Molecular Dissection of Tumor Invasion

描述(申请人提供)：细胞侵袭和转移标志着癌症最致命的阶段，但人们对启动这一关键转折点的关键分子事件知之甚少。我们对果蝇的系统遗传分析表明，基侧连接蛋白在动物和人类中都高度保守，并精确定位于细胞间接触的特定位置，是关键的入侵抑制因子。它们既控制上皮性结构，又防止上皮性肿瘤细胞扩散。基侧连接由免疫球蛋白超家族成员Fasciclin2(人NCAM)和Neuroglian(人L1)，以及支架分子DiscsLarge(HDIg)和致死巨型幼虫(HLgl)组成。我们已经确定了作用于基底外侧交界处下游的第一条抑制上皮细胞侵袭的途径。三个编码信号分子的基因，疣(人类Lats1/2)，Mats(人类Mobla)和York ki(人类YAP)，都与人类的癌症发生有关。我们的数据是第一个证据表明它们处于对抑制肿瘤侵袭至关重要的基底外侧连接通路中。这一途径的一个关键靶点是在乳腺癌中放大的果蝇-1(DAIB1)，它在人类中是一种类固醇转录辅助激活因子，起到了癌基因的作用。AIB1参与乳腺癌治疗药物他莫昔芬的耐药，但对AIB1表达的调控知之甚少。我们的数据表明，底边结信号和DAIB1处于正反馈回路中。此外，我们发现AIB1在超过90%的人卵巢癌中过度表达，而Lats2和YAP在60%的乳腺癌中丢失，特别是在向侵袭的过渡阶段。我们的具体目标是：(1)通过WTS和MATS(LATS和MOBLA)调控基侧连接信号激活DAIB1(AIB1)在细胞核中的表达的途径；(2)建立基侧连接信号向AIB1/DAIB1传递信号的分子机制；(3)建立基侧连接信号通路在抑制人类肿瘤细胞侵袭中的重要性。这些目标将勾勒出基底外侧连接控制上皮侵袭性的第一条途径，这可能为浸润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.