LRRK2 G2019S Promotes Colon Cancer Potentially via LRRK2-GSDMD Axis-Mediated Gut Inflammation

Area of Science:

• Molecular Biology
• Oncology
• Gastroenterology

Background:

• Leucine-rich repeat kinase 2 (LRRK2) is a serine-threonine kinase.
• The LRRK2 G2019S mutation is linked to Parkinson's disease and increased cancer risk.
• Mechanisms connecting LRRK2 G2019S to colon cancer are not well understood.

Purpose of the Study:

• To investigate the role of LRRK2 G2019S in colon cancer development.
• To elucidate the molecular mechanisms by which LRRK2 G2019S influences colorectal tumorigenesis.

Main Methods:

• Utilized a colitis-associated cancer (CAC) mouse model.
• Employed LRRK2 G2019S knock-in (KI) mouse models.
• Administered dextran sulfate sodium (DSS) to induce colitis.
• Assessed tumor development, inflammation, cell proliferation, and inflammasome activation.
• Tested the efficacy of LRRK2 kinase inhibitors and GSDMD inhibitors.

Main Results:

• LRRK2 G2019S significantly increased tumor number and size in KI mice.
• LRRK2 G2019S enhanced intestinal epithelial cell proliferation and inflammation.
• KI mice showed increased susceptibility to DSS-induced colitis.
• LRRK2 G2019S promoted inflammasome activation and gut epithelium necrosis.
• Inhibition of LRRK2 kinase activity and GSDMD attenuated colitis and CAC progression.

Conclusions:

• Gain-of-kinase activity in LRRK2 promotes colorectal tumorigenesis.
• LRRK2 G2019S exacerbates inflammation and cell death in the colon.
• LRRK2 represents a potential therapeutic target for colon cancer patients with elevated kinase activity.