Tumor suppression by merlin: Mechanisms and therapeutic potentials

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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.