A recellularized human colon model identifies cancer driver genes.
A recellularized human colon model identifies cancer driver genes.
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DOI：
10.1038/nbt.3586
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发表时间：
2016-08
影响因子：
46.9
通讯作者：
Shuler ML
中科院分区：
文献类型：
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作者：
Chen HJ;Wei Z;Sun J;Bhattacharya A;Savage DJ;Serda R;Mackeyev Y;Curley SA;Bu P;Wang L;Chen S;Cohen-Gould L;Huang E;Shen X;Lipkin SM;Copeland NG;Jenkins NA;Shuler ML
需要完善的癌症模型来弥合细胞系、动物和临床研究之间的差距。在这里，我们描述了一个有机型结肠癌模型的工程，通过一个天然的人基质的再细胞化，其中包含细胞填充的粘膜和完整的肌层粘膜层。这个离体系统概括了从apc突变型肿瘤到粘膜下浸润性肿瘤的病理生理进展。我们利用它进行了睡美人转座子突变筛选，以确定与突变APC合作驱动侵袭性肿瘤的基因。共鉴定出38个候选侵袭驱动基因，其中17个先前与结直肠癌进展有关，包括TCF7L2、TWIST2、MSH2、DCC和EPHB1/2。据我们所知，以前没有描述过的六个入侵驱动基因在体外通过细胞增殖、迁移和入侵试验进行了验证，在体外使用再细胞化的人类结肠进行了验证。这些结果证明了我们的类器官模型在研究癌症生物学方面的实用性。
Refined cancer models are needed to bridge the gap between cell-line, animal and clinical research. Here we describe the engineering of an organotypic colon cancer model by recellularization of a native human matrix that contains cell-populated mucosa and an intact muscularis mucosa layer. This ex vivo system recapitulates the pathophysiological progression from APC-mutant neoplasia to submucosal invasive tumor. We used it to perform a Sleeping Beauty transposon mutagenesis screen to identify genes that cooperate with mutant APC in driving invasive neoplasia. 38 candidate invasion driver genes were identified, 17 of which have been previously implicated in colorectal cancer progression, including TCF7L2, TWIST2, MSH2, DCC and EPHB1/2. Six invasion driver genes that to our knowledge have not been previously described were validated in vitro using cell proliferation, migration and invasion assays, and ex vivo using recellularized human colon. These results demonstrate the utility of our organoid model for studying cancer biology.