Short-form Ron Kinase in Tumor Progression and Metastasis

描述（由申请人提供）：Met和罗恩是两种相关的受体酪氨酸激酶，与肿瘤生长和转移有关。尽管Met在癌症中的功能已经研究了二十多年，最终在临床试验中开发了靶向治疗，但罗恩最近已经成为癌症的主要参与者，其表达通常与更具侵袭性的疾病和不良结局相关。我们的工作揭示了一种被称为“短型”或sf罗恩的N-末端截短的罗恩的替代转录形式，是患者乳腺肿瘤中主要的活性罗恩同种型，并且它在肿瘤的侵袭性中起着重要作用。sfRon表达式足以转换 缓慢生长的非转移性肿瘤转化为快速生长的肿瘤，自发地从乳腺转移到肝脏和骨骼。机制研究揭示了sfRon和PI 3 K之间的相互作用，这是sfRon功能所需的。阻断sfRon与PI 3 K相互作用的能力彻底消除了sfRon赋予侵袭性肿瘤行为的能力并完全阻断了转移。相反，全长罗恩似乎通过激活多种信号传导途径促进转移。我们假设乳腺肿瘤中sf罗恩蛋白的生产失调通过选择性激活PI 3 K信号传导促进转移，这一功能与罗恩活性不同。此外，我们假设抑制罗恩和sf罗恩激酶活性将是减少或阻断肿瘤进展和/或转移的有效方法。我们设计了三个具体目标来检验我们的假设。首先，我们将通过阐明sfRon在转录后水平的调节，以及sfRon的泛素化是否在肿瘤中被选择性地稳定，来确定sfRon mRNA或蛋白质是否在肿瘤中被选择性地稳定。 sfRon在其功能中起作用。其次，我们将通过检查乳腺癌细胞中每种蛋白质的信号伴侣以及罗恩和sf罗恩是否干扰其他蛋白质的信号传导，来确定罗恩和sf罗恩是否通过不同的途径促进转移。第三，我们将通过在细胞系异种移植模型和我们的新的患者来源的肿瘤移植模型中测试新化合物来确定罗恩和/或PI 3 K抑制剂是否预防肿瘤生长/转移。

DESCRIPTION (provided by applicant): Met and Ron are two related receptor-tyrosine kinases that have been implicated in tumor growth and metastasis. Although the function of Met in cancer has been studied for more than twenty years, culminating in development of targeted therapies now in clinical trials, Ron has more recently emerged as a major player in cancer, where its expression usually correlates with more aggressive disease and poor outcomes. Our work has revealed that an alternatively transcribed, N-terminally truncated form of Ron, called 'short-form' or sfRon, is the major active Ron isoform in breast tumors from patients, and that it plays a significant role in the aggressiveness of tumors. sfRon expression is sufficient to convert slow growing, non-metastatic tumors into fast growing tumors that spontaneously metastasized from the mammary gland to liver and bones. Mechanistic studies revealed an interaction between sfRon and PI3K that was required for sfRon function. Blocking the ability of sfRon to interact with PI3K thoroughly abrogated the ability of sfRon to confer aggressive tumor behavior and completely blocked metastasis. In contrast, full length Ron appears to promote metastasis through activation of multiple signaling pathways. We hypothesize that deregulated production of sfRon protein in breast tumors promotes metastasis through selective activation of PI3K signaling, a function that is distinct from Ron activity. Furthermore, we hypothesize that inhibition of Ron and sfRon kinase activity will be a valid approach to reduce or block tumor progression and/or metastasis. We have devised three specific aims to test our hypothesis. First, we will determine if sfRon mRNA or protein is selectively stabilized in tumors by elucidating how sfRon is regulated at the post-transcriptional level, and whether ubiquitylation of sfRon plays a role in its function. Second, we will determine if Ron and sfRon promote metastasis through different pathways, by examining the signaling partners of each protein in breast cancer cells and whether Ron and sfRon interfere with the others' signaling. Third, we will determine whether Ron and/or PI3K inhibitors prevent tumor growth/metastasis by testing new compounds in both cell line xenograft models and in our new patient-derived tumorgraft models.