Linnekamp, Janneke F., van Hooff, Sander R., Prasetyanti, Pramudita R., Kandimalla, Raju ORCID: 0000-0002-0342-5229, Buikhuisen, Joyce Y., Fessler, Evelyn, Ramesh, Prashanthi, Lee, Kelly A. S. T., Bochove, Grehor G. W., de Jong, Johan H., Cameron, Kate, van Leersum, Ronald, Rodermond, Hans M., Franitza, Marek, Nuernberg, Peter, Mangiapane, Laura R., Wang, Xin, Clevers, Hans, Vermeulen, Louis, Stassi, Giorgio and Medema, Jan Paul (2018). Consensus molecular subtypes of colorectal cancer are recapitulated in in vitro and in vivo models. Cell Death Differ., 25 (3). S. 616 - 634. LONDON: NATURE PUBLISHING GROUP. ISSN 1476-5403

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Abstract

Colorectal cancer (CRC) is a highly heterogeneous disease both from a molecular and clinical perspective. Several distinct molecular entities, such as microsatellite instability (MSI), have been defined that make up biologically distinct subgroups with their own clinical course. Recent data indicated that CRC can be best segregated into four groups called consensus molecular subtypes (CMS1-4), each of which has a unique biology and gene expression pattern. In order to develop improved, subtype-specific therapies and to gain insight into the molecular wiring and origin of these subtypes, reliable models are needed. This study was designed to determine the heterogeneity and identify the presence of CMSs in a large panel of CRC cell lines, primary cultures and patient-derived xenografts (PDX). We provide a repository encompassing this heterogeneity and moreover describe that a large part of the models can be robustly assigned to one of the four CMSs, independent of the stromal contribution. We subsequently validate our CMS stratification by functional analysis which for instance shows mesenchymal enrichment in CMS4 and metabolic dysregulation in CMS3. Finally, we observe a clear difference in sensitivity to chemotherapy-induced apoptosis, specifically between CMS2 and CMS4. This relates to the in vivo efficacy of chemotherapy, which delays outgrowth of CMS2, but not CMS4 xenografts. Combined our data indicate that molecular subtypes are faithfully modelled in CRC cell cultures and PDXs, representing tumour cell intrinsic and stable features. This repository provides researchers with a platform to study CRC using the existing heterogeneity.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Linnekamp, Janneke F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Hooff, Sander R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Prasetyanti, Pramudita R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kandimalla, RajuUNSPECIFIEDorcid.org/0000-0002-0342-5229UNSPECIFIED
Buikhuisen, Joyce Y.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fessler, EvelynUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ramesh, PrashanthiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lee, Kelly A. S. T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bochove, Grehor G. W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
de Jong, Johan H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cameron, KateUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Leersum, RonaldUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rodermond, Hans M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Franitza, MarekUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mangiapane, Laura R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wang, XinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Clevers, HansUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vermeulen, LouisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stassi, GiorgioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Medema, Jan PaulUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-193232
DOI: 10.1038/s41418-017-0011-5
Journal or Publication Title: Cell Death Differ.
Volume: 25
Number: 3
Page Range: S. 616 - 634
Date: 2018
Publisher: NATURE PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 1476-5403
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
COLON-CANCER; POOR-PROGNOSIS; CELL-LINES; PRECISION MEDICINE; DRUG-SENSITIVITY; PHASE-3 TRIAL; EXPRESSION; IDENTIFICATION; TUMORIGENESIS; METASTASISMultiple languages
Biochemistry & Molecular Biology; Cell BiologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/19323

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