Consensus molecular subtypes of colorectal cancer are recapitulated in in vitro and in vivo models
Consensus molecular subtypes of colorectal cancer are recapitulated in in vitro and in vivo models
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DOI：
10.1038/s41418-017-0011-5
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发表时间：
2018-03-01
影响因子：
12.4
通讯作者：
Medema, Jan Paul
中科院分区：
文献类型：
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作者：
Linnekamp, Janneke F.;van Hooff, Sander R.;Medema, Jan Paul
结直肠癌（CRC）无论从分子还是临床角度来看都是一种高度异质性的疾病。一些不同的分子实体，如微卫星不稳定性（MSI），已经被定义为构成生物学上不同的亚群，具有自己的临床过程。最近的数据表明，CRC可以最好地分为四组，称为共识分子亚型（CMS1-4），每一组都有独特的生物学和基因表达模式。为了开发改进的、针对亚型的治疗方法，并深入了解这些亚型的分子连接和起源，需要可靠的模型。本研究旨在确定cms在大量CRC细胞系、原代培养和患者来源的异种移植物（PDX）中的异质性和存在。我们提供了一个包含这种异质性的存储库，并且描述了大部分模型可以健壮地分配到四个cms中的一个，独立于基质的贡献。随后，我们通过功能分析验证了我们的CMS分层，例如显示了CMS4的间质富集和CMS3的代谢失调。最后，我们观察到对化疗诱导的细胞凋亡的敏感性有明显差异，特别是在CMS2和CMS4之间。这与化疗的体内疗效有关，化疗会延迟CMS2的生长，但不会延迟CMS4异种移植。综合我们的数据表明，分子亚型在CRC细胞培养和pdx中被忠实地模拟，代表了肿瘤细胞的内在和稳定特征。该存储库为研究人员提供了一个利用现有异构性研究CRC的平台。
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.