GREM1 is required to maintain cellular heterogeneity in pancreatic cancer

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, Jessica Nelson, Gabriela Koifman, Joana Carvalho, Emma L. Nye, Yulong He, Changhua Zhang, Anguraj Sadanandam and Axel Behrens ()
Additional contact information
Linxiang Lan: The Institute of Cancer Research
Theodore Evan: The Institute of Cancer Research
Huafu Li: The Institute of Cancer Research
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
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
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
Axel Behrens: The Institute of Cancer Research

Nature, 2022, vol. 607, issue 7917, 163-168

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41586-022-04888-7

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