ArticleProceedings of the National Academy of Sciences of the United States of America2013
Lineage tracing reveals multipotent stem cells maintain human adenomas and the pattern of clonal expansion in tumor evolution.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 60 papers.
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Who cites it
60 citing papers in PubMed, 102 citations in OpenAlex.
- Gastrointestinal conventional carcinoma with neuroendocrine differentiation: From pathological phenomenon to clinical importance (Review).Oncology letters · 2026Review
- MEX3A Modulates PPARγ Pathway Activity and Colorectal Cancer Growth.Cellular and molecular gastroenterology and hepatology · 2026Article
- TyCHE enables time-resolved lineage tracing of heterogeneously-evolving populations.bioRxiv : the preprint server for biology · 2025Article
- High-content confocal analysis of tumorigenesis, cancer stem cells, and drug response in 3D cholangiocarcinoma cultures.Scientific reports · 2025Article
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- Resolving tumor evolution: a phylogenetic approach.Journal of the National Cancer Center · 2024Review
- The frequency of dysplastic branching crypts in colorectal polypoid tubular adenomas.International journal of experimental pathology · 2023Article
- Grave-to-cradle: human embryonic lineage tracing from the postmortem body.Experimental & molecular medicine · 2023Review
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- Formation of benign tumors by stem cell deregulation.PLoS genetics · 2022Review
- Liver Colonization by Colorectal Cancer Metastases Requires YAP-Controlled Plasticity at the Micrometastatic Stage.Cancer research · 2022Article
- Fluctuating methylation clocks for cell lineage tracing at high temporal resolution in human tissues.Nature biotechnology · 2022Article
- Article
- Cytokine-mediated crosstalk between cancer stem cells and their inflammatory niche from the colorectal precancerous adenoma stage to the cancerous stage: Mechanisms and clinical implications.Frontiers in immunology · 2022Review
- Article
- Review
- Integrative Analysis of Biomarkers Through Machine Learning Identifies Stemness Features in Colorectal Cancer.Frontiers in cell and developmental biology · 2021Article
- Genetic Alterations of Metastatic Colorectal Cancer.Biomedicines · 2020Review
- Minimal barriers to invasion during human colorectal tumor growth.Nature communications · 2020Article
- Case report: recurrent pituitary adenoma has increased load of somatic variants.BMC endocrine disorders · 2020Article
Corrections and comments
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Authors and funding
15 authors at 4 institutions in 3 countries.
Funding
Abstract
The genetic and morphological development of colorectal cancer is a paradigm for tumorigenesis. However, the dynamics of clonal evolution underpinning carcinogenesis remain poorly understood. Here we identify multipotential stem cells within human colorectal adenomas and use methylation patterns of nonexpressed genes to characterize clonal evolution. Numerous individual crypts from six colonic adenomas and a hyperplastic polyp were microdissected and characterized for genetic lesions. Clones deficient in cytochrome c oxidase (CCO(-)) were identified by histochemical staining followed by mtDNA sequencing. Topographical maps of clone locations were constructed using a combination of these data. Multilineage differentiation within clones was demonstrated by immunofluorescence. Methylation patterns of adenomatous crypts were determined by clonal bisulphite sequencing; methylation pattern diversity was compared with a mathematical model to infer to clonal dynamics. Individual adenomatous crypts were clonal for mtDNA mutations and contained both mucin-secreting and neuroendocrine cells, demonstrating that the crypt contained a multipotent stem cell. The intracrypt methylation pattern was consistent with the crypts containing multiple competing stem cells. Adenomas were epigenetically diverse populations, suggesting that they were relatively mitotically old populations. Intratumor clones typically showed less diversity in methylation pattern than the tumor as a whole. Mathematical modeling suggested that recent clonal sweeps encompassing the whole adenoma had not occurred. Adenomatous crypts within human tumors contain actively dividing stem cells. Adenomas appeared to be relatively mitotically old populations, pocketed with occasional newly generated subclones that were the result of recent rapid clonal expansion. Relative stasis and occasional rapid subclone growth may characterize colorectal tumorigenesis.
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