Spatially-Resolved Multiomic Atlas of Leiomyosarcoma Identifies Two Clinically Relevant Epigenetically-Driven Cell...

Area of Science:

• Oncology
• Molecular Biology
• Epigenetics

Background:

• Leiomyosarcoma (LMS) is a heterogeneous smooth muscle malignancy with poorly understood cellular and molecular underpinnings.
• Existing knowledge gaps hinder effective therapeutic strategies for LMS.

Purpose of the Study:

• To investigate the transcriptomic and epigenomic landscape of untreated primary leiomyosarcoma.
• To identify distinct cellular states and their molecular drivers within LMS.
• To uncover subtype-specific tumor-immune interactions and therapeutic vulnerabilities.

Main Methods:

• Single-nucleus multiome sequencing on primary LMS tissues.
• Chromatin accessibility profiling to identify transcription factor motifs.
• Spatial transcriptomics to analyze tumor microenvironment.
• Epigenetic inhibitor screening for therapeutic targets.

Main Results:

• Identified two novel, epigenetically distinct LMS subtypes: mesenchymal-like (MES) and smooth muscle-enriched (SMC).
• Discovered subtype-specific transcription factor enrichment (NFI in MES, AP-1/FOSL2 in SMC) crucial for tumor growth.
• Revealed preferential clustering of immunosuppressive macrophages around MES regions, forming a distinct tumor-immune niche.
• MES-dominant tumors showed significantly worse patient outcomes.
• Validated SMARCA4/2 inhibition as a therapeutic vulnerability for MES LMS.

Conclusions:

• Defined two epigenetically driven, transcription factor-regulated LMS states (MES and SMC).
• Elucidated mechanistic underpinnings of LMS heterogeneity and subtype-specific tumor-immune interactions.
• Identified SMARCA4/2 inhibition as a promising therapeutic strategy for MES leiomyosarcoma.