RHOA^L57V drives the development of diffuse gastric cancer through IGF1R-PAK1-YAP1 signaling

Area of Science:

• Oncology
• Molecular Biology
• Cell Biology

Background:

• Mutations in the guanosine triphosphatase (GTPase) RHOA are implicated in cancer, with specific prevalent mutations in diffuse gastric cancer (DGC).
• RHOA^Y42C is a known oncogenic driver in DGC, but the mechanisms by which RHOA^L57V promotes DGC remain less understood.

Purpose of the Study:

• To elucidate the molecular mechanisms by which the RHOA^L57V mutation drives the progression of diffuse gastric cancer (DGC).
• To compare the distinct signaling pathways utilized by RHOA^L57V and RHOA^Y42C in promoting DGC.

Main Methods:

• Utilized mouse gastric organoids with Cdh1 deletion to model DGC.
• Assessed RHOA^L57V gain-of-function, GTP hydrolysis, effector interactions, and downstream signaling pathways including YAP1, IGF1R, PAK1, and FAK.
• Introduced analogous mutations in KRAS to investigate GTPase-specific effects.

Main Results:

• RHOA^L57V expression in mouse gastric organoids induced abnormal morphology and promoted F-actin stress fiber formation and cell migration, similar to patient-derived DGC.
• RHOA^L57V exhibited impaired GTP hydrolysis, favoring the active GTP-bound state, and retained effector interactions.
• Both RHOA^L57V and RHOA^Y42C activated YAP1; however, RHOA^L57V additionally activated IGF1R and PAK1, whereas RHOA^Y42C utilized FAK.

Conclusions:

• RHOA^L57V acts as an oncogenic driver in DGC through distinct gain-of-function mechanisms involving impaired GTP hydrolysis and specific kinase activation (IGF1R, PAK1).
• The study reveals differential signaling mechanisms between RHOA^L57V and RHOA^Y42C in driving DGC progression.
• These findings highlight the importance of understanding specific mutation-driven pathways for targeted DGC therapies.