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

The Journal of Experimental Medicine
Eva Marina SchmidtD Horst

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.

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Citations

Aug 11, 2020·World Journal of Gastroenterology : WJG·Sinem Cil GonulcuGulsum Ozlem Elpek
Sep 27, 2018·World Journal of Gastrointestinal Oncology·Ashok Kumar PanduranganGanapasam Sudhandiran
May 24, 2019·Cancer Science·Christoph SpartalisDavid Horst

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Methods Mentioned

BETA
xenografts
xenograft
RNA-Seq
surgical resection
biopsy
PCR
HTseq

Software Mentioned

DEseq2
SPSS
Photoshop
Volocity
ZEN
GraphPad
Prism
edgeR
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GSEA

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