Role of IGF-I Receptor Signaling Pathways in Cell Survival and Migration

描述(申请人提供)：胰岛素样生长因子-L(胰岛素样生长因子-I)信号与乳腺癌和其他癌症的发病机制有关。IGF-I受体(IGF-IR)激活调控与肿瘤发生相关的关键过程的通路--过度增殖、增强存活和迁移。使用体外3-D乳腺上皮模型来研究IGF-IR通路，我观察到IGF-I的过度刺激会导致形成充满管腔的过度增殖结构；这些结构类似于原位癌。利用这个模型，我发现了Akt和其他参与IGF-I刺激存活、迁移和侵袭的信号蛋白的新活性，并计划研究其潜在机制。在具体目标1中，我将调查负责调节IGF-I迁移和入侵的机制。观察到AKT1抑制IGF-I和EGF刺激的迁移，而Akt2是迁移所必需的。将进行研究，以阐明这些对比的、异构体特定功能的潜在基础，并确定Akt的异构体特定靶点。在特定的目标2中，我将研究通过IGF-I调节细胞存活和管腔充盈的细胞通路。虽然Akt2被发现在IGF-L诱导的管腔充盈相关的抗凋亡活性中起关键作用，但雷帕霉素介导的对Akt信号的下游靶点mTOR的抑制并不抑制IGF-I的抗凋亡作用。这些结果揭示了雷帕霉素不敏感通路(S)在胰岛素样生长因子-I介导的细胞存活中的作用。利用基于候选人的方法和筛选方法，该项目旨在识别这些途径，以及其他对IGF-I介导的细胞存活和腔形成至关重要的未表征的新分子。靶向治疗，特别是抑制肿瘤中激活的分子，正在成为一种常见的策略，靶向IGF-IR/PI-3K/Akt的抑制剂正处于早期临床开发阶段。鉴于肿瘤细胞中信号网络之间相互作用的复杂性，彻底了解这些蛋白质的功能对于优化使用新的生物疗法至关重要。识别新靶点的策略也至关重要，因为肿瘤细胞利用多种机制来逃避治疗抑制。Hanna Irie是一名研究人员和医学肿瘤学家，专门研究乳腺癌，她致力于成为一名独立的实验室科学家，致力于了解生长因子在乳腺肿瘤发生中的作用。

DESCRIPTION (provided by applicant): Insulin-like growth factor-l (IGF-I) signaling has been implicated in the pathogenesis of breast and other cancers. The IGF-I receptor (IGF-IR) activates pathways that regulate key processes associated with tumorigenesis- hyperproliferation, enhanced survival and migration. Using an in vitro 3-D breast epithelial model to investigate IGF-IR pathways that specifically regulate these processes, I observed that IGF-I hyper-stimulation leads to formation of hyperproliferative structures with filled lumen; these structures resemble carcinoma-in-situ. Using this model, I uncovered novel activities of Akt and other signaling proteins involved in IGF-I stimulated effects on survival, migration and invasion and I plan to investigate the underlying mechanisms. In Specific Aim 1, I will investigate mechanisms responsible for regulation of migration and invasion by IGF-I. Akt1 was observed to suppress IGF-I- and EGF-stimulated migration whereas Akt2 is required for migration. Studies to elucidate the underlying basis for these contrasting, isoform-specific functions and to identify isoform-specific targets of Akt will be performed. In Specific Aim 2, I will examine the cellular pathways that regulate cell survival and filling of the lumen by IGF-I. While Akt2 was found to be critical for anti-apoptotic activity associated with IGF-l-induced luminal filling, rapamycin-mediated inhibition of mTOR, a downstream target of Akt signaling, does not suppress the anti-apoptotic effects of IGF-I. These results revealed the contribution of rapamycin-insensitive pathway(s) to IGF-I mediated cell survival. Utilizing both candidate-based and screening approaches, this project aims to identify these pathways, as well as other uncharacterized, novel molecules critical for IGF-I mediated cell survival and luminal filing. Targeted therapies, which specifically inhibit molecules activated in tumors, are becoming a common strategy and inhibitors targeting IGF-IR/PI-3K/Akt are in early clinical development. Given the complexity of interactions between signaling networks in tumor cells, a thorough understanding of the functions of these proteins is critical for optimal use of new biological therapies. Strategies to identify novel targets are also critical as tumor cells utilize multiple mechanisms to evade therapeutic inhibition. Hanna Irie is a researcher and a medical oncologist specializing in breast cancer who is committed to becoming an independent laboratory-based scientist dedicated to understanding the role of growth factors in breast tumorigenesis.