A novel genome-wide in vivo screen for metastatic suppressors in human colon cancer identifies the positive WNT-TCF pathway modulators TMED3 and SOX12.
A novel genome-wide in vivo screen for metastatic suppressors in human colon cancer identifies the positive WNT-TCF pathway modulators TMED3 and SOX12.
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DOI：
10.15252/emmm.201303799
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发表时间：
2014-07
影响因子：
11.1
通讯作者：
Ruiz i Altaba A
中科院分区：
文献类型：
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作者：
Duquet A;Melotti A;Mishra S;Malerba M;Seth C;Conod A;Ruiz i Altaba A
肿瘤进展到转移状态涉及转移抑制功能的丧失。然而，发现这些是困难的，因为体外测定不能完全预测转移行为，并且大多数研究使用克隆细胞系，其不能反映原发性肿瘤异质性。在这里，我们设计了一种新的全基因组筛选，以确定转移抑制使用原代人肿瘤细胞在小鼠中，这允许饱和筛选。使用这种无偏的方法，我们已经测试了内源性结肠癌转移抑制因子影响WNT-TCF信号传导的假设。我们的筛选已经确定了两种新的转移抑制因子：TMED 3和SOX 12，其敲除增加了直接接种后的转移生长。此外，两者都改变了自我更新球状体的类型，但只有TMED 3的敲低也诱导球状体细胞扩散和皮下异种移植物的肺转移。重要的是，尽管TMED 3和SOX 12属于参与蛋白质分泌和转录调控的不同家族，但两者都促进内源性WNT-TCF活性。因此，晚期或转移性结肠癌的治疗可能无法从WNT阻滞剂中获益，这些药物可能会导致更差的结果。
The progression of tumors to the metastatic state involves the loss of metastatic suppressor functions. Finding these, however, is difficult as in vitro assays do not fully predict metastatic behavior, and the majority of studies have used cloned cell lines, which do not reflect primary tumor heterogeneity. Here, we have designed a novel genome-wide screen to identify metastatic suppressors using primary human tumor cells in mice, which allows saturation screens. Using this unbiased approach, we have tested the hypothesis that endogenous colon cancer metastatic suppressors affect WNT-TCF signaling. Our screen has identified two novel metastatic suppressors: TMED3 and SOX12, the knockdown of which increases metastatic growth after direct seeding. Moreover, both modify the type of self-renewing spheroids, but only knockdown of TMED3 also induces spheroid cell spreading and lung metastases from a subcutaneous xenograft. Importantly, whereas TMED3 and SOX12 belong to different families involved in protein secretion and transcriptional regulation, both promote endogenous WNT-TCF activity. Treatments for advanced or metastatic colon cancer may thus not benefit from WNT blockers, and these may promote a worse outcome.