6533b838fe1ef96bd12a3ebc
RESEARCH PRODUCT
Consensus molecular subtypes of colorectal cancer are recapitulated in in vitro and in vivo models
Pramudita R. PrasetyantiRonald Van LeersumJanneke F. LinnekampLouis VermeulenEvelyn FesslerPeter NürnbergMarek FranitzaHans CleversLaura Rosa MangiapaneRaju KandimallaKate CameronSander R. Van HooffGiorgio StassiKelly A S T LeeJohan H De JongJoyce Y. BuikhuisenHans M. RodermondXin WangJan Paul MedemaPrashanthi RameshGrehor G W Bochovesubject
0301 basic medicineStromal cellColorectal cancerCellMice NudeAntineoplastic AgentsApoptosisComputational biologyBiologyModels BiologicalArticle03 medical and health sciencesMiceStructure-Activity Relationship0302 clinical medicineIn vivomedicineBiomarkers TumorTumor Cells CulturedAnimalsHumansMolecular BiologyCell ProliferationRegulation of gene expressionDose-Response Relationship DrugGene Expression ProfilingMesenchymal stem cellMicrosatellite instabilityCell DifferentiationNeoplasms ExperimentalCell Biologymedicine.diseaseGene expression profilingGene Expression Regulation NeoplasticOxaliplatin030104 developmental biologymedicine.anatomical_structure030220 oncology & carcinogenesisFluorouracilDrug Screening Assays AntitumorColorectal Neoplasmsdescription
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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2018-03-01 | Cell death and differentiation |