Biology and genetics of metastatic disease

转移性疾病的生物学和遗传学

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/10700103
• 关键词: Apolipoprotein E; Award; Biology