A Drosophila Model for Src-Mediated Oncogenesis

描述（由申请人提供）：在上皮成熟过程中，利用大量信号转导分子来调节细胞周期和细胞死亡。当被突变激活时，这些相同的因子可以引起不受控制的生长，这是癌症发展中的一个常见步骤。例如，Ret受体酪氨酸激酶中的激活突变可引起致癌疾病，如多发性内分泌瘤2型（MEN 2）。通过将类似形式的活化Ret靶向发育中的果蝇视网膜，开发了体内模型以探索负责MEN 2疾病的下游信号传导组分。这种方法确定了几种途径，当突变时，改变Ret激活的结果。目前正在探索这些途径在人类肿瘤组织中的重要性。 修饰Ret（MEN 2）表型的一个下游途径是Src信号传导途径。Src是一种细胞质激酶，与包括结肠癌、乳腺癌和血液癌在内的数十种癌症有关。C-末端Src激酶（Csk）是Src信号的主要抑制剂。降低果蝇Csk活性导致Src的激活和伴随的细胞周期的细胞自主激活，这反过来又导致不受控制的生长。结果是一只放大的，异常图案的眼睛。重要的是，降低STAT信号通路的活性可以防止这种致癌生长：果蝇STAT的突变导致原本增生的Csk组织死亡。这表明了一种治疗性干预含有激活的Src途径的肿瘤的策略。 该提案旨在通过使用基因筛选来识别“杀伤”途径，更好地了解STAT杀死Csk缺陷细胞的能力的本质。此外，Src信号下游的一些受体的作用将进一步探讨。最后，果蝇视网膜作为信号传导，过度生长和细胞死亡的灵敏测定的优点将被利用作为也可以改善Csk/Src介导的过度生长的药物的体内筛选。

DESCRIPTION (provided by applicant): During epithelial maturation, a large number of signal transduction molecules are utilized to regulate cell cycle and cell death. When activated by mutation these same factors can provoke uncontrolled growth, a common step in the development of cancer. For example, activating mutations in the Ret receptor tyrosine kinase can provoke oncogenic diseases such as Multiple Endocrine Neoplasia Type 2 (MEN2). By targeting analogous forms of activated Ret to the developing Drosophila retina, an in vivo model was developed to explore the downstream signaling components that are responsible for aspects of the MEN2 disease. This approach identified several pathways that, when mutated, alter the outcome of Ret activation. The importance of these pathways in human tumor tissue is currently being explored. One downstream pathway that modified the Ret (MEN2) phenotype was the Src signaling pathway. Src is a cytoplasmic kinase that has been linked to dozens of cancer types including those of the colon and breast, as well as blood-based cancers. C-terminal Src kinase (Csk) is the major inhibitor of Src signaling. Reducing Drosophila Csk activity led to activation of Src and a concomitant cell-autonomous activation of the cell cycle, which in turn led to uncontrolled growth. The result was an enlarged, abnormally patterned eye. Importantly, reducing activity of the STAT signaling pathway prevented this oncogenic growth: mutations in Drosophila STAT led to death of otherwise proliferative Csk tissue. This suggests a strategy for therapeutic intervention of tumors that contain an activated Src pathway. This Proposal seeks to better understand the nature of STAT's ability to kill Csk-deficient cells by using genetic screens to identify 'killing' pathways. In addition, the role of Src signaling downstream of a number of receptors will be further explored. Finally, the advantages of the Drosophila retina as a sensitive assay of signaling, overgrowth, and cell death will be exploited as an in vivo screen for drugs that can also ameliorate Csk/Src-mediated overgrowth.