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GREM1 is required to maintain cellular heterogeneity in pancreatic cancer

Author

Listed:
  • Linxiang Lan

    (The Institute of Cancer Research)

  • Theodore Evan

    (The Institute of Cancer Research)

  • Huafu Li

    (The Institute of Cancer Research
    The Seventh Affiliated Hospital of Sun Yat-Sen University)

  • Aasia Hussain

    (The Institute of Cancer Research)

  • E. Josue Ruiz

    (The Institute of Cancer Research)

  • May Zaw Thin

    (The Institute of Cancer Research)

  • Rute M. M. Ferreira

    (The Francis Crick Institute)

  • Hari Ps

    (The Institute of Cancer Research)

  • Eva M. Riising

    (Samplix ApS)

  • Yoh Zen

    (King’s College Hospital)

  • Jorge Almagro

    (The Institute of Cancer Research
    The Francis Crick Institute)

  • Kevin W. Ng

    (The Francis Crick Institute)

  • Pablo Soro-Barrio

    (The Francis Crick Institute)

  • Jessica Nelson

    (The Institute of Cancer Research)

  • Gabriela Koifman

    (The Institute of Cancer Research)

  • Joana Carvalho

    (The Francis Crick Institute
    Champalimaud Foundation)

  • Emma L. Nye

    (The Francis Crick Institute)

  • Yulong He

    (The Seventh Affiliated Hospital of Sun Yat-Sen University)

  • Changhua Zhang

    (The Seventh Affiliated Hospital of Sun Yat-Sen University)

  • Anguraj Sadanandam

    (The Institute of Cancer Research
    The Institute of Cancer Research)

  • Axel Behrens

    (The Institute of Cancer Research
    Imperial College London
    Imperial College)

Abstract

Pancreatic ductal adenocarcinoma (PDAC) shows pronounced epithelial and mesenchymal cancer cell populations1–4. Cellular heterogeneity in PDAC is an important feature in disease subtype specification3–5, but how distinct PDAC subpopulations interact, and the molecular mechanisms that underlie PDAC cell fate decisions, are incompletely understood. Here we identify the BMP inhibitor GREM16,7 as a key regulator of cellular heterogeneity in pancreatic cancer in human and mouse. Grem1 inactivation in established PDAC in mice resulted in a direct conversion of epithelial into mesenchymal PDAC cells within days, suggesting that persistent GREM1 activity is required to maintain the epithelial PDAC subpopulations. By contrast, Grem1 overexpression caused an almost complete ‘epithelialization’ of highly mesenchymal PDAC, indicating that high GREM1 activity is sufficient to revert the mesenchymal fate of PDAC cells. Mechanistically, Grem1 was highly expressed in mesenchymal PDAC cells and inhibited the expression of the epithelial–mesenchymal transition transcription factors Snai1 (also known as Snail) and Snai2 (also known as Slug) in the epithelial cell compartment, therefore restricting epithelial–mesenchymal plasticity. Thus, constant suppression of BMP activity is essential to maintain epithelial PDAC cells, indicating that the maintenance of the cellular heterogeneity of pancreatic cancer requires continuous paracrine signalling elicited by a single soluble factor.

Suggested Citation

  • Linxiang Lan & Theodore Evan & Huafu Li & Aasia Hussain & E. Josue Ruiz & May Zaw Thin & Rute M. M. Ferreira & Hari Ps & Eva M. Riising & Yoh Zen & Jorge Almagro & Kevin W. Ng & Pablo Soro-Barrio & Je, 2022. "GREM1 is required to maintain cellular heterogeneity in pancreatic cancer," Nature, Nature, vol. 607(7917), pages 163-168, July.
    • Handle: RePEc:nat:nature:v:607:y:2022:i:7917:d:10.1038_s41586-022-04888-7
    DOI: 10.1038/s41586-022-04888-7
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    Cited by:

    1. Lee Shaashua & Aviad Ben-Shmuel & Meirav Pevsner-Fischer & Gil Friedman & Oshrat Levi-Galibov & Subhiksha Nandakumar & Debra Barki & Reinat Nevo & Lauren E. Brown & Wenhan Zhang & Yaniv Stein & Chen L, 2022. "BRCA mutational status shapes the stromal microenvironment of pancreatic cancer linking clusterin expression in cancer associated fibroblasts with HSF1 signaling," Nature Communications, Nature, vol. 13(1), pages 1-21, December.

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