Cited by 456Immune Cell Function and InteractionImmune cells in cancerCancer Immunotherapy and Biomarkers

The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells

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Paolino, Magdalena, Choidas, Axel, Wallner, Stephanie, Pranjic, Blanka, Uribesalgo, Iris, Loeser, Stefanie, Jamieson, Amanda M., Langdon, Wallace Y. +16 more·2014·Nature

Abstract

Tumour metastasis is the primary cause of mortality in cancer patients and remains the key challenge for cancer therapy. New therapeutic approaches to block inhibitory pathways of the immune system have renewed hopes for the utility of such therapies. Here we show that genetic deletion of the E3 ubiquitin ligase Cbl-b (casitas B-lineage lymphoma-b) or targeted inactivation of its E3 ligase activity licenses natural killer (NK) cells to spontaneously reject metastatic tumours. The TAM tyrosine kinase receptors Tyro3, Axl and Mer (also known as Mertk) were identified as ubiquitylation substrates for Cbl-b. Treatment of wild-type NK cells with a newly developed small molecule TAM kinase inhibitor conferred therapeutic potential, efficiently enhancing anti-metastatic NK cell activity in vivo. Oral or intraperitoneal administration using this TAM inhibitor markedly reduced murine mammary cancer and melanoma metastases dependent on NK cells. We further report that the anticoagulant warfarin exerts anti-metastatic activity in mice via Cbl-b/TAM receptors in NK cells, providing a molecular explanation for a 50-year-old puzzle in cancer biology. This novel TAM/Cbl-b inhibitory pathway shows that it might be possible to develop a 'pill' that awakens the innate immune system to kill cancer metastases.

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  • Immune cells can attenuate metastasis.

    “On one hand, there is evidence that immune cells have the capability to attenuate metastasis[54–59], which provides insight into how to restore or enhance their ability to combat cancer.”

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Authors
Paolino, M., Choidas, A., Wallner, S., Pranjic, B., Uribesalgo, I., Loeser, S., Jamieson, A. M., Langdon, W. Y., Ikeda, F., Fededa, J. P., Cronin, S. J., Nitsch, R., Schultz-Fademrecht, C., Eickhoff, J., Menninger, S., Unger, A., Torka, R., Gruber, T., Hinterleitner, R., Baier, G., Wolf, D., Ullrich, A., Klebl, B. M., & Penninger, J. M.
Affiliations
  • Institute of Molecular Biotechnology (AT)
  • Lead Discovery Center (Germany) (DE)
  • Innsbruck Medical University (AT)
  • Brown University (US)
  • The University of Western Australia (AU)
  • Max Planck Institute of Biochemistry (DE)
Corresponding author
Penninger, Josef M.
Venue
Nature
Published
2014-02-19
Volume
507
Issue
7493
Pages
508-512
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
OpenAlex
W2088565779
Cited by
456
References
38
Citations by year
2026: 13 · 2025: 35 · 2024: 31 · 2023: 43 · 2022: 29 · 2021: 44 · 2020: 47 · 2019: 40 · 2018: 39 · 2017: 44 · 2016: 45 · 2015: 22 · 2014: 23
FWCI
20.54
Type
journal article
Language
en
Open access
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • UWA Profiles and Research Repository (UWA) (submittedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • Max Planck Digital Library (submittedVersion)
  • MPG.PuRe (Max Planck Society) (submittedVersion)
  • CONICET Digital (CONICET) (submittedVersion, cc-by-nc-sa)
Funders
Österreichischen Akademie der Wissenschaften
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Cell Function and Interaction
  • Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Keywords
Cbl-b, E3 ubiquitin ligase, TAM receptors, natural killer cells, metastasis, Tyro3, AXL, Mer, MERTK, warfarin, anti-metastatic therapy, melanoma metastasis, innate immunity
MeSH terms
c-Mer Tyrosine Kinase, Axl Receptor Tyrosine Kinase, Animals, Anticoagulants, Female, Killer Cells, Natural, Male, Mammary Neoplasms, Experimental, Melanoma, Experimental, Mice, Inbred BALB C, Mice, Inbred C57BL, Neoplasm Metastasis, Proto-Oncogene Proteins, Warfarin, Receptor Protein-Tyrosine Kinases, Ubiquitin-Protein Ligases, Adaptor Proteins, Signal Transducing, Proto-Oncogene Proteins c-cbl, Mice, Ubiquitination

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