Proteogenomic Network Analysis of Context-Specific KRAS Signaling in Mouse-to-Human Cross-Species Translation

Area of Science:

• Oncology
• Molecular Biology
• Systems Biology

Background:

• KRAS mutations are frequent drivers in colorectal carcinoma (CRC) and pancreatic ductal adenocarcinoma (PDAC).
• Targeting KRAS oncogenicity is challenging due to limited understanding of signaling modulation by contextual cues.
• Context-specific signaling alterations by mutant KRAS impact therapeutic strategies.

Purpose of the Study:

• To investigate how tissue context and genetic background modulate oncogenic signaling in KRAS-mutant cancers.
• To identify novel therapeutic targets by integrating mouse and human cancer datasets.
• To understand the context-dependent plasticity of oncogenic KRAS signaling.

Main Methods:

• Mass spectrometry was employed on mouse tissues with wild-type or mutant Kras.
• Proteomic and phosphoproteomic analyses were performed on preneoplastic and neoplastic colon and pancreas.
• A statistical approach was developed to "humanize" mouse networks with human cancer data.

Main Results:

• Mutant Kras significantly altered proteomes and phosphoproteomes in a context-specific manner in colon and pancreas.
• Humanized CRC and PDAC networks revealed genes synthetically lethal with mutant KRAS.
• Non-canonical mediators of KRAS oncogenicity were identified within the signaling network.

Conclusions:

• Oncogenic KRAS signaling exhibits context-dependent plasticity.
• Statistical integration of cross-species data can uncover therapeutic insights.
• This study provides a framework for identifying novel therapeutic targets in KRAS-driven cancers.