Single-cell analyses define a continuum of cell state and composition changes in the malignant transformation of polyps to colorectal cancer

To chart cell composition and cell state changes that occur during the transformation of healthy colon to precancerous adenomas to colorectal cancer (CRC), we generated single-cell chromatin accessibility profiles and single-cell transcriptomes from 1,000 to 10,000 cells per sample for 48 polyps, 27...

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Veröffentlicht in:Nature genetics Jg. 54; H. 7; S. 985 - 995
Hauptverfasser: Becker, Winston R., Nevins, Stephanie A., Chen, Derek C., Chiu, Roxanne, Horning, Aaron M., Guha, Tuhin K., Laquindanum, Rozelle, Mills, Meredith, Chaib, Hassan, Ladabaum, Uri, Longacre, Teri, Shen, Jeanne, Esplin, Edward D., Kundaje, Anshul, Ford, James M., Curtis, Christina, Snyder, Michael P., Greenleaf, William J.
Format: Journal Article
Sprache:Englisch
Veröffentlicht: New York Nature Publishing Group US 01.07.2022
Nature Publishing Group
Schlagworte:
631/208/176
631/208/191
631/208/200
631/67
631/67/1504
Accessibility
Adenoma - genetics
Adenoma - pathology
Adenomatous polyposis coli
Agriculture
Animal Genetics and Genomics
Antigen-presenting cells
Biomedical and Life Sciences
Biomedicine
Cancer
Cancer Research
Cell Transformation, Neoplastic - genetics
Chromatin
Colon
Colorectal cancer
Colorectal carcinoma
Colorectal Neoplasms - genetics
Colorectal Neoplasms - pathology
Composition
Datasets
DNA methylation
DNA Methylation - genetics
Epigenetics
Fibroblasts
Gene expression
Gene Function
Generalized linear models
Genetic transformation
Genomics
Hepatocyte nuclear factor 4
Homeostasis
Human Genetics
Humans
Immunoregulation
Lymphocytes
Lymphocytes T
Mutation
Phenotypes
Polyps
Runx1 protein
Single-Cell Analysis
Stems
Transcriptomes
Tumors
ISSN:1061-4036, 1546-1718, 1546-1718
Online-Zugang:Volltext
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Zusammenfassung:To chart cell composition and cell state changes that occur during the transformation of healthy colon to precancerous adenomas to colorectal cancer (CRC), we generated single-cell chromatin accessibility profiles and single-cell transcriptomes from 1,000 to 10,000 cells per sample for 48 polyps, 27 normal tissues and 6 CRCs collected from patients with or without germline APC mutations. A large fraction of polyp and CRC cells exhibit a stem-like phenotype, and we define a continuum of epigenetic and transcriptional changes occurring in these stem-like cells as they progress from homeostasis to CRC. Advanced polyps contain increasing numbers of stem-like cells, regulatory T cells and a subtype of pre-cancer-associated fibroblasts. In the cancerous state, we observe T cell exhaustion, RUNX1-regulated cancer-associated fibroblasts and increasing accessibility associated with HNF4A motifs in epithelia. DNA methylation changes in sporadic CRC are strongly anti-correlated with accessibility changes along this continuum, further identifying regulatory markers for molecular staging of polyps. Single-cell ATAC-seq and RNA-seq profiling traces the transformation of healthy colon to precancerous adenomas to colorectal cancer (CRC). A large proportion of polyp and CRC cells show a stem-like phenotype.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
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ISSN:1061-4036
1546-1718
1546-1718
DOI:10.1038/s41588-022-01088-x