Signaling and Targeting of CRTC1-MAML2 Fusion Oncoprotein in Salivary Gland

项目摘要/摘要 本提案重点关注致癌的CRTC1-MAML2融合，这是发展的基础 粘液表皮样癌(MEC)是唾液腺癌中最常见的一种。晚期患者， 转移性和复发性微血管内皮细胞预后较差，目前尚无靶向治疗方法。一个 全面了解这种癌基因融合的功能和机制对于揭示 有效的诊断和治疗方法。 我们证明CRTC1-MAML2融合是MEC启动和维持的主要驱动力。 我们对CRTC1-MAML2诱导的致癌转录程序的研究涉及Long 非编码RNA(LncRNAs)在MEC肿瘤发生和维持中的作用LncRNAs属于一类新的基因 调节剂在人类癌症中扮演着新的角色，并有可能作为诊断标志物，因为 它们的组织和疾病特异性。然而，lncRNAs的参与和机制基础仍然很差。 在MEC中定义。此外，我们的数据揭示了CRTC1-MAML2融合与转录的相互作用 CREB因子是诱导主要致癌转录程序的关键；因此，针对这种相互作用 INTERFACE将具有阻断多个关键融合靶基因/通路的优势。然而， 这种融合相互作用作为治疗靶点的意义仍需在体内进行测试。因此，目标是 这一建议的目的是阐明CRTC1-MAML2中致癌转录程序的lncRNA方面。 驱动MEC和控制致癌转录的关键融合蛋白相互作用的意义 程序在MEC。提出了两个目标来检验CRTC1-MAM2融合导致 独特的lncRNA程序促进MEC和CRTC1-MAML2/CREB相互作用在诱导 MEC中主要的致癌转录程序。因此，关键的lncRNA和融合相互作用可以 作为MEC抑制的目标。目的1研究CRTC1中lncRNAs的作用机制和靶向。 MAML2融合驱动的肿瘤发生。目的2将研究CRTC1-MAML2的意义和靶向性 MEC中Fusion/CREB的相互作用。这些拟议研究的完成将揭示新的机制和 对lncRNAs和CRTC1-MAML2癌基因融合的功能洞察，并揭示新的方法 阻止MEC。我们期待这些努力将增进我们对CRTC1-MAML2融合的了解 癌基因和微血管内皮细胞生物学，并导致新的诊断和治疗策略的确定。

Project Summary/Abstract This proposal focuses on the oncogenic CRTC1-MAML2 fusion that underlies the development of mucoepidermoid carcinomas (MEC), the most common type of salivary gland cancers. Patients with advanced, metastatic and recurrent MECs have poor outcomes and no targeted therapy is currently available. A comprehensive understanding of functions and mechanisms of this oncogenic fusion is essential for uncovering effective diagnostic and therapeutic approaches. We demonstrated that the CRTC1-MAML2 fusion is a major driver for MEC initiation and maintenance. Our investigations into the CRTC1-MAML2-induced oncogenic transcriptional program implicated long noncoding RNAs (lncRNAs) in MEC tumorigenesis and maintenance. LncRNAs belong to a novel class of gene regulators with emerging roles in human cancer and have the potential to serve as diagnostic markers due to their tissue and disease specificity. However, the involvement and mechanistic basis of lncRNAs remain poorly defined in MEC. Moreover, our data revealed the interaction of the CRTC1-MAML2 fusion with the transcription factor CREB is critical for inducing the major oncogenic transcriptional program; thus, targeting this interaction interface will have the advantage of blocking multiple critical fusion target genes/pathways. However, the significance of this fusion interaction as a therapeutic target remains to be tested in vivo. Therefore, the objectives of this proposal are to elucidate the lncRNA aspect of the oncogenic transcriptional program in CRTC1-MAML2- driven MEC and the significance of the critical fusion protein interaction governing the oncogenic transcriptional program in MEC. Two aims are proposed to test the overall hypothesis that the CRTC1-MAM2 fusion induces a unique lncRNA program in promoting MEC and that the CRTC1-MAML2/CREB interaction is critical for inducing the major oncogenic transcriptional program in MEC. Consequently, critical lncRNAs and fusion interaction can be targeted for MEC inhibition. Aim 1 will investigate the mechanisms and targeting of lncRNAs in CRTC1- MAML2 fusion-driven tumorigenesis. Aim 2 will Investigate the significance and targeting of the CRTC1-MAML2 fusion/CREB interaction in MEC. The completion of these proposed studies will uncover new mechanistic and functional insights into lncRNAs and the CRTC1-MAML2 oncogenic fusion and reveal new approaches for blocking MEC. We anticipate that these efforts will enhance our understanding of the CRTC1-MAML2 fusion oncogene and MEC biology and lead to the identification of novel diagnostic and therapeutic strategies.