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

Autores
Paolino, Magdalena; Choidas, Axel; Wallner, Stephanie; Pranjic, Blanka; Uribesalgo, Iris; Loeser, Stefanie; Jamieson, Amanda M.; Langdon, Wallace Y.; Ikeda, Fumiyo; Fededa, Juan Pablo; Cronin, Shane J.; Nitsch, Roberto; Schultz-Fademrecht, Carsten; Eickhoff, Jan; Menninger, Sascha; Unger, Anke; Torka, Robert; Gruber, Thomas; Hinterleitner, Reinhard; Baier, Gottfried; Wolf, Dominik; Ullrich, Axel; Klebl, Bert M.; Penninger, Josef M.
Año de publicación
2014
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
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. © 2014 Macmillan Publishers Limited.
Fil: Paolino, Magdalena. Institute Of Molecular Biotechnology, Vienna; Austria
Fil: Choidas, Axel. Lead Discovery Center GmbH; Alemania
Fil: Wallner, Stephanie. Medizinische Universitat Innsbruck; Austria
Fil: Pranjic, Blanka. Institute Of Molecular Biotechnology, Vienna; Austria
Fil: Uribesalgo, Iris. Institute Of Molecular Biotechnology, Vienna; Austria
Fil: Loeser, Stefanie. Institute Of Molecular Biotechnology, Vienna; Austria
Fil: Jamieson, Amanda M.. University Brown; Estados Unidos
Fil: Langdon, Wallace Y.. University of Western Australia; Australia
Fil: Ikeda, Fumiyo. Institute Of Molecular Biotechnology, Vienna; Austria
Fil: Fededa, Juan Pablo. Institute Of Molecular Biotechnology, Vienna; Austria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina
Fil: Cronin, Shane J.. Institute Of Molecular Biotechnology, Vienna; Austria
Fil: Nitsch, Roberto. Institute Of Molecular Biotechnology, Vienna; Austria
Fil: Schultz-Fademrecht, Carsten. Lead Discovery Center GmbH; Alemania
Fil: Eickhoff, Jan. Lead Discovery Center GmbH; Alemania
Fil: Menninger, Sascha. Lead Discovery Center GmbH; Alemania
Fil: Unger, Anke. Lead Discovery Center GmbH; Alemania
Fil: Torka, Robert. Institute for Biochemistry Max-Planck; Alemania
Fil: Gruber, Thomas. Medizinische Universitat Innsbruck; Austria
Fil: Hinterleitner, Reinhard. Medizinische Universitat Innsbruck; Austria
Fil: Baier, Gottfried. Medizinische Universitat Innsbruck; Austria
Fil: Wolf, Dominik. University Hospital Bonn; Alemania. Medical University Innsbruck; Austria
Fil: Ullrich, Axel. Institute for Biochemistry Max-Planck; Alemania
Fil: Klebl, Bert M.. Lead Discovery Center GmbH; Alemania
Fil: Penninger, Josef M.. Institute Of Molecular Biotechnology, Vienna; Austria
Materia
Immunosurveillance
Tumor Metastasis
Natural Killer Cells
Innate Immunity
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/37324
Acceder
id CONICETDig_7a542e64ee724f193b33144430bf75e9
oai_identifier_str oai:ri.conicet.gov.ar:11336/37324
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cellsPaolino, MagdalenaChoidas, AxelWallner, StephaniePranjic, BlankaUribesalgo, IrisLoeser, StefanieJamieson, Amanda M.Langdon, Wallace Y.Ikeda, FumiyoFededa, Juan PabloCronin, Shane J.Nitsch, RobertoSchultz-Fademrecht, CarstenEickhoff, JanMenninger, SaschaUnger, AnkeTorka, RobertGruber, ThomasHinterleitner, ReinhardBaier, GottfriedWolf, DominikUllrich, AxelKlebl, Bert M.Penninger, Josef M.ImmunosurveillanceTumor MetastasisNatural Killer CellsInnate Immunityhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Tumour 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. © 2014 Macmillan Publishers Limited.Fil: Paolino, Magdalena. Institute Of Molecular Biotechnology, Vienna; AustriaFil: Choidas, Axel. Lead Discovery Center GmbH; AlemaniaFil: Wallner, Stephanie. Medizinische Universitat Innsbruck; AustriaFil: Pranjic, Blanka. Institute Of Molecular Biotechnology, Vienna; AustriaFil: Uribesalgo, Iris. Institute