The aggressive brain tumor glioblastoma (GBM) is characterized by rapid cellular infiltration of brain tissue, raising the possibility that disease progression could potentially be slowed by disrupting the machinery of cell migration. The LIM kinase isoforms LIMK1 and LIMK2 (LIMK1/2) play important roles in cell polarization, migration, and invasion and are markedly upregulated in GBM and many other infiltrative cancers. Yet, it remains unclear whether LIMK suppression could serve as a viable basis for combating GBM infiltration. In this study, we investigated effects of LIMK1/2 suppression on GBM invasion by combining GBM culture models, engineered invasion paradigms, and mouse xenograft models. While knockdown of either LIMK1 or LIMK2 only minimally influenced invasion in culture, simultaneous knockdown of both isoforms strongly reduced the invasive motility of continuous culture models and human GBM tumor-initiating cells (TIC) in both Boyden chamber and 3D hyaluronic acid spheroid invasion assays. Furthermore, LIMK1/2 functionally regulated cell invasiveness, in part, by disrupting polarized cell motility under confinement and cell chemotaxis. In an orthotopic xenograft model, TICs stably transduced with LIMK1/2 shRNA were implanted intracranially in immunocompromised mice. Tumors derived from LIMK1/2 knockdown TICs were substantially smaller and showed delayed growth kinetics and more distinct margins than tumors derived from control TICs. Overall, LIMK1/2 suppression increased mean survival time by 30%. These findings indicate that LIMK1/2 strongly regulate GBM invasive motility and tumor progression and support further exploration of LIMK1/2 as druggable targets. Significance: Targeting the actin-binding proteins LIMK1 and LIMK2 significantly diminishes glioblastoma invasion and spread, suggesting the potential value of these proteins as therapeutic targets.

中文翻译：

---

LIM激酶1和LIM激酶2的抑制限制了胶质母细胞瘤的侵袭。

侵袭性脑肿瘤胶质母细胞瘤（GBM）的特征在于脑组织的快速细胞浸润，从而增加了疾病发展可能因破坏细胞迁移机制而减慢的可能性。LIM激酶同工型LIMK1和LIMK2（LIMK1 / 2）在细胞极化，迁移和侵袭中起重要作用，并且在GBM和许多其他浸润性癌症中明显上调。但是，目前还不清楚LIMK抑制是否可以作为对抗GBM渗透的可行基础。在这项研究中，我们通过结合GBM培养模型，工程入侵范例和小鼠异种移植模型，研究了LIMK1 / 2抑制对GBM侵袭的影响。虽然敲低LIMK1或LIMK2的影响仅微乎其微，但 在Boyden室和3D透明质酸球体浸润试验中，同时敲除这两种同工型可大大降低连续培养模型和人GBM肿瘤起始细胞（TIC）的侵袭力。此外，LIMK1 / 2在功能上调节细胞的侵袭性，部分是通过在封闭和细胞趋化作用下破坏极化的细胞运动。在原位异种移植模型中，用LIMK1 / 2 shRNA稳定转导的TIC被颅内植入免疫受损的小鼠中。与对照TIC相比，源自LIMK1 / 2敲除TIC的肿瘤要小得多，并且显示出延迟的生长动力学和更明显的切缘。总体而言，LIMK1 / 2抑制可将平均生存时间延长30％。这些发现表明，LIMK1 / 2强烈调节GBM的侵袭性和肿瘤进展，并支持进一步探索LIMK1 / 2作为可治疗的靶标。意义：靶向肌动蛋白结合蛋白LIMK1和LIMK2大大减少了胶质母细胞瘤的侵袭和扩散，表明这些蛋白作为治疗靶标的潜在价值。