From Normal Mucosa to Colorectal Cancer in Lynch Syndrome: Single-Cell Dissection of Cellular Heterogeneity and...

Area of Science:

• Genomics and Molecular Biology
• Cancer Research
• Immunology

Background:

• Lynch syndrome (LS) significantly increases colorectal cancer (CRC) risk.
• Understanding the cellular dynamics of LS-CRC development is crucial for targeted therapies.
• A comprehensive single-cell atlas of LS-CRC progression is lacking.

Purpose of the Study:

• To create a single-cell atlas of colorectal cancer (CRC) development in Lynch syndrome (LS).
• To identify cellular reprogramming events during LS-CRC progression.
• To delineate intercellular communication networks in the LS-CRC microenvironment.

Main Methods:

• Single-cell RNA sequencing (scRNA-seq) on matched normal, adenoma, and carcinoma tissues from LS patients.
• Bioinformatic analyses including UMAP clustering, differential gene expression, and Gene Set Variation Analysis (GSVA).
• Functional validation using patient-derived organoids and transwell assays; Cell Chat for communication network inference.

Main Results:

• Identified twelve cell clusters with significant compositional shifts during CRC progression (increased lymphocytes/macrophages, decreased epithelial cells).
• Revealed a differentiation trajectory from BEST4+ to CEMIP+/EGFR+ epithelial cells.
• Demonstrated DMBT1 downregulation activates WNT/β-catenin, promoting growth and migration; identified an immunosuppressive microenvironment with expanded regulatory T cells and specific macrophage populations.

Conclusions:

• This study provides a valuable single-cell resource for LS-associated CRC.
• Highlights DMBT1 loss, epithelial remodeling, and immune dysregulation as key features of LS-CRC.
• Suggests these factors as potential therapeutic targets for LS-CRC.