Of Molecular Biotechnology, Vienna; AustriaFil: Loeser, Stefanie. Institute Of Molecular Biotechnology, Vienna; AustriaFil: Jamieson, Amanda M.. University Brown; Estados UnidosFil: Langdon, Wallace Y.. University of Western Australia; AustraliaFil: Ikeda, Fumiyo. Institute Of Molecular Biotechnology, Vienna; AustriaFil: Fededa, Juan Pablo. Institute Of Molecular Biotechnology, Vienna; Austria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Cronin, Shane J.. Institute Of Molecular Biotechnology, Vienna; AustriaFil: Nitsch, Roberto. Institute Of Molecular Biotechnology, Vienna; AustriaFil: Schultz-Fademrecht, Carsten. Lead Discovery Center GmbH; AlemaniaFil: Eickhoff, Jan. Lead Discovery Center GmbH; AlemaniaFil: Menninger, Sascha. Lead Discovery Center GmbH; AlemaniaFil: Unger, Anke. Lead Discovery Center GmbH; AlemaniaFil: Torka, Robert. Institute for Biochemistry Max-Planck; AlemaniaFil: Gruber, Thomas. Medizinische Universitat Innsbruck; AustriaFil: Hinterleitner, Reinhard. Medizinische Universitat Innsbruck; AustriaFil: Baier, Gottfried. Medizinische Universitat Innsbruck; AustriaFil: Wolf, Dominik. University Hospital Bonn; Alemania. Medical University Innsbruck; AustriaFil: Ullrich, Axel. Institute for Biochemistry Max-Planck; AlemaniaFil: Klebl, Bert M.. Lead Discovery Center GmbH; AlemaniaFil: Penninger, Josef M.. Institute Of Molecular Biotechnology, Vienna; AustriaNature Publishing Group2014-03info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/37324Paolino, Magdalena; Choidas, Axel; Wallner, Stephanie; Pranjic, Blanka; Uribesalgo, Iris; et al.; The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells; Nature Publishing Group; Nature; 507; 7493; 3-2014; 508-5120028-0836CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://www.nature.com/nature/journal/v507/n7493/full/nature12998.htmlinfo:eu-repo/semantics/altIdentifier/doi/10.1038/nature12998info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-10T13:16:09Zoai:ri.conicet.gov.ar:11336/37324instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-10 13:16:09.478CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells
title The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells
spellingShingle The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells
Paolino, Magdalena
Immunosurveillance
Tumor Metastasis
Natural Killer Cells
Innate Immunity
title_short The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells
title_full The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells
title_fullStr The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells
title_full_unstemmed The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells
title_sort The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells
dc.creator.none.fl_str_mv Paolino, Magdalena
Choidas, Axel
Wallner, Stephanie
Pranjic, Blanka
Uribesalgo, Iris
Loeser, Stefanie
Jamieson, Amanda M.
Langdon, Wallace Y.
Ikeda, Fumiyo
Fededa, Juan Pablo
Cronin, Shane J.
Nitsch, Roberto
Schultz-Fademrecht, Carsten
Eickhoff, Jan
Menninger, Sascha
Unger, Anke
Torka, Robert
Gruber, Thomas
Hinterleitner, Reinhard
Baier, Gottfried
Wolf, Dominik
Ullrich, Axel
Klebl, Bert M.
Penninger, Josef M.
author Paolino, Magdalena
author_facet Paolino, Magdalena
Choidas, Axel
Wallner, Stephanie
Pranjic, Blanka
Uribesalgo, Iris
Loeser, Stefanie
Jamieson, Amanda M.
Langdon, Wallace Y.
Ikeda, Fumiyo
Fededa, Juan Pablo
Cronin, Shane J.
Nitsch, Roberto
Schultz-Fademrecht, Carsten
Eickhoff, Jan
Menninger, Sascha
Unger, Anke
Torka, Robert
Gruber, Thomas
Hinterleitner, Reinhard
Baier, Gottfried
Wolf, Dominik
Ullrich, Axel
Klebl, Bert M.
