Integrins and Caspase 8 in Tumor Progression

Caspase 8和整合素与肿瘤进展 在之前的资金支持期间，我们证明了caspase 8与未连接的 体内整合素促进细胞凋亡，caspase 8或整合素下调 神经母细胞瘤促进肿瘤转移。在这些研究中确认了细胞凋亡的滚动，我们做出了 在抗凋亡细胞中，caspase 8表达的矛盾观察 显著增强整合素介导的体外迁移和体内转移。的总目标是 因此，这一建议是为了了解caspase 8的凋亡与非凋亡功能是如何调节的。 作为caspase的起始者，caspase 8在死亡受体Toll样受体下游触发细胞凋亡。 和整合素。在侵袭性神经母细胞瘤和其他 神经内分泌肿瘤。这促使临床策略寻求恢复或放大其 表情。然而，caspase 8不足以诱导细胞凋亡，但需要顺应性的下游。 Caspase级联。在凋亡受损的细胞中，我们提供了caspase 8的证据 表达实际上起到了促进肿瘤转移的作用。这一令人惊讶的结果是有理由的 重新考虑简单上调caspase 8是普遍有益的概念；相反，它 可能会加剧疾病的发展。而caspase 8在免疫系统中的非凋亡功能 和血管间隔是已知的，使caspase 8发挥这些功能的机制是 不。在这里，我们提供的初步结果表明，增强的细胞迁移同时发生在 整合素灶粘连接触中caspase8酪氨酸的磷酸化及定位 结扎术。本提案的目标1将描述特定的caspase 8酪氨酸残基。 在黏附过程中被磷酸化，并确定对迁移至关重要的那些。目标2将评估哪一项 酪氨酸残基影响caspase8催化和促凋亡活性，包括蛋白质-蛋白质 互动。最后，AIM 3将测试这些调节酪氨酸残基对疾病的影响 在体内的进展。综上所述，这些研究的结果将揭示 Caspase8调控对抗转移治疗的发展具有重要意义。

Caspase 8 and Integrins in Tumor Progression During the previous funding period, we demonstrated that caspase 8 association with unligated integrins in vivo promoted apoptosis, and that down-regulation of caspase 8 or integrins in neuroblastoma promoted tumor metastasis. Confirming the roll of apoptosis in these studies, we made the paradoxical observation that, among apoptosis-resistant cells, the expression of caspase 8 significantly enhanced integrin-mediated migration in vitro and metastasis in vivo. The overall goal of this proposal is therefore to understand how caspase 8 apoptotic vs nonapoptotic function is regulated. As an initiator caspase, caspase 8 triggers apoptosis downstream of death receptors, toll-like receptors and integrins. Its expression is frequently lost among aggressive neuroblastoma and other neuroendocrine tumors. This has prompted clinical strategies seeking to restore or amplify its expression. However, caspase 8 is not sufficient for apoptosis, but requires a compliant downstream caspase cascade. Among apoptosis-compromised cells, we provide evidence that caspase 8 expression actually functions to enhance tumor metastasis. This surprising result warrants reconsideration of the concept that simple upregulation of caspase 8 is universally beneficial; rather, it may exacerbate disease progression. While nonapoptotic functions of caspase 8 within the immune and vascular compartments are known, the mechanisms committing caspase 8 to these functions are not. Here, we provide preliminary results showing that enhanced cell migration occurs concurrent with caspase 8 tyrosine phosphorylation and localization in focal adhesion contacts following integrin ligation. AIM 1 of this proposal will characterize the specific caspase 8 tyrosine residues phosphorylated during adhesion, and identify those critical for migration. AIM 2 will evaluate which tyrosine residues influence caspase 8 catalytic and proapoptotic activities, including protein-protein interactions. Finally, AIM 3 will test the impact of these regulatory tyrosine residues on disease progression in vivo. Together, the results of these studies will reveal molecular mechanisms of caspase 8 regulation important for the development of anti-metastatic therapies.