Tumor suppression by merlin: Mechanisms and therapeutic potentials

肿瘤抑制蛋白merlin在接触性增殖抑制（CIP）中起关键作用。merlin失活经常发生在许多类型的肿瘤中，如神经鞘瘤、脑膜瘤和间皮瘤。因此，merlin似乎在广泛的细胞类型中发挥其肿瘤抑制功能。尽管事实上，merlin与大量致癌信号通路的抑制有关，但merlin介导CIP的确切机制仍不清楚，从而阻碍了有效治疗策略的发展。我们的初步工作已经确定了merlin的新型相互作用物，并表明merlin通过多模式途径介导肿瘤抑制，包括抑制Ras-MAPK和Src-FAK信号。通过阐明其分子机制、生物学和临床相关性，本研究将从三个方面拓宽我们对merlins功能的理解：(1)merlins对Ras-MAPK和Src-FAK信号传导的影响涉及与各自途径核心组分的未知相互作用。我们将对这些相互作用进行详细分析，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确定由梅林蛋白缺乏引起的常见分子变化；复发性改变将被认为可能是必要的，因此是最有希望的治疗目标。(3)我们将为基于候选药物（Ras-MAPK, Src-FAK）和无偏倚药物筛选建立一个全面的、患者衍生的发现和验证管道，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。我们将结合候选途径的详细分析和对一系列梅林蛋白相关肿瘤类型的全球转录组、蛋白质组和激酶组变化的无偏筛选；我们将定义梅林靶和肿瘤类型之间的异同。我们合作的附加价值来自于高度互补的专业知识的结合：对分子机制进行精细的详细分析，并结合其重要性的体内验证；最先进的、以核心设施为动力的基础研究，结合临床前、患者来源的药物筛选和验证能力。我们的合作将有助于获得对梅林蛋白作用模式的更广泛的理解，而我们的发现管道将为未来无偏见的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.