TGFβ signaling directs serrated adenomas to the mesenchymal colorectal cancer subtype.
TGFβ signaling directs serrated adenomas to the mesenchymal colorectal cancer subtype.
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DOI：
10.15252/emmm.201606184
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发表时间：
2016-07
影响因子：
11.1
通讯作者：
Medema JP
中科院分区：
文献类型：
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作者：
Fessler E;Drost J;van Hooff SR;Linnekamp JF;Wang X;Jansen M;De Sousa E Melo F;Prasetyanti PR;IJspeert JE;Franitza M;Nürnberg P;van Noesel CJ;Dekker E;Vermeulen L;Clevers H;Medema JP
结直肠癌（CRC）的异质性使预后变得复杂，并且被认为是个体患者辅助治疗疗效的决定因素。根据基因表达谱，CRC 目前分为四种共有分子亚型 (CMS)，其特征在于特定的生物学程序，从而表明每种 CMS 存在统一的发育驱动因素。使用人类类器官培养物，我们研究了此类发育驱动因素在不同 CRC 亚型的癌前阶段的作用，发现 TGFβ 在间充质 CMS4 的发育中发挥着重要作用，由于其与不良预后相关，因此引起了特别关注。我们发现，在进展为经典 CRC 的管状腺瘤 (TA) 中，对 TGFβ 的主要反应是细胞凋亡导致的死亡。相比之下，在携带 BRAFV 600E 突变的基因工程类器官培养物中，TGFβ 治疗后普遍诱导间充质表型，构成无蒂锯齿状腺瘤 (SSA) 的模型系统。我们的数据表明，TGFβ 信号传导在 SSA 前体病变中已经很活跃，并且 TGFβ 是将 SSA 引导至 CRC 的间质、预后不良 CMS4 的关键线索。
The heterogeneous nature of colorectal cancer (CRC) complicates prognosis and is suggested to be a determining factor in the efficacy of adjuvant therapy for individual patients. Based on gene expression profiling, CRC is currently classified into four consensus molecular subtypes (CMSs), characterized by specific biological programs, thus suggesting the existence of unifying developmental drivers for each CMS. Using human organoid cultures, we investigated the role of such developmental drivers at the premalignant stage of distinct CRC subtypes and found that TGFβ plays an important role in the development of the mesenchymal CMS4, which is of special interest due to its association with dismal prognosis. We show that in tubular adenomas (TAs), which progress to classical CRCs, the dominating response to TGFβ is death by apoptosis. By contrast, induction of a mesenchymal phenotype upon TGFβ treatment prevails in a genetically engineered organoid culture carrying a BRAFV 600E mutation, constituting a model system for sessile serrated adenomas (SSAs). Our data indicate that TGFβ signaling is already active in SSA precursor lesions and that TGFβ is a critical cue for directing SSAs to the mesenchymal, poor‐prognosis CMS4 of CRC.