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Cited by 114Cancer Cells and MetastasisWnt/β-catenin signaling in development and cancerDevelopmental Biology and Gene Regulation

Tracing oncogene-driven remodelling of the intestinal stem cell niche

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Yum, Min Kyu, Han, Seungmin, Fink, Juergen, Wu, Szu-Hsien Sam, Dabrowska, Catherine, Trendafilova, Teodora, Mustata, Roxana, Chatzeli, Lemonia +10 more·2021·Nature
DOI 10.1038/s41586-021-03605-0PMC PMC7614896
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Abstract

Interactions between tumour cells and the surrounding microenvironment contribute to tumour progression, metastasis and recurrence 1-3. Although mosaic analyses in Drosophila have advanced our understanding of such interactions 4,5, it has been difficult to engineer parallel approaches in vertebrates. Here we present an oncogene-associated, multicolour reporter mouse model-the Red2Onco system-that allows differential tracing of mutant and wild-type cells in the same tissue. By applying this system to the small intestine, we show that oncogene-expressing mutant crypts alter the cellular organization of neighbouring wild-type crypts, thereby driving accelerated clonal drift. Crypts that express oncogenic KRAS or PI3K secrete BMP ligands that suppress local stem cell activity, while changes in PDGFR lo CD81+ stromal cells induced by crypts with oncogenic PI3K alter the WNT signalling environment. Together, these results show how oncogene-driven paracrine remodelling creates a niche environment that is detrimental to the maintenance of wild-type tissue, promoting field transformation dominated by oncogenic clones.

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  • The precursor cells of basal keratinocytes, squamous cells, and melanocytes are present within the skin organoid, setting the stage for researchers to investigate mechanisms of cancer initiation.

    “The precursor cells of basal keratinocytes, squamous cells, and melanocytes are present within the skin organoid, setting the stage for researchers to investigate mechanisms of cancer initiation”

    From Generation and characterization of hair-bearing skin organoids from human pluripotent stem cells (2022) · cites this paper as [56]

    The Methods section describes intestinal epithelial organoids made from mouse small-intestinal crypts, not skin organoids. Searches for skin organoids, keratinocyte and melanocyte precursors found no passage addressing the claimed cell types or their use to investigate cancer initiation. The Extended Data mention imaging skin tissue, but not a skin organoid. (LLM, conf=0.76)

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Authors
Yum, M. K., Han, S., Fink, J., Wu, S.-H. S., Dabrowska, C., Trendafilova, T., Mustata, R., Chatzeli, L., Azzarelli, R., Pshenichnaya, I., Lee, E., England, F., Kim, J. K., Stange, D. E., Philpott, A., Lee, J.-H., Koo, B.-K., & Simons, B. D.
Affiliations
  • Wellcome/MRC Cambridge Stem Cell Institute (GB)
  • Institute of Molecular Biotechnology (AT)
  • Daegu Gyeongbuk Institute of Science and Technology (KR)
  • University Hospital Carl Gustav Carus (DE)
Corresponding author
  • Koo, Bon-Kyoung
  • Simons, Benjamin D.
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2021-06-02
Volume
594
Issue
7863
Pages
442-447
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-021-03605-0
PMC
PMC7614896
OpenAlex
W3164768747
Cited by
114
References
7
Citations by year
2026: 13 · 2025: 19 · 2024: 30 · 2023: 16 · 2022: 24 · 2021: 12
FWCI
7.36
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • Apollo (University of Cambridge) (submittedVersion)
  • Apollo
Funders
  • Wellcome Trust (092096/Z/10/Z, 679411, 107633/Z/15/Z, 098357/Z/12/Z, 219478/Z/19/Z, 092096)
  • Cancer Research UK (25636, 23363, A25636)
  • Royal Society (RP\R1\180165)
  • Medical Research Council (MC_PC_17230)
Topics
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
Keywords
intestinal stem cell niche, field transformation, KRAS, phosphatidylinositol 3-kinase, BMP signaling, Wnt signaling, paracrine signaling, tumor microenvironment, small intestine crypts, tumor progression
MeSH terms
Animals, Clone Cells, Female, Intestine, Small, Male, Mutation, Oncogenes, Neoplastic Stem Cells, Colorectal Neoplasms, Reproducibility of Results, Phosphatidylinositol 3-Kinases, Wnt Proteins, Mice, Stem Cell Niche, Single-Cell Analysis, Tumor Microenvironment, Wnt Signaling Pathway

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