CDCA7 finely tunes cytoskeleton dynamics to promote lymphoma migration and invasion
CDCA7 finely tunes cytoskeleton dynamics to promote lymphoma migration and invasion
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DOI：
10.3324/haematol.2018.215459
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发表时间：
2020-03-01
期刊：
影响因子：
10.1
通讯作者：
Campanero, Miguel R.
中科院分区：
文献类型：
--
作者：
Martin-Cortazar, Carla;Chiodo, Yuri;Campanero, Miguel R.
转移是癌症死亡的主要原因，需要细胞获得迁移能力，并涉及多个步骤，包括局部肿瘤细胞侵袭和基底膜渗透。某些淋巴瘤是高度转移性的，但淋巴瘤细胞的侵袭机制知之甚少。我们最近发现，CDCA7，一种由MYC诱导的蛋白质，在淋巴肿瘤中过表达，并且其敲低降低了淋巴肿瘤的生长而不抑制正常细胞的增殖。在这里，我们表明CDCA7是淋巴瘤细胞的侵袭和迁移的关键。事实上，淋巴瘤细胞中的CDCA7敲低限制了基质胶包被的transwell板中的肿瘤细胞侵袭以及小鼠异种移植模型和细胞侵袭的斑马鱼模型中的邻近组织的肿瘤侵袭。CDCA7沉默显着抑制淋巴瘤细胞迁移纤连蛋白，而不改变细胞粘附到这种蛋白质。相反，CDCA7敲低显著破坏了有效迁移所需的肌动球蛋白和微管蛋白细胞骨架的精确动态重组。特别是，CDCA7沉默损害微管蛋白和肌动球蛋白细胞骨架极化，增加丝状肌动蛋白的形成，并诱导肌球蛋白活化。值得注意的是，肌动蛋白聚合抑制剂，肌球蛋白II，或ROCK重建CDCA7沉默的淋巴瘤细胞的迁移能力。鉴于CDCA 7在淋巴瘤发生和侵袭中的关键作用，旨在抑制其表达或活性的疗法可能提供对淋巴瘤生长、侵袭和转移性播散的显著控制。
Metastases, the major cause of death from cancer, require cells' acquisition of the ability to migrate and involve multiple steps, including local tumor cell invasion and basement membrane penetration. Certain lymphoid tumors are highly metastatic, but the mechanisms of invasion by lymphoma cells are poorly understood. We recently showed that CDCA7, a protein induced by MYC, is overexpressed in lymphoid tumors and that its knockdown decreases lymphoid tumor growth without inhibiting the proliferation of normal cells. Here we show that CDCA7 is critical for invasion and migration of lymphoma cells. Indeed, CDCA7 knockdown in lymphoma cells limited tumor cell invasion in matrigel-coated transwell plates and tumor invasion of neighboring tissues in a mouse xenograft model and in a zebrafish model of cell invasion. CDCA7 silencing markedly inhibited lymphoma cell migration on fibronectin without modifying cell adhesion to this protein. Instead, CDCA7 knockdown markedly disrupted the precise dynamic reorganization of actomyosin and tubulin cytoskeletons required for efficient migration. In particular, CDCA7 silencing impaired tubulin and actomyosin cytoskeleton polarization, increased filamentous actin formation, and induced myosin activation. Of note, inhibitors of actin polymerization, myosin II, or ROCK reestablished the migration capacity of CDCA7-silenced lymphoma cells. Given the critical role of CDCA7 in lymphomagenesis and invasion, therapies aimed at inhibiting its expression or activity might provide significant control of lymphoma growth, invasion, and metastatic dissemination.