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A Diffusion-like Pr...
A Diffusion-like Process Accommodates New Crypts During Clonal Expansion in Human Colonic Epithelium
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- Olpe, Cora (author)
- Li Ka Shing Ctr, Canc Res UK Cambridge Inst, Robinson Way, Cambridge CB2 0RE, England; Wellcome Trust Med Res Council, Cambridge Stem Cell Inst, Cambridge, England
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- Khamis, Doran (author)
- Univ Oxford, John Radcliffe Hosp, MRC Weatherall Inst Mol Med, Oxford OX3 9DS, England
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- Chukanova, Maria (author)
- Li Ka Shing Ctr, Canc Res UK Cambridge Inst, Robinson Way, Cambridge CB2 0RE, England
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- Skoufou-Papoutsaki, Nefeli (author)
- Li Ka Shing Ctr, Canc Res UK Cambridge Inst, Robinson Way, Cambridge CB2 0RE, England; Wellcome Trust Med Res Council, Cambridge Stem Cell Inst, Cambridge, England
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- Kemp, Richard (author)
- Li Ka Shing Ctr, Canc Res UK Cambridge Inst, Robinson Way, Cambridge CB2 0RE, England
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- Marks, Kate (author)
- St James Univ Hosp, Pathol & Data Analyt, Leeds, W Yorkshire, England
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- Tatton, Cerys (author)
- Li Ka Shing Ctr, Canc Res UK Cambridge Inst, Robinson Way, Cambridge CB2 0RE, England
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- Lindskog, Cecilia (author)
- Uppsala universitet,Science for Life Laboratory, SciLifeLab,Klinisk och experimentell patologi
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- Nicholson, Anna (author)
- Li Ka Shing Ctr, Canc Res UK Cambridge Inst, Robinson Way, Cambridge CB2 0RE, England
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- Brunton-Sim, Roxanne (author)
- Norwich Res Pk BioRepository, Norwich, Norfolk, England
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- Malhotra, Shalini (author)
- Univ Cambridge, Dept Oncol, Cambridge, England
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- ten Hoopen, Rogier (author)
- Univ Cambridge, Dept Oncol, Cambridge, England
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- Stanley, Rachael (author)
- Norwich Res Pk BioRepository, Norwich, Norfolk, England
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- Winton, Douglas J. (author)
- Li Ka Shing Ctr, Canc Res UK Cambridge Inst, Robinson Way, Cambridge CB2 0RE, England; Wellcome Trust Med Res Council, Cambridge Stem Cell Inst, Cambridge, England
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- Morrissey, Edward (author)
- Li Ka Shing Ctr, Canc Res UK Cambridge Inst, Robinson Way, Cambridge CB2 0RE, England.;Univ Oxford, John Radcliffe Hosp, MRC Weatherall Inst Mol Med, Oxford OX3 9DS, England
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(creator_code:org_t)
- Elsevier, 2021
- 2021
- English.
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In: Gastroenterology. - : Elsevier. - 0016-5085 .- 1528-0012. ; 161:2, s. 548-559
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Abstract
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- Background & AimsColorectal cancer (CRC) is thought to arise when the cumulative mutational burden within colonic crypts exceeds a certain threshold that leads to clonal expansion and ultimately neoplastic transformation. Therefore, quantification of the fixation and subsequent expansion of somatic mutations in normal epithelium is key to understanding colorectal cancer initiation. The aim of the present study was to determine how advantaged expansions can be accommodated in the human colon.MethodsImmunohistochemistry was used to visualize loss of the cancer driver KDM6A in formalin-fixed paraffin-embedded (FFPE) normal human colonic epithelium. Combining microscopy with neural network-based image analysis, we determined the frequencies of KDM6A-mutant crypts and fission/fusion intermediates as well as the spatial distribution of clones. Mathematical modeling then defined the dynamics of their fixation and expansion.ResultsInterpretation of the age-related behavior of KDM6A-negative clones revealed significant competitive advantage in intracrypt dynamics as well as a 5-fold increase in crypt fission rate. This was not accompanied by an increase in crypt fusion. Mathematical modeling of crypt spacing identifies evidence for a crypt diffusion process. We define the threshold fission rate at which diffusion fails to accommodate new crypts, which can be exceeded by KRAS activating mutations.ConclusionsAdvantaged gene mutations in KDM6A expand dramatically by crypt fission but not fusion. The crypt diffusion process enables accommodation of the additional crypts up to a threshold value, beyond which polyp growth may occur. The fission rate associated with KRAS mutations offers a potential explanation for KRAS-initiated polyps.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Gastroenterologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Gastroenterology and Hepatology (hsv//eng)
Keyword
- Colorectal Cancer Initiation
- Intestinal Crypt
- Crypt Fission
- Crypt Fusion
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Olpe, Cora
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Khamis, Doran
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Chukanova, Maria
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Skoufou-Papoutsa ...
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Kemp, Richard
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Marks, Kate
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Tatton, Cerys
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Lindskog, Cecili ...
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Nicholson, Anna
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Brunton-Sim, Rox ...
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Malhotra, Shalin ...
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ten Hoopen, Rogi ...
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Stanley, Rachael
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Winton, Douglas ...
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Morrissey, Edwar ...
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Cancer and Oncol ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Gastroenterology ...
- Articles in the publication
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Gastroenterology
- By the university
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Uppsala University