Tumor suppression by merlin: Mechanisms and therapeutic potentials

肿瘤抑制蛋白merlin在接触性增殖抑制（CIP）中起着重要作用。梅林基因的失活经常发生在许多肿瘤类型中，如神经鞘瘤、脑膜瘤和间皮瘤。因此，梅林似乎在广泛的细胞类型中发挥其肿瘤抑制功能。尽管merlin参与抑制大量致癌信号通路，但merlin介导CIP的确切机制仍不清楚，因此阻碍了有效治疗策略的开发。我们的初步工作已经确定了新的相互作用的梅林，并表明梅林介导的肿瘤抑制在一个多模式的方法，包括抑制Ras-MAPK和Src-FAK信号。通过阐明其分子机制、生物学和临床意义，本工作将从三个方面拓宽我们对merlin蛋白功能的理解：（1）Merlin蛋白对Ras-MAPK和Src-FAK信号通路的作用涉及先前未知的与各自通路的核心组分的相互作用。我们将对这些相互作用进行详细的分析，以剖析潜在的分子机制。(2)我们将在一系列物种和肿瘤类型中识别由merlin缺陷诱导的常见分子变化;复发性变化将被认为是可能必要的，因此是最有希望的治疗靶点。(3)我们将建立一个全面的，患者衍生的发现和验证管道，用于基于候选人（Ras-MAPK，Src-FAK）和无偏见的药物筛选，以确定治疗靶点。为了实现我们的目标，我们组建了一个由合作研究人员和临床医生组成的团队，每个人都提供从分子生物学到临床专业知识的特定技能。我们将结合联合收割机的候选途径的详细分析与无偏筛选的全球转录组，蛋白质组和激酶组的变化在一系列梅林相关的肿瘤类型，我们将确定梅林目标和肿瘤类型之间的相似性和差异。我们合作的附加值来自于高度互补的专业知识类型的结合：分子机制的精细详细分析与其意义的体内验证相结合;最先进的，核心设施驱动的基础研究与临床前，患者源性药物筛选和验证能力相结合。我们的合作努力将有助于获得对梅林作用模式的更广泛的理解，而我们的发现管道将为未来的无偏见药物筛选提供全面的基础设施-无论是基于细胞系的高通量还是以患者为中心的个性化治疗方法。

The tumor suppressor protein merlin is critically involved in contact inhibition of proliferation (CIP). Inactivation of merlin occurs frequently in many tumor types such as schwannomas, meningiomas, and mesotheliomas. Thus, merlin appears to exert its tumor suppressive function in a broad spectrum of cell types. Despite the fact that merlin has been implicated in the inhibition of a large number of oncogenic signaling pathways, the exact mechanism by which merlin mediates CIP still remains unclear, thus impeding development of efficient therapeutic strategies. Our preliminary work has identified novel interactors of merlin and suggests merlin mediates tumor suppression in a multimodal approach including inhibition of both Ras-MAPK and Src-FAK signaling. By clarifying its molecular mechanism, biological and clinical relevance, the present work will broaden our understanding of merlins function in a three-fold approach: (1) Merlins effect on Ras-MAPK and Src-FAK signaling involves previously unknown interactions with core components of the respective pathways. We will perform a detailed analysis of these interactions to dissect the underlying molecular mechanisms. (2) We will identify common molecular changes induced by merlin-deficiency over a range of species and tumor types; recurrent changes will be considered as likely essential and thus most promising therapeutic targets. (3) We will establish a comprehensive, patient-derived discovery and validation pipeline for both candidate-based (Ras-MAPK, Src-FAK) and unbiased drug screening to identify therapeutic targets. To reach our goals, we have assembled a team of collaborating researchers and clinicians, each providing specific skills ranging from molecular biology to clinical expertise. We will combine detailed analysis of candidate pathways with unbiased screening of global transcriptome, proteome and kinome changes over a range of merlin-associated tumor types; we will define similarities and differences between merlin targets and tumor types. The added value of our collaboration arises from the combination of highly complementary types of expertise: Fine detailed analysis of molecular mechanism combined with in vivo validation of their significance; state-of-the-art, core-facility-powered basic research combined with pre-clinical, patient-derived drug screening and validation capabilities. Our collaborative efforts will help to derive a more generalized understanding of merlins mode(s) of action, while our discovery pipeline will provide a comprehensive infrastructure for future unbiased drug screening - both for cell line-based high-throughput and patient-centered, personalized therapy approaches.