A proteogenomic atlas of 1032 brain metastases identifies molecular subtypes, immune landscapes, and therapeutic...

Area of Science:

• Oncology
• Molecular Biology
• Genomics

Background:

• Brain metastases exhibit significant molecular heterogeneity, complicating effective therapeutic strategies.
• A comprehensive understanding of brain metastases subtypes is crucial for advancing treatment development.

Purpose of the Study:

• To construct a multi-omic, single-cell, and spatially resolved atlas of 1,032 pan-cancer brain metastases.
• To identify and characterize distinct molecular subtypes of brain metastases.
• To uncover subtype-specific vulnerabilities and potential therapeutic targets.

Main Methods:

• Generation of a comprehensive atlas using multi-omic, single-cell, and spatial resolution techniques.
• Analysis of 1,032 pan-cancer brain metastases samples.
• Utilized patient-derived organoids and targeted drug screening.

Main Results:

• Identified four robust molecular subtypes of brain metastases (BrMS): neural-like (BrMS1), immune-infiltrated (BrMS2), metabolic (BrMS3), and proliferative/immune-excluded (BrMS4).
• BrMS2 exhibits a coordinated epithelial-mesenchymal transition program.
• Subtype-specific dependencies identified, including mTOR signaling in BrMS3 and CDK4/6 axis in BrMS4.

Conclusions:

• The developed atlas provides a rigorous classification framework for brain metastases.
• Distinct biological programs and clinical associations characterize the identified BrMS subtypes.
• Insights into subtype-specific vulnerabilities offer potential avenues for targeted therapies.