Elucidation of Focal Adhesion Kinase as a Modulator of Migration and Invasion and as a Potential Therapeutic Target in Chronic Lymphocytic Leukemia.
Elucidation of Focal Adhesion Kinase as a Modulator of Migration and Invasion and as a Potential Therapeutic Target in Chronic Lymphocytic Leukemia.
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DOI：
10.3390/cancers14071600
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发表时间：
2022-03-22
期刊：
影响因子：
5.2
通讯作者：
Pepper C
中科院分区：
文献类型：
--
作者：
Burley TA;Hesketh A;Bucca G;Kennedy E;Ladikou EE;Towler BP;Mitchell S;Smith CP;Fegan C;Johnston R;Pepper A;Pepper C
尽管成功引入了靶向治疗，但慢性淋巴细胞白血病（CLL）仍然无法治愈。这被认为部分是由于CLL细胞从淋巴结微环境接收的促存活和抗凋亡信号。因此，抑制CLL迁移到淋巴结中是一种有吸引力的治疗选择。在这里，我们的目的是进一步了解什么转录组学和miRNomic变化驱动CLL迁移，并从中选择有希望的治疗靶点。我们鉴定了粘着斑激酶（FAK）作为一种这样的潜在靶点，并证明了在原发性CLL样品中抑制FAK有效地降低了CXCL 12诱导的体外迁移和侵袭。成功抑制CLL迁移可以增加CLL细胞对目前使用的靶向治疗剂的敏感性，从而改善患者的预后。认为慢性淋巴细胞白血病细胞滞留和再迁移到细胞保护和增殖性淋巴小生境中有助于产生耐药性，导致随后的疾病复发。本研究的目的是阐明控制CLL细胞迁移的分子过程，以引起对肿瘤细胞迁移的更完全抑制。我们比较了CLL细胞诱导的表型和转录变化，使用两种不同的模型，旨在重演外周循环，CLL细胞迁移通过内皮屏障，以及CLL细胞和活化T细胞之间的淋巴结相互作用。最初，CLL细胞与表达CD 40 L的成纤维细胞共培养，并表现出活化的B细胞表型，其转录特征表明促存活和抗凋亡基因的上调以及NF-κB信号通路的过度表达。使用我们的动态循环模型，我们能够研究与CLL迁移相关的转录组学和miRNomics。当CLL细胞经历跨内皮迁移时，超过3000个基因被改变，其中粘附和细胞迁移基因组的表达过多。从该分析中，观察到FAK信号传导途径的上调。重要的是，PTK 2（FAK）基因表达在迁移性CLL细胞中显著上调（PTK 2倍数变化= 4.9）。在这里，我们证明了TLR 9激动增加了p-FAK的水平（p ≤ 0.05），这可以通过用defactinib药理学抑制FAK来预防（p ≤ 0.01）。此外，当FAK被抑制时，观察到CLL细胞迁移和侵袭减少（p ≤ 0.0001），支持FAK在CLL迁移和组织侵袭中的作用。当综合考虑时，我们的数据突出了FAK抑制与当前靶向治疗相结合作为CLL更有效治疗方案的潜力。
Despite the successful introduction of targeted therapies, Chronic Lymphocytic Leukemia (CLL) remains incurable. This is thought to be partially due to the pro-survival and anti-apoptotic signaling that CLL cells receive from the lymph node microenvironment. Therefore, inhibition of CLL migration into the lymph nodes is an attractive therapeutic option. Here, our aim was to gain a further understanding of what transcriptomic and miRNomic changes drive CLL migration and, from this, select promising therapeutic targets. We identified focal adhesion kinase (FAK) as one such potential target and demonstrated that inhibition of FAK in primary CLL samples effectively reduces both CXCL12 induced migration and invasion in vitro. Successful inhibition of CLL migration could increase the sensitivity of CLL cells to the currently used targeted therapeutics and therefore improve patient outcomes. The retention and re-migration of Chronic Lymphocytic Leukemia cells into cytoprotective and proliferative lymphoid niches is thought to contribute to the development of resistance, leading to subsequent disease relapse. The aim of this study was to elucidate the molecular processes that govern CLL cell migration to elicit a more complete inhibition of tumor cell migration. We compared the phenotypic and transcriptional changes induced in CLL cells using two distinct models designed to recapitulate the peripheral circulation, CLL cell migration across an endothelial barrier, and the lymph node interaction between CLL cells and activated T cells. Initially, CLL cells were co-cultured with CD40L-expressing fibroblasts and exhibited an activated B-cell phenotype, and their transcriptional signatures demonstrated the upregulation of pro-survival and anti-apoptotic genes and overrepresentation of the NF-κB signaling pathway. Using our dynamic circulating model, we were able to study the transcriptomics and miRNomics associated with CLL migration. More than 3000 genes were altered when CLL cells underwent transendothelial migration, with an overrepresentation of adhesion and cell migration gene sets. From this analysis, an upregulation of the FAK signaling pathway was observed. Importantly, PTK2 (FAK) gene expression was significantly upregulated in migrating CLL cells (PTK2 Fold-change = 4.9). Here we demonstrate that TLR9 agonism increased levels of p-FAK (p ≤ 0.05), which could be prevented by pharmacological inhibition of FAK with defactinib (p ≤ 0.01). Furthermore, a reduction in CLL cell migration and invasion was observed when FAK was inhibited (p ≤ 0.0001), supporting a role for FAK in both CLL migration and tissue invasion. When taken together, our data highlights the potential for combining FAK inhibition with current targeted therapies as a more effective treatment regime for CLL.
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