Two Hippo signaling modules orchestrate liver size and tumorigenesis

Area of Science:

• Cellular biology
• Molecular biology
• Cancer research

Background:

• The Hippo pathway is a critical regulator of organ size and a key player in tumorigenesis.
• Its complex regulatory network involves numerous proteins, including kinase cascades.

Purpose of the Study:

• To elucidate the roles of two distinct Hippo signaling modules (HPO1 and HPO2) in regulating LATS1/2 kinases and YAP/TAZ transcriptional co-activators.
• To investigate their impact on organ size control and tumorigenesis in mouse liver models.

Main Methods:

• Genetic inactivation of HPO1 and HPO2 modules in mouse liver models.
• Analysis of YAP/TAZ activation, cell proliferation, and tumor development.
• Assessment of organ size changes and survival rates.

Main Results:

• Inactivation of either HPO1 or HPO2 led to partial YAP/TAZ activation, bile duct hyperplasia, and hepatocellular carcinoma (HCC).
• Simultaneous inactivation of both modules caused full YAP/TAZ activation, rapid intrahepatic cholangiocarcinoma (iCCA) development, and early lethality.
• HPO1 predominantly regulates organ size, with its inactivation causing uniform YAP/TAZ activation and liver enlargement.

Conclusions:

• The HPO1 and HPO2 modules act in concert to precisely control LATS1/2 and YAP/TAZ activity.
• Differential regulation by these modules dictates distinct cell fates, organ size alterations, and tumorigenesis outcomes.
• This study reconstructs the Hippo signaling network order, revealing its intricate role in maintaining tissue homeostasis and preventing cancer.