Harnessing receptor pleiotropy to control cancer

项目总结/摘要： 这项建议的目的是了解重要的受体之间的差异信号传导机制， 并利用这些知识来设计抑制恶性疾病的策略。 癌症经常劫持胚胎发育的信号逻辑，以促进生长、转移和旁路 自然调控。这使得癌细胞上的受体保持永久的“开启状态”。电流 因此，治疗方法试图通过促进非信号传导能力的受体活化来防止受体活化， 受体“关闭状态”。然而，这产生了一个巨大的选择压力，推动了快速生长 抗战最近的研究结果表明，对肿瘤发生重要的受体实际上允许不同的 信号输出，而不仅仅是离散的开/关状态-功能更像变阻器，而不是数字 - 是的这一新发现的特性开启了主动“调谐”肿瘤信号远离肿瘤的可能性。 转移该提案调查了发育和发育过程中控制受体信号偏差的机制， 使用一系列技术的疾病模型，这些技术跨越了揭示 受体和细胞信号动力学。我的方法结合了尖端的生物物理技术 （包括低温电磁和干涉测量），这将有助于破译"逻辑"控制信号偏置， 致癌受体差分信号过程的定量和高分辨率视图将提供 重要的基本见解癌症受体生物学，并应开辟新的途径，设计 限制疾病进展的调节疗法。

Project summary / abstract: The goal of this proposal is to understand the mechanisms of differential signaling among receptors important for the development of cancer, and to use this knowledge to design strategies to suppress malignant disease. Cancers often highjack the signaling logic of embryonic development for growth and metastasis and bypass natural regulatory controls. This allows receptors on cancer cells to remain in a perpetual “on-state”. Current therapeutic approaches therefore attempt to prevent receptor activation by promoting non-signaling competent receptor “off-states”. This, however, produces an enormous selective pressure that drives the rapid outgrowth of resistance. Recent findings suggest that receptors important for oncogenesis actually allow for diverse signaling outputs rather than just discrete on/off states – functioning more like a rheostat than a digital convertor. This newly discovered property opens the possibility of actively `tuning' tumor signaling away from metastasis. This proposal investigates the mechanisms that control receptor signal bias in developmental and disease models using an array of techniques that span the relevant length and time scales necessary to reveal receptor and cellular signaling dynamics. My approach incorporates cutting-edge biophysical technologies (including cryo-EM and interferometry) that will help decipher the `logic' governing signal bias among oncogenic receptors. A quantitative and high-resolution view of the differential signaling process will provide important fundamental insight into cancer receptor biology and should open new avenues for the design of modulatory therapeutics that limit disease progression.