Regulation of Desmosomal Cadherins in Oral Cancer

描述(申请人提供)：细胞-细胞黏附分子中钙粘附素家族的成员是肿瘤进展中公认的参与者，但桥粒钙粘附素亚类的重要性还知之甚少。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自我更新的复杂上皮中。我们的主要假设是，双链葡萄糖通过维持基底层的增殖，同时促进细胞的分化来调节动态平衡。 分层，在肿瘤进展过程中发生的改变打破了这种平衡。这项研究的重点是桥粒芯糖蛋白1(DSG1)，在检测的钙粘附素中，它与头颈部鳞状细胞癌(HNSCC)患者的不良预后唯一相关。DSG1是当细胞从基底层分化并形成保护性屏障时表达的。我们发现DSG1通过抑制ErbB/MAPK信号通路，促进表皮角质形成细胞的分化，从而积极参与上皮细胞的形态发生。重要的是，90%以上的HNSCC表达升高的ErbB1。我们假设DSG1通过与ErbB结合蛋白Erbin相互作用促进分化，同时限制肿瘤进展，从而调节HNSCC的动态平衡，而DSG1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DSG1促进HNSCC分化的假设，测试这种情况是否通过减弱MAPK信号发生，并在动物模型和人HNSCCs中确定DSG1丢失是否与抑制分化和增加增殖/侵袭有关；2)确定支架蛋白Erbin是否通过干扰Ras/Raf/Shoc2复合体在体外和体内介导DSG1依赖的信号转导；3)测试DSGs既是ADAM脱落酶活性的底物又是ADAM脱落酶活性的抑制剂的假说，并确定这种双向关系在DSG依赖的黏附和体外信号转导以及体内肿瘤进展中的影响。从这项研究中获得的知识为创新疗法的设计带来了希望，包括那些针对ErbB/MAPK通路上游成员的药物耐药性的规避。

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.