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Differential pre-malignant programs and microenvironment chart distinct paths to malignancy in human colorectal
Bob Chen1, Cherie' R Scurrah2, Eliot T McKinley2
1Program in Chemical and Physical Biology, Vanderbilt University School of Medicine, Nashville, TN, USA; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA.
Cell
|December 15, 2021
Summary
This study reveals distinct cellular origins for common colorectal polyps, differentiating between adenomas and serrated polyps. Understanding these origins offers new avenues for colorectal cancer (CRC) prevention and precision surveillance.
Area of Science:
- Cellular and Molecular Biology
- Oncology
- Immunology
Background:
- Colorectal cancers (CRCs) develop from precursor polyps.
- Understanding polyp cellular origins and molecular features is crucial for CRC diagnosis and treatment.
- High-resolution analysis can uncover key insights into polyp progression.
Purpose of the Study:
- To create a single-cell transcriptomic and imaging atlas of conventional adenomas and serrated polyps.
- To investigate the cellular origins and molecular differences between these polyps and their CRC counterparts.
- To identify immune microenvironment characteristics associated with malignant progression.
Main Methods:
- Single-cell transcriptomic and imaging analysis of 128 datasets from 62 participants.
- Integrative analysis of polyp and CRC samples.
- Comparative analysis of cellular origins, molecular profiles, and immune microenvironments.
Main Results:
- Adenomas originate from WNT-driven stem cell expansion.
- Serrated polyps develop from differentiated cells via gastric metaplasia.
- Metaplasia-associated damage correlates with a cytotoxic immune microenvironment and hypermutation.
- Microsatellite unstable CRCs show distinct non-metaplastic regions with stem cell properties and depleted cytotoxic immune cells.
Conclusions:
- The study provides a multi-omic atlas detailing colorectal polyp malignant progression.
- Distinct pathways for adenoma and serrated polyp development are elucidated.
- Insights into the immune microenvironment offer a framework for CRC precision surveillance and prevention.
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