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Nature genetics
12, 2022;54 (12): 1827-1838.

The NALCN channel regulates metastasis and nonmalignant cell dissemination.

Eric P Rahrmann, David Shorthouse, Amir Jassim, Linda P Hu, Mariaestela Ortiz, Betania Mahler-Araujo, Peter Vogel, Marta Paez-Ribes, Atefeh Fatemi, Gregory J Hannon, Radhika Iyer, Jay A Blundon, Filipe C Lourenço, Jonathan Kay, Rosalynn M Nazarian, Benjamin A Hall, Stanislav S Zakharenko, Douglas J Winton, Liqin Zhu, Richard J Gilbertson
Author Information
  1. Eric P Rahrmann: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
  2. David Shorthouse: Department of Medical Physics and Biomedical Engineering, University College London, London, UK. ORCID
  3. Amir Jassim: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
  4. Linda P Hu: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
  5. Mariaestela Ortiz: Molecular Pharmacology Lab, Organoid Models Research and Biology, National Cancer Institute, Leidos Biomedical Research, Frederick, MD, USA.
  6. Betania Mahler-Araujo: Wellcome-MRC Institute of Metabolic Science, Histopathology Core, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
  7. Peter Vogel: Veterinary Pathology Core Laboratory, St Jude Children's Research Hospital, Memphis, TN, USA. ORCID
  8. Marta Paez-Ribes: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
  9. Atefeh Fatemi: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
  10. Gregory J Hannon: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK. ORCID
  11. Radhika Iyer: Texas Children's Cancer and Hematology Centers, Houston, TX, USA.
  12. Jay A Blundon: Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, TN, USA.
  13. Filipe C Lourenço: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK. ORCID
  14. Jonathan Kay: Departments of Medicine and of Population and Quantitative Health Sciences, University of Massachusetts Medical School and UMass Memorial Medical Center, Worcester, MA, USA. ORCID
  15. Rosalynn M Nazarian: Massachusetts General Hospital, Pathology Service, Dermatopathology Unit, Boston, MA, USA.
  16. Benjamin A Hall: Department of Medical Physics and Biomedical Engineering, University College London, London, UK. ORCID
  17. Stanislav S Zakharenko: Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, TN, USA. ORCID
  18. Douglas J Winton: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK. ORCID
  19. Liqin Zhu: Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN, USA. ORCID
  20. Richard J Gilbertson: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK. Richard.Gilbertson@cruk.cam.ac.uk. ORCID
PMID: 36175792 DOI: 10.1038/s41588-022-01182-0

Abstract

We identify the sodium leak channel non-selective protein (NALCN) as a key regulator of cancer metastasis and nonmalignant cell dissemination. Among 10,022 human cancers, NALCN loss-of-function mutations were enriched in gastric and colorectal cancers. Deletion of Nalcn from gastric, intestinal or pancreatic adenocarcinomas in mice did not alter tumor incidence, but markedly increased the number of circulating tumor cells (CTCs) and metastases. Treatment of these mice with gadolinium-a NALCN channel blocker-similarly increased CTCs and metastases. Deletion of Nalcn from mice that lacked oncogenic mutations and never developed cancer caused shedding of epithelial cells into the blood at levels equivalent to those seen in tumor-bearing animals. These cells trafficked to distant organs to form normal structures including lung epithelium, and kidney glomeruli and tubules. Thus, NALCN regulates cell shedding from solid tissues independent of cancer, divorcing this process from tumorigenesis and unmasking a potential new target for antimetastatic therapies.

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Grants

  1. MR/S000216/1/Medical Research Council
  2. MR/S000216/2/Medical Research Council
  3. R56 MH097742/NIMH NIH HHS
  4. 22492/Cancer Research UK
  5. R01 MH097742/NIMH NIH HHS
  6. P30 CA021765/NCI NIH HHS
  7. R01 DC012833/NIDCD NIH HHS

MeSH Term

Humans
Mice
Animals
Neoplasms
Ion Channels
Membrane Proteins

Chemicals

NALCN protein, human
Ion Channels
Membrane Proteins
NALCN protein, mouse
Journal Article Research Support, Non-U.S. Gov't Research Support, N.I.H., Extramural

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