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

Author:

Schmidt Eva Marina1ORCID,Lamprecht Sebastian1ORCID,Blaj Cristina1,Schaaf Christian1,Krebs Stefan2,Blum Helmut2,Hermeking Heiko134,Jung Andreas134ORCID,Kirchner Thomas134,Horst David1345ORCID

Affiliation:

1. Pathologisches Institut, Ludwig-Maximilians-Universität München, Munich, Germany

2. Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, Ludwig-Maximilians-Universität München, Munich, Germany

3. German Cancer Consortium (DKTK), Heidelberg, Germany

4. German Cancer Research Center (DKFZ), Heidelberg, Germany

5. Institut für Pathologie, Charité – Universitätsmedizin Berlin, Berlin, Germany

Abstract

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.

Funder

Deutsche Krebshilfe

Rudolf Bartling Stiftung

Curt-Bohnewand-Fonds

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

Cited by 31 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3