Short-form Ron Kinase in Tumor Progression and Metastasis

描述(申请人提供)：MET和RON是两个相关的受体酪氨酸激酶，与肿瘤的生长和转移有关。尽管Met在癌症中的作用已经研究了20多年，最终开发出了靶向治疗方法，目前正在进行临床试验，但最近Ron已经成为癌症的主要参与者，在癌症中，其表达通常与更具侵袭性的疾病和不良预后相关。我们的工作揭示了一种选择性转录的、N端截短的RON形式，称为‘短形’或sfRon，是患者乳腺肿瘤中主要的活性RON亚型，并且它在肿瘤的侵袭性中起着重要的作用。SfRon表达式足以转换 缓慢生长的非转移性肿瘤转变为快速生长的肿瘤，自发地从乳腺转移到肝脏和骨骼。机制研究揭示了sfRon和PI3K之间的相互作用，这是sfRon功能所必需的。阻断sfRon与PI3K的相互作用彻底取消了sfRon赋予肿瘤侵袭性行为的能力，并完全阻止了转移。相反，全长RON似乎通过激活多个信号通路促进肿瘤转移。我们假设，乳腺肿瘤中sfRon蛋白的非调控产生通过选择性地激活PI3K信号来促进转移，这是一种不同于Ron活性的功能。此外，我们假设抑制RON和sfRON激酶活性将是减少或阻止肿瘤进展和/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是如何在转录后水平调节的，以及sfRon泛素化是否在肿瘤中泛素化，来确定sfRon mrna或蛋白在肿瘤中是否选择性稳定。 SfRon在其功能中发挥了作用。其次，我们将通过检测乳腺癌细胞中每种蛋白质的信号伙伴，以及RON和sfRon是否干扰其他蛋白质的信号传导，来确定RON和sfRon是否通过不同的途径促进转移。第三，我们将通过在异种细胞系移植模型和我们新的患者来源的肿瘤移植模型中测试新化合物来确定RON和/或PI3K抑制剂是否可以防止肿瘤的生长/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.