Biology and genetics of metastatic disease

转移性疾病的生物学和遗传学

基本信息

批准号：
10700103
负责人：
Sohail F. Tavazoie
金额：
$ 99.67万
依托单位：
ROCKEFELLER UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-07 至 2029-08-31
项目状态：
未结题

项目摘要

Biology and Genetics of Metastatic Disease My laboratory studies the molecular alterations that contribute to metastasis formation, a poorly understood process and primary cause of solid cancer deaths. It has long been thought that metastasis is caused by somatic metastasis driver mutations—postulated alterations that have yet to be identified. By showing that levels of specific microRNAs become altered in metastatic tumors and identifying their target genes, my lab identified and characterized critical pathways and processes underlying metastasis formation. By studying germline variants of one such target metastasis gene, we discovered that metastatic potential can also pre- date tumor formation and be genetically inherited—revealing an unanticipated genetic underpinning for metastasis and opening up a new direction for the field. Specifically, we determined that two common human germline variants of the secreted glycoprotein ApoE promote or suppress metastasis in melanoma, with recent data suggesting this principle may apply to additional cancers. ApoE signaling was found to govern vascular and immune interactions as well as cellular invasiveness that collectively contribute to metastasis formation. These insights have significant translational potential and formed the basis of clinical trials that are providing proof-of-concept for ‘metastasis targeting therapy’, where multiple metastasis regression responses were observed in advanced stage patients for whom standard of care and immunotherapy treatments had failed. Going forward, we will use allelic variants of ApoE as powerful genetic entry points to understand the molecular events underlying metastasis formation, where we will define how ApoE signals are received by cells and how ApoE mediates intracellular events. We will also extend the concept of hereditary metastasis genetics to additional cancers and genes, applying our reverse genetic and mouse modeling approaches to breast and colorectal cancer metastasis. To achieve this understanding, we will employ innovative optical, physiological, genetic modeling and screening methods to interrogate mouse and human metastatic transitions. This award will enable our group to establish the first genetically guided framework for understanding the molecular mechanisms governing metastasis formation—enabling new avenues for its therapeutic treatment and prevention.

转移性疾病的生物学和遗传学我的实验室研究有助于转移形成的分子改变，这是一个知之甚少固体癌症死亡的过程和主要原因。长期以来一直认为转移是由体细胞转移驱动突变 - 尚未确定的验证变化。通过显示特定microRNA的水平在转移性肿瘤中改变并识别其靶基因，我的实验室确定并表征了临界途径和过程的基础转移形成。通过学习一个这样的靶向转移基因的种系变异，我们发现转移潜力也可以预先形成日期的肿瘤并遗传遗传 - 为意外的遗传基础揭示转移并为该领域打开新方向。具体来说，我们确定了两个共同的人分泌的糖蛋白APOE的种系变异促进或抑制黑色素瘤的转移，最近暗示此原则的数据可能适用于其他癌症。发现APOE信号传导控制血管和免疫学相互作用以及统称有助于转移形成的细胞侵袭性。这些见解具有巨大的翻译潜力，并构成了提供的临床试验的基础 “转移靶向疗法”的概念证明，其中多个转移回归反应是在高级阶段患者中观察到的护理和免疫疗法治疗失败。展望未来，我们将使用APOE的等位基因变体作为强大的遗传进入点来了解分子事件的基础转移形成，我们将在其中定义如何通过细胞以及APOE如何介导细胞内事件。我们还将扩展遗传转移的概念遗传学对其他癌症和基因，将我们的反向遗传和小鼠建模方法应用于乳腺癌和结直肠癌转移。为了实现这一理解，我们将采用创新的光学，物理，遗传建模和筛查方法，以询问小鼠和人类转移性过渡。该奖项将使我们的小组能够建立第一个遗传指导框架了解控制转移形成的分子机制，以实现其新途径治疗和预防。