Molecular Dissection of Tumor Invasion

描述（由申请人提供）：细胞侵袭和转移标志着癌症的最致命阶段，但对启动这一关键转折点的关键分子事件知之甚少。我们在果蝇中的系统遗传分析表明，基底外侧连接蛋白，这是高度保守的，精确地定位在动物和人的细胞间接触的特定位点，作为关键的入侵抑制因子。它们控制上皮结构并防止上皮肿瘤细胞的传播。基底外侧连接由免疫球蛋白超家族成员Fasciclin 2（人NCAM）和神经胶质细胞（人L1）以及支架分子Discslarge（hDIg）和致死巨人幼虫（hLgl）组成。我们已经确定了第一条作用于基底外侧连接下游的抑制上皮侵袭的途径。编码信号分子的三个基因Warts（人类Lats 1/2）、Mats（人类Mobla）和Yorki（人类雅普）都与人类致癌有关。我们的数据是第一个证据表明，他们是在基底外侧连接途径抑制肿瘤侵袭至关重要。该途径的一个关键靶标是乳腺癌中扩增的果蝇-1（DAIB 1），其在人类中是充当致癌基因的类固醇转录共激活剂。AIB 1参与了乳腺癌治疗药物他莫昔芬的耐药性，但对AIB 1表达的控制知之甚少。我们的数据表明，基底外侧连接信号和DAIB 1是在一个正反馈回路。此外，我们发现AIB 1在超过90%的人卵巢癌中过度表达，Lats 2和雅普在60%的乳腺癌中丢失，特别是在向侵袭的过渡中。我们的具体目标是：（1）整理基底外侧连接通过Wts和Mats（Lats和Mobla）发出信号以激活细胞核中DAIB 1（AIB 1）表达的途径，（2）建立基底外侧连接向AIB 1/DAIB 1发出信号的分子机制，（3）建立基底外侧连接信号传导途径对抑制人类肿瘤细胞侵袭的重要性。这些目标将描绘基底外侧连接控制上皮侵袭性的第一条途径，这可能为侵袭性癌症的诊断和治疗提供重要工具。

DESCRIPTION (provided by applicant): Cell invasion and metastasis mark the most lethal phase of cancer, but little is known about the key molecular events that initiate this crucial turning point. Our systematic genetic analysis in Drosophila has revealed that basolateral junction proteins, which are highly conserved and precisely localized at specific sites of intercellular contact in both animals and man, act as key invasion suppressors. They control both epithelial architecture and prevent dissemination of epithelial tumor cells. The basolateral junction is comprised of Immunoglobulin superfamily members Fasciclin2 (human NCAM) and Neuroglian (human L1), and scaffolding molecules Discslarge (hDIg) and Lethal Giant larvae (hLgl). We have identified the first pathway that acts down stream of the basolateral junction that suppresses epithelial invasion. Three genes encoding signaling molecules, Warts (human Lats1/2), Mats (human Mobla), and Yorki (human Yap), are all implicated in human carcinogenesis. Our data is the first evidence that they are in a basolateral junction pathway crucial for suppressing tumor invasion. A key target of this pathway is Drosophila Amplified in Breast Cancer-1 (DAIB1), which in humans is a steroid transcriptional co- activator that acts as an oncogene. AIB1 is involved in resistance to breast cancer therapeutic tamoxifen, but little is known about control of AIB1 expression. Our data indicate that basolateral junction signals and DAIB1 are in a positive feedback loop. Further, we find that AIB1 is over expressed in greater than 90% of human ovarian cancers, and that Lats2 and Yap are lost in 60% of breast cancers, specifically at the transition to invasion. Our specific aims are to: (1) Order the pathway by which the basolateral junction signals through Wts and Mats (Lats and Mobla) to activate DAIB1 (AIB1) expression in the nucleus, (2) Establish the molecular mechanisms by which the basolateral junction signals to AIB1/DAIB1, and (3) Establish the importance of the basolateral junction signaling pathway for suppressing human tumor cell invasion. These aims will delineate the first pathway by which basolateral junctions control epithelial invasiveness, which may provide important tools for diagnosis and treatment of invasive cancers.