Glycogen accumulation and phase separation drives liver tumor initiation

Area of Science:

• Biochemistry
• Oncology
• Cell Biology

Background:

• Tumor cells typically increase glucose consumption.
• Glycogen accumulation, a form of glucose storage, is identified as a crucial early event in liver cancer development.

Purpose of the Study:

• To investigate the role of glycogen accumulation in liver malignant transformation.
• To elucidate the molecular mechanisms by which glycogen impacts liver tumorigenesis.

Main Methods:

• Analysis of glucose-6-phosphatase (G6PC) and liver glycogen phosphorylase (PYGL) in pre-malignant and malignant liver cells.
• Investigating glycogen's physical properties and its interaction with the Laforin-Mst1/2 complex and Hippo kinases.
• Utilizing mouse models with G6PC or PYGL deficiency and evaluating Yap-dependent liver growth and tumorigenesis.

Main Results:

• Downregulation of G6PC promotes glucose storage and glycogen accumulation in pre-malignant liver cells.
• Accumulated glycogen undergoes liquid-liquid phase separation, sequestering Hippo kinases (Mst1/2) and relieving Yap inhibition.
• Deficiency in G6PC or PYGL leads to glycogen storage disease, liver enlargement, and Yap-dependent tumorigenesis in humans and mice.
• Eliminating glycogen accumulation prevents liver growth and cancer, while increased storage accelerates it.

Conclusions:

• Cancer-initiating cells adopt a glycogen-storing phenotype.
• Glycogen phase separation inhibits Hippo signaling by sequestering kinases, thereby promoting Yap activity.
• Targeting glycogen metabolism or its phase separation properties may offer novel therapeutic strategies for liver cancer.