic approach for hepatocellular carcinoma

Researchers from the Department of Pathology, School of Clinical Medicine, LKS Faculty of Medicine, University of Hong Kong (HKUMed) have identified a novel metabolic mechanism in liver cancer cells, whereby macropinocytosis, an endocytic process, is used to engulf extracellular proteins as fuels to support unlimited growth of hepatocellular carcinoma (HCC) in hypoxia (oxygen deprivation).

This finding indicates that targeting macropinocytosis could represent a new and effective therapeutic approach for HCC. The results have now been published in Communication Nature.


HCC is the most common form of primary liver cancer. In Hong Kong, HCC is the fifth most common cancer and the third deadliest. Despite the increase in treatment options, the median life expectancy of patients with advanced HCC is still less than two years.

Blood provides oxygen, an important nutrient for HCC. However, the oxygen content in solid tumors, including HCC, is generally lower than in normal organs due to the abnormally high growth rate of tumors, far exceeding the growth of blood vessels.

HCC cells are resistant to oxygen deprivation because they have a great capacity to adapt to this “nutritive stress” by stabilizing a transcription factor called hypoxia-induced factor 1 (HIF-1). The HKUMed study identified a novel gene, EHD2, regulated by HIF-1, that initiates a macropinocytosis-dependent metabolic program to facilitate adaptation and proliferation of HCC cells under ‘nutrient stress’. The study also showed that therapeutic targeting of the macropinocytosis pathway can effectively suppress HCC.

Research methods and results

Macropinocytosis is an endocytic pathway that allows cells to engulf extracellular proteins. Using confocal microscopy, it was shown that hypoxia could cause HCC cells to exhibit 5-10 times macropinocyte level induction.

Through mass spectrometry analysis, the HKUMed team also found that engulfed proteins were digested and broken down into amino acids which, in turn, served as fuel to support HCC cell proliferation. This process was mediated by HIF-1 which transcribedly activated a new gene called EH domain-containing protein 2 (EHD2), resulting in the formation of membrane frills, which is the critical first step in macropinocytosis.

Deletion of EHD2 in mice prevented the development of HCC. Treatment with an HIF inhibitor, digoxin or a macropinocytosis inhibitor – IPA-3, also resulted in greater than 50% inhibition of tumor burden in mouse models of HCC (Figure A, Figure B). More importantly, EHD2 was significantly overexpressed at least two-fold in approximately 40% of HCC patients. Taken together, the study demonstrated that HIF-1/EHD2-mediated macropinocytosis supports HCC growth. Inhibition of macropinocytosis represents a powerful therapeutic approach for HCC.

Importance of research

Liver cancer has a poor prognosis, in part because its cancer cells are smart enough to find ways to survive under conditions of deprivation. Understanding the biology and metabolism of liver cancer is therefore fundamental to identify therapeutic targets and effective treatments. In this study, we found that liver cancer cells would begin to adapt alternative and unusual metabolic programs to scavenge proteins from the environment as a source of nutrients. Furthermore, the identified HIF-1/EHD2 pathway mediates macropinocytosis-induced metabolic reprogramming in cancer, providing an important molecular basis for the design of innovative cancer therapeutic strategies against macropinocytosis. It is important to note that hypoxia is not limited to liver cancer but to all solid cancers. Therefore, our discovery will also be applicable to other types of cancer..”

Dr. Carmen Wong Chak-lui, Associate Professor, Department of Pathology, School of Clinical Medicine, University of Hong Kong


The University of Hong Kong

Journal reference:

Zhang, MS, et al. (2022) Hypoxia-induced macropinocytosis represents a metabolic pathway for liver cancer. Nature Communication.

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