Penninger, Josef M.
author_role author
author2 Choidas, Axel
Wallner, Stephanie
Pranjic, Blanka
Uribesalgo, Iris
Loeser, Stefanie
Jamieson, Amanda M.
Langdon, Wallace Y.
Ikeda, Fumiyo
Fededa, Juan Pablo
Cronin, Shane J.
Nitsch, Roberto
Schultz-Fademrecht, Carsten
Eickhoff, Jan
Menninger, Sascha
Unger, Anke
Torka, Robert
Gruber, Thomas
Hinterleitner, Reinhard
Baier, Gottfried
Wolf, Dominik
Ullrich, Axel
Klebl, Bert M.
Penninger, Josef M.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Immunosurveillance
Tumor Metastasis
Natural Killer Cells
Innate Immunity
topic Immunosurveillance
Tumor Metastasis
Natural Killer Cells
Innate Immunity
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv 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. © 2014 Macmillan Publishers Limited.
Fil: Paolino, Magdalena. Institute Of Molecular Biotechnology, Vienna; Austria
Fil: Choidas, Axel. Lead Discovery Center GmbH; Alemania
Fil: Wallner, Stephanie. Medizinische Universitat Innsbruck; Austria
Fil: Pranjic, Blanka. Institute Of Molecular Biotechnology, Vienna; Austria
Fil: Uribesalgo, Iris. Institute Of Molecular Biotechnology, Vienna; Austria
Fil: Loeser, Stefanie. Institute Of Molecular Biotechnology, Vienna; Austria
Fil: Jamieson, Amanda M.. University Brown; Estados Unidos
Fil: Langdon, Wallace Y.. University of Western Australia; Australia
Fil: Ikeda, Fumiyo. Institute Of Molecular Biotechnology, Vienna; Austria
Fil: Fededa, Juan Pablo. Institute Of Molecular Biotechnology, Vienna; Austria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina
Fil: Cronin, Shane J.. Institute Of Molecular Biotechnology, Vienna; Austria
Fil: Nitsch, Roberto. Institute Of Molecular Biotechnology, Vienna; Austria
Fil: Schultz-Fademrecht, Carsten. Lead Discovery Center GmbH; Alemania
Fil: Eickhoff, Jan. Lead Discovery Center GmbH; Alemania
Fil: Menninger, Sascha. Lead Discovery Center GmbH; Alemania
Fil: Unger, Anke. Lead Discovery Center GmbH; Alemania
Fil: Torka, Robert. Institute for Biochemistry Max-Planck; Alemania
Fil: Gruber, Thomas. Medizinische Universitat Innsbruck; Austria
Fil: Hinterleitner, Reinhard. Medizinische Universitat Innsbruck; Austria
Fil: Baier, Gottfried. Medizinische Universitat Innsbruck; Austria
Fil: Wolf, Dominik. University Hospital Bonn; Alemania. Medical University Innsbruck; Austria
Fil: Ullrich, Axel. Institute for Biochemistry Max-Planck; Alemania
Fil: Klebl, Bert M.. Lead Discovery Center GmbH; Alemania
Fil: Penninger, Josef M.. Institute Of Molecular Biotechnology, Vienna; Austria
description 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. © 2014 Macmillan Publishers Limited.
publishDate 2014
dc.date.none.fl_str_mv 2014-03
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/37324
Paolino, Magdalena; Choidas, Axel; Wallner, Stephanie; Pranjic, Blanka; Uribesalgo, Iris; et al.; The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells; Nature Publishing Group; Nature; 507; 7493; 3-2014; 508-512
0028-0836
CONICET Digital
CONICET
url http://hdl.handle.net/11336/37324
identifier_str_mv Paolino, Magdalena; Choidas, Axel; Wallner, Stephanie; Pranjic, Blanka; Uribesalgo, Iris; et al.; The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells; Nature Publishing Group; Nature; 507; 7493; 3-2014; 508-512
0028-0836
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://www.nature.com/nature/journal/v507/n7493/full/nature12998.html
info:eu-repo/semantics/altIdentifier/doi/10.1038/nature12998
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 12.993085

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