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Tracing oncogene-driven remodelling of the intestinal stem cell niche

Author

Listed:
  • Min Kyu Yum

    (University of Cambridge
    University of Cambridge)

  • Seungmin Han

    (University of Cambridge
    University of Cambridge)

  • Juergen Fink

    (University of Cambridge)

  • Szu-Hsien Sam Wu

    (Vienna Biocenter (VBC)
    Doctoral School at the University of Vienna and Medical University of Vienna)

  • Catherine Dabrowska

    (University of Cambridge
    University of Cambridge)

  • Teodora Trendafilova

    (University of Cambridge)

  • Roxana Mustata

    (University of Cambridge)

  • Lemonia Chatzeli

    (University of Cambridge
    University of Cambridge)

  • Roberta Azzarelli

    (University of Cambridge
    University of Cambridge, Hutchison–MRC Research Centre)

  • Irina Pshenichnaya

    (University of Cambridge)

  • Eunmin Lee

    (DGIST)

  • Frances England

    (University of Cambridge
    University of Cambridge)

  • Jong Kyoung Kim

    (DGIST)

  • Daniel E. Stange

    (University Hospital Carl Gustav Carus, Medical Faculty, Technische Universität Dresden)

  • Anna Philpott

    (University of Cambridge
    University of Cambridge, Hutchison–MRC Research Centre)

  • Joo-Hyeon Lee

    (University of Cambridge
    University of Cambridge)

  • Bon-Kyoung Koo

    (University of Cambridge
    Vienna Biocenter (VBC))

  • Benjamin D. Simons

    (University of Cambridge
    University of Cambridge
    University of Cambridge)

Abstract

Interactions between tumour cells and the surrounding microenvironment contribute to tumour progression, metastasis and recurrence1–3. Although mosaic analyses in Drosophila have advanced our understanding of such interactions4,5, 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 PDGFRloCD81+ 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.

Suggested Citation

  • Min Kyu Yum & Seungmin Han & Juergen Fink & Szu-Hsien Sam Wu & Catherine Dabrowska & Teodora Trendafilova & Roxana Mustata & Lemonia Chatzeli & Roberta Azzarelli & Irina Pshenichnaya & Eunmin Lee & Fr, 2021. "Tracing oncogene-driven remodelling of the intestinal stem cell niche," Nature, Nature, vol. 594(7863), pages 442-447, June.
    • Handle: RePEc:nat:nature:v:594:y:2021:i:7863:d:10.1038_s41586-021-03605-0
    DOI: 10.1038/s41586-021-03605-0
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    Citations

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    Cited by:

    1. Kazuki Nakai & Hancheng Lin & Shotaro Yamano & Shinya Tanaka & Sho Kitamoto & Hitoshi Saitoh & Kenta Sakuma & Junpei Kurauchi & Eilma Akter & Masamitsu Konno & Kojiro Ishibashi & Ryo Kamata & Akihiro , 2023. "Wnt activation disturbs cell competition and causes diffuse invasion of transformed cells through NF-κB-MMP21 pathway," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Szu-Hsien Sam Wu & Somi Kim & Heetak Lee & Ji-Hyun Lee & So-Yeon Park & Réka Bakonyi & Isaree Teriyapirom & Natalia Hallay & Sandra Pilat-Carotta & Hans-Christian Theussl & Jihoon Kim & Joo-Hyeon Lee , 2024. "Red2Flpe-SCON: a versatile, multicolor strategy for generating mosaic conditional knockout mice," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    3. Ignacio Bordeu & Lemonia Chatzeli & Benjamin D. Simons, 2023. "Inflationary theory of branching morphogenesis in the mouse salivary gland," Nature Communications, Nature, vol. 14(1), pages 1-11, December.

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