Regulation of Desmosomal Cadherins in Oral Cancer

描述（由申请人提供）：细胞间粘附分子的钙粘蛋白家族成员是肿瘤进展中公认的参与者，但桥粒钙粘蛋白亚类的重要性知之甚少。特别令人感兴趣的是桥粒芯糖蛋白（Dsg）亚家族，其中三个以不同的模式分布在口腔的自我更新的复杂上皮细胞内。我们的总体假设是，Dsgs通过维持基底层的增殖同时促进细胞分化来调节稳态 分层，且在肿瘤进展期间发生改变打破了这种平衡。这项建议的重点是桥粒芯糖蛋白1（Dsg 1），其中，钙粘蛋白测试，是唯一与头部和颈部鳞状细胞癌（HNSCC）的患者预后不良。当细胞从基底层出现分化并形成保护屏障时，Dsg 1表达。我们发现Dsg 1通过抑制ErbB/MAPK信号传导，通过促进表皮角质形成细胞的分化程序，积极参与上皮形态发生。重要的是，超过90%的HNSCC表达升高的ErbB 1。我们推测Dsg 1通过促进分化同时通过与ErbB结合蛋白ERBIN的相互作用限制肿瘤进展来调节HNSCC中的稳态，并且Dsgs与ADAM家族中的膜结合脱落酶之间的双向相互作用进一步调节肿瘤细胞的命运。我们的目标是：1）测试Dsg 1促进HNSCC分化程序的假设，以测试这是否通过减弱MAPK信号传导而发生，并确定Dsg 1损失是否与动物模型和人HNSCC中的分化抑制和增殖/侵袭增加相关，2）确定支架蛋白ERBIN，通过干扰Ras/Raf/Shoc 2复合物在体外和体内介导Dsg 1依赖性信号传导，和3）测试Dsgs既是ADAM脱落酶活性的底物又是其抑制剂的假设，并确定这种双-体外Dsg依赖性粘附和信号传导与体内肿瘤进展的方向关系。从这项研究中获得的知识为创新疗法的设计提供了希望，包括那些规避针对ErbB/MAPK通路上游参与者的药物耐药性的疗法。 公共卫生相关性：该项目旨在了解头颈部鳞状细胞癌（HNSCC）细胞表面上称为桥粒芯糖蛋白的粘性分子如何执行超出其细胞凝聚作用的功能，以调节肿瘤细胞行为和肿瘤进展。从这些研究中获得的知识有望解决与HNSCC相关的诊断和治疗挑战。

DESCRIPTION (provided by applicant): Members of the cadherin family of cell-cell adhesion molecules are well-established players in tumor progression, but the importance of the desmosomal cadherin sub-class is poorly understood. Of particular interest is the desmoglein (Dsg) subfamily, three of which are distributed in distinct patterns within the self-renewing, complex epithelia of the oral cavity. Our overarching hypothesis is that Dsgs regulate homeostasis by sustaining proliferation in the basal layer while promoting differentiation as cells stratify, and that alterations occurring during tumor progression upset this balance. This proposal focuses on desmoglein 1 (Dsg1), which, among cadherins tested, was uniquely associated with poor patient outcome in head and neck squamous cell carcinoma (HNSCC). Dsg1 is expressed as cells emerge from the basal layer to differentiate and form a protective barrier. We showed that Dsg1 actively participates in epithelial morphogenesis by promoting a differentiation program in epidermal keratinocytes, via suppression of ErbB/MAPK signaling. Importantly, over 90% of HNSCC express elevated ErbB1. We hypothesize that Dsg1 regulates homeostasis in HNSCC by promoting differentiation while limiting tumor progression through an interaction with the ErbB binding protein ERBIN, and that bi-directional interactions between Dsgs and membrane bound sheddases in the ADAM family further regulate tumor cell fate. Our aims are to: 1) test the hypothesis that Dsg1 promotes a program of HNSCC differentiation, to test whether this occurs by attenuating MAPK signaling, and to determine whether Dsg1 loss is associated with suppressed differentiation and increased proliferation/invasion in an animal model and human HNSCCs, 2) determine whether the scaffolding protein, ERBIN, mediates Dsg1-dependent signaling in vitro and in vivo by interfering with a Ras/Raf/Shoc2 complex, and 3) test the hypothesis that Dsgs are both substrates and inhibitors of ADAM sheddase activity and determine the impact of this bi-directional relationship on Dsg-dependent adhesion and signaling in vitro, and tumor progression in vivo. Knowledge gained from this study holds promise for the design of innovative therapies including those that circumvent resistance to drugs targeting upstream players in the ErbB/MAPK pathway. PUBLIC HEALTH RELEVANCE: This project aims to understand how sticky molecules called desmogleins on the surface of head and neck squamous cell carcinoma (HNSCC) cells perform functions beyond their role in cell coherence, to regulate tumor cell behavior and tumor progression. Knowledge gained from these studies holds promise for addressing the diagnostic and therapeutic challenges associated with HNSCC.