@article{b27c29a41ac248f58bebcd26fc50d354,
title = "The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells",
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 therapies2. 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 biology3. This novel TAM/Cbl-b inhibitory pathway shows that it might be possible to develop a a 'pill' that awakens the innate immune system to kill cancer metastases.",
author = "Magdalena Paolino and Axel Choidas and Stephanie Wallner and Blanka Pranjic and Iris Uribesalgo and Stefanie Loeser and Jamieson, {Amanda M.} and Langdon, {Wallace Y.} and Fumiyo Ikeda and Fededa, {Juan Pablo} and Cronin, {Shane J.} and Roberto Nitsch and Carsten Schultz-Fademrecht and Jan Eickhoff and Sascha Menninger and Anke Unger and Robert Torka and Thomas Gruber and Reinhard Hinterleitner and Gottfried Baier and Dominik Wolf and Axel Ullrich and Klebl, {Bert M.} and Penninger, {Josef M.}",
note = "Funding Information: Acknowledgements We thank T. Hanada, R. Hanada, R. Karim and all other members of the Penninger laboratory for discussions and technical support. We thank all members of the IMP-IMBA BioOptics service facility for assistance in cell sorting and image quantification, and S. Soto and H. Popper for pathology analysis of tumour metastases. We thank A. L. Prieto, E. Vivier, D. Raulet and C. Melief for providing us with critical reagents and C. Martinez, A. Majoros and P. C. Esk for sharing reagents and for discussions. We also thank G. K{\'e}ri, L. {\"O}rfi and colleagues from Vichem Kft., Budapest, for their initial synthetic work on the quinoline-based Axl inhibitors, which served as the basis for the current rationale design of LDC1267. M.P. is supported by the European Research Council (ERC) and Era of Hope/DoD Innovator Award. J.M.P. is supported by grants from the Institute of Molecular Biotechnology (IMBA), the Austrian National Foundation, the Austrian Academy of Sciences, GEN-AU (AustroMouse), an Era of Hope/DoD Innovator Award and an EU ERC Advanced Grant.",
year = "2014",
doi = "10.1038/nature12998",
language = "English",
volume = "507",
pages = "508--512",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7493",
}
