Cargando…
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...
Autores principales: | , , , , , , , , , |
---|---|
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 |
_version_ | 1783329208018141184 |
---|---|
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. |
format | Online Article Text |
id | pubmed-5987917 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Rockefeller University Press |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT schmidtevamarina targetingtumorcellplasticitybycombinedinhibitionofnotchandmapksignalingincoloncancer AT lamprechtsebastian targetingtumorcellplasticitybycombinedinhibitionofnotchandmapksignalingincoloncancer AT blajcristina targetingtumorcellplasticitybycombinedinhibitionofnotchandmapksignalingincoloncancer AT schaafchristian targetingtumorcellplasticitybycombinedinhibitionofnotchandmapksignalingincoloncancer AT krebsstefan targetingtumorcellplasticitybycombinedinhibitionofnotchandmapksignalingincoloncancer AT blumhelmut targetingtumorcellplasticitybycombinedinhibitionofnotchandmapksignalingincoloncancer AT hermekingheiko targetingtumorcellplasticitybycombinedinhibitionofnotchandmapksignalingincoloncancer AT jungandreas targetingtumorcellplasticitybycombinedinhibitionofnotchandmapksignalingincoloncancer AT kirchnerthomas targetingtumorcellplasticitybycombinedinhibitionofnotchandmapksignalingincoloncancer AT horstdavid targetingtumorcellplasticitybycombinedinhibitionofnotchandmapksignalingincoloncancer |