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Targeting tumor cell plasticity by combined inhibition of NOTCH and MAPK signaling in colon cancer

In colorectal cancer, signaling pathways driving tumor progression are promising targets for systemic therapy. Besides WNT and MAPK signaling, activation of NOTCH signaling is found in most tumors. Here, we demonstrate that high NOTCH activity marks a distinct colon cancer cell subpopulation with lo...

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Autores principales: Schmidt, Eva Marina, Lamprecht, Sebastian, Blaj, Cristina, Schaaf, Christian, Krebs, Stefan, Blum, Helmut, Hermeking, Heiko, Jung, Andreas, Kirchner, Thomas, Horst, David
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5987917/
https://www.ncbi.nlm.nih.gov/pubmed/29769248
http://dx.doi.org/10.1084/jem.20171455
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author Schmidt, Eva Marina
Lamprecht, Sebastian
Blaj, Cristina
Schaaf, Christian
Krebs, Stefan
Blum, Helmut
Hermeking, Heiko
Jung, Andreas
Kirchner, Thomas
Horst, David
author_facet Schmidt, Eva Marina
Lamprecht, Sebastian
Blaj, Cristina
Schaaf, Christian
Krebs, Stefan
Blum, Helmut
Hermeking, Heiko
Jung, Andreas
Kirchner, Thomas
Horst, David
author_sort Schmidt, Eva Marina
collection PubMed
description In colorectal cancer, signaling pathways driving tumor progression are promising targets for systemic therapy. Besides WNT and MAPK signaling, activation of NOTCH signaling is found in most tumors. Here, we demonstrate that high NOTCH activity marks a distinct colon cancer cell subpopulation with low levels of WNT and MAPK activity and with a pronounced epithelial phenotype. Therapeutic targeting of MAPK signaling had limited effects on tumor growth and caused expansion of tumor cells with high NOTCH activity, whereas upon targeting NOTCH signaling, tumor cells with high MAPK activity prevailed. Lineage-tracing experiments indicated high plasticity between both tumor cell subpopulations as a mechanism for treatment resistance. Combined targeting of NOTCH and MAPK had superior therapeutic effects on colon cancer growth in vivo. These data demonstrate that tumor cells may evade systemic therapy through tumor cell plasticity and provide a new rationale for simultaneous targeting of different colon cancer cell subpopulations.
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spelling pubmed-59879172018-12-04 Targeting tumor cell plasticity by combined inhibition of NOTCH and MAPK signaling in colon cancer Schmidt, Eva Marina Lamprecht, Sebastian Blaj, Cristina Schaaf, Christian Krebs, Stefan Blum, Helmut Hermeking, Heiko Jung, Andreas Kirchner, Thomas Horst, David J Exp Med Research Articles In colorectal cancer, signaling pathways driving tumor progression are promising targets for systemic therapy. Besides WNT and MAPK signaling, activation of NOTCH signaling is found in most tumors. Here, we demonstrate that high NOTCH activity marks a distinct colon cancer cell subpopulation with low levels of WNT and MAPK activity and with a pronounced epithelial phenotype. Therapeutic targeting of MAPK signaling had limited effects on tumor growth and caused expansion of tumor cells with high NOTCH activity, whereas upon targeting NOTCH signaling, tumor cells with high MAPK activity prevailed. Lineage-tracing experiments indicated high plasticity between both tumor cell subpopulations as a mechanism for treatment resistance. Combined targeting of NOTCH and MAPK had superior therapeutic effects on colon cancer growth in vivo. These data demonstrate that tumor cells may evade systemic therapy through tumor cell plasticity and provide a new rationale for simultaneous targeting of different colon cancer cell subpopulations. Rockefeller University Press 2018-06-04 /pmc/articles/PMC5987917/ /pubmed/29769248 http://dx.doi.org/10.1084/jem.20171455 Text en © 2018 Schmidt et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Research Articles
Schmidt, Eva Marina
Lamprecht, Sebastian
Blaj, Cristina
Schaaf, Christian
Krebs, Stefan
Blum, Helmut
Hermeking, Heiko
Jung, Andreas
Kirchner, Thomas
Horst, David
Targeting tumor cell plasticity by combined inhibition of NOTCH and MAPK signaling in colon cancer
title Targeting tumor cell plasticity by combined inhibition of NOTCH and MAPK signaling in colon cancer
title_full Targeting tumor cell plasticity by combined inhibition of NOTCH and MAPK signaling in colon cancer
title_fullStr Targeting tumor cell plasticity by combined inhibition of NOTCH and MAPK signaling in colon cancer
title_full_unstemmed Targeting tumor cell plasticity by combined inhibition of NOTCH and MAPK signaling in colon cancer
title_short Targeting tumor cell plasticity by combined inhibition of NOTCH and MAPK signaling in colon cancer
title_sort targeting tumor cell plasticity by combined inhibition of notch and mapk signaling in colon cancer
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5987917/
https://www.ncbi.nlm.nih.gov/pubmed/29769248
http://dx.doi.org/10.1084/jem.20171455
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