A molecular sub-cluster of colon cancer cells with low VDR expression is sensitive to chemotherapy, BRAF inhibitors and PI3K-mTOR inhibitors treatment
A molecular sub-cluster of colon cancer cells with low VDR expression is sensitive to chemotherapy, BRAF inhibitors and PI3K-mTOR inhibitors treatment
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DOI：
10.18632/aging.102349
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发表时间：
2019-10-15
期刊：
影响因子：
5.2
通讯作者：
Cao, Hua
中科院分区：
文献类型：
--
作者：
Wang, Haiwei;Wang, Xinrui;Cao, Hua
基于基因表达的共识分子亚型(CMS)和非负矩阵分解(NMF)亚群是结肠癌的可靠分类系统。尽管分子特征是明确的，但基于结肠癌亚组的干预是有限的。为了解决这个问题，我们分析了CMS和NMF亚组在结肠癌细胞系中引导的药物敏感性。CMS3亚型细胞对5-FU敏感，而CMS4亚型细胞对顺铂敏感。在NMF分类中，亚群对化疗、BRAF抑制剂、PI3K-mTOR抑制剂和Notch抑制剂治疗特别敏感。该亚群具有低频率的TP53、POL、PIK3CA和BRAF突变。转录分析显示，在这个亚群中，Notch信号活性低，CDX2和VDR表达低。CDX2和VDR与化疗、BRAF抑制剂和PI3K-mTOR抑制剂的敏感性显著相关。此外，VDR和CDX2之间存在正相关。构建了VDR和CDX2介导的调控网络。最后对结肠癌患者进行了三个或四个亚类分类的验证。总体而言，我们的结果提示CDX2和VDR低表达的结肠癌细胞分子亚群对化疗、BRAF抑制剂和PI3K-mTOR抑制剂治疗敏感，并提供了将癌症分类转换为亚组指导治疗的范例。
Gene expression based consensus molecular subtypes (CMS) and non-negative matrix factorization (NMF) sub-clusters are robust colon cancer classification systems. Although, the molecular features are clear, colon cancer subgroups based interventions are limited. To address this problem, we analyze the CMS and NMF subgroup guided drug sensitivity in colon cancer cell lines. CMS3 subtype cells are sensitive to 5-Fluorouracil, while, CMS4 subtype cells are sensitive to cisplatin treatment. In NMF classification, a sub-cluster is specifically sensitive to chemotherapy, BRAF inhibitors, PI3K-mTOR inhibitors and NOTCH inhibitor treatment. This sub-cluster has low frequency of TP53, POLE, PIK3CA and BRAF mutation. Transcriptional analysis demonstrates low NOTCH signaling activity, low CDX2 and VDR expression in this sub-cluster. CDX2 and VDR are significantly associated with the sensitivity of chemotherapy, BRAF inhibitors and PI3K-mTOR inhibitors. Moreover, a positive correlation between VDR and CDX2 is identified. VDR and CDX2 mediated regulatory networks are constructed. At last, three or four sub-clusters classification is validated in colon cancer patients. Overall, our results suggest a molecular sub-cluster of colon cancer cells with low CDX2 and VDR expression is sensitive to chemotherapy, BRAF inhibitors and PI3K-mTOR inhibitors treatment and provide an example of translation of cancer classification to subgroup guided therapies.