Spatially defined multicellular functional units in colorectal cancer revealed from single cell and spatial...

Area of Science:

• Genomics
• Cancer Biology
• Spatial Transcriptomics

Background:

• Single cell genomics advances tumor ecosystem analysis but struggles with spatial organization and interactions.
• Characterizing cellular spatial organization is crucial for understanding tumor progression and disease outcomes.

Purpose of the Study:

• To create a detailed spatial map of healthy and dysplastic colon cellular ecosystems.
• To investigate the association between cellular spatial organization and colorectal cancer (CRC) progression.
• To develop a framework for extrapolating findings from mouse models to human diseases.

Main Methods:

• Combined single cell RNA sequencing (scRNA-seq), Slide-seq spatial transcriptomics, and in situ multiplex RNA analysis.
• Profiled inducible genetic CRC mouse models that recapitulate human CRC features.
• Assigned cell types and expression programs to spatial locations and computationally identified regional features.

Main Results:

• Tumors organized into distinct cellular neighborhoods with unique cell subtypes, expression programs, and local interactions.
• Cell composition and spatial layout features were conserved between mouse models and human CRC.
• Mouse tumor neighborhoods correlated with malignancy and clinical outcome in human patient tumors.

Conclusions:

• The study provides a comprehensive framework for spatial mapping of cellular ecosystems applicable across various tissues and diseases.
• Identified conserved spatial organization principles in CRC across species.
• Highlights the translational relevance of mouse models for understanding human colorectal cancer progression and outcomes.