Cdc42EP3/BORG2 and Septin Network Enables Mechano-transduction and the Emergence of Cancer-Associated Fibroblasts.
Cdc42EP3/BORG2 and Septin Network Enables Mechano-transduction and the Emergence of Cancer-Associated Fibroblasts.
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DOI：
10.1016/j.celrep.2015.11.052
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发表时间：
2015-12-29
期刊：
影响因子：
8.8
通讯作者：
Sahai E
中科院分区：
文献类型：
--
作者：
Calvo F;Ranftl R;Hooper S;Farrugia AJ;Moeendarbary E;Bruckbauer A;Batista F;Charras G;Sahai E
癌症相关成纤维细胞（CAF）是实体瘤中发现的非癌细胞，可重塑肿瘤基质并促进癌症侵袭和血管生成。在这里，我们证明 Cdc42EP3/BORG2 是 CAF 的基质重塑、侵袭、血管生成和肿瘤生长促进能力所必需的。 Cdc42EP3 通过协调肌动蛋白和隔膜网络发挥作用。此外，SEPT2 的缺失与 Cdc42EP3 缺失具有相似的影响，表明 Septin 网络在肿瘤基质中的作用。 Cdc42EP3 在成纤维细胞激活早期上调，并且先于 CAF 的高度收缩表型特征出现。正常成纤维细胞中 Cdc42EP3 的消耗可防止癌细胞激活它们。我们认为 Cdc42EP3 使成纤维细胞对进一步的信号敏感，特别是那些激活肌动球蛋白收缩性的信号，从而能够产生病理性激活的成纤维细胞状态。 Cdc42EP3 介导的肌动蛋白和隔膜蛋白的协调是 CAF 功能所必需的 隔膜蛋白网络在 CAF 中发生变化，并且是其功能所必需的 Cdc42EP3 能够对基质硬度的变化做出反应 正常成纤维细胞的激活需要 Cdc42EP3 的上调 Calvo 等人。确定 Cdc42EP3 是癌症相关成纤维细胞促肿瘤功能的调节剂。 Cdc42EP3 在成纤维细胞激活过程中上调，并协调机械转导和 CAF 功能所需的肌动蛋白和隔膜重排。
Cancer-associated fibroblasts (CAFs) are non-cancerous cells found in solid tumors that remodel the tumor matrix and promote cancer invasion and angiogenesis. Here, we demonstrate that Cdc42EP3/BORG2 is required for the matrix remodeling, invasion, angiogenesis, and tumor-growth-promoting abilities of CAFs. Cdc42EP3 functions by coordinating the actin and septin networks. Furthermore, depletion of SEPT2 has similar effects to those of loss of Cdc42EP3, indicating a role for the septin network in the tumor stroma. Cdc42EP3 is upregulated early in fibroblast activation and precedes the emergence of the highly contractile phenotype characteristic of CAFs. Depletion of Cdc42EP3 in normal fibroblasts prevents their activation by cancer cells. We propose that Cdc42EP3 sensitizes fibroblasts to further cues—in particular, those activating actomyosin contractility—and thereby enables the generation of the pathological activated fibroblast state. Cdc42EP3-mediated coordination of actin and septin is required for CAF function The septin network is changed in CAFs and is required for their function Cdc42EP3 enables responses to changes in matrix stiffness Upregulation of Cdc42EP3 is required for the activation of normal fibroblasts Calvo et al. identify Cdc42EP3 as a regulator of the pro-tumorigenic functions of cancer-associated fibroblasts. Cdc42EP3 is upregulated during fibroblast activation and coordinates actin and septin rearrangements that are required for mechanotransduction and CAF functions.