Baro Lautaro, Almhassneh Rabeah A, Islam Asifa, Juanes M Angeles
Cytoskeletal Dynamics in Cell Migration and Cancer Invasion Laboratory, Centro de Investigación Príncipe Felipe, 46012 Valencia, Spain.
School of Health and Life Sciences, Teesside University, Middlesbrough TS1 3BX, UK.
iScience. 2024 Apr 8;27(5):109687. doi: 10.1016/j.isci.2024.109687. eCollection 2024 May 17.
Tumor cell invasion is the initial step in metastasis, the leading cause of death from cancer. Invasion requires protrusive cellular structures that steer the migration of leader cells emanating from the tumor mass toward neighboring tissues. Actin is central to these processes and is therefore the prime target of drugs known as migrastatics. However, the broad effects of general actin inhibitors limit their therapeutic use. Here, we delineate the roles of specific actin nucleators in tuning actin-rich invasive protrusions and pinpoint potential pharmacological targets. We subject colorectal cancer spheroids embedded in collagen matrix-a preclinical model mirroring solid tumor invasiveness-to pharmacologic and/or genetic treatment of specific actin arrays to assess their roles in invasiveness. Our data reveal coordinated yet distinct involvement of actin networks nucleated by adenomatous polyposis coli, formins, and actin-related protein 2/3 complex in the biogenesis and maintenance of invasive protrusions. These findings may open avenues for better targeted therapies.
肿瘤细胞侵袭是转移的起始步骤，而转移是癌症致死的主要原因。侵袭需要突出的细胞结构，引导从肿瘤块发出的前沿细胞向邻近组织迁移。肌动蛋白是这些过程的核心，因此是被称为迁移抑制剂的药物的主要靶点。然而，一般肌动蛋白抑制剂的广泛作用限制了它们的治疗用途。在这里，我们阐述了特定肌动蛋白成核剂在调节富含肌动蛋白的侵袭性突起中的作用，并确定了潜在的药理学靶点。我们将嵌入胶原基质中的结直肠癌球体（一种模拟实体瘤侵袭性的临床前模型）进行特定肌动蛋白阵列的药理学和/或基因治疗，以评估它们在侵袭性中的作用。我们的数据揭示了由腺瘤性息肉病大肠杆菌、formin和肌动蛋白相关蛋白2/3复合物成核的肌动蛋白网络在侵袭性突起的生物发生和维持中协同但不同的参与情况。这些发现可能为更好的靶向治疗开辟道路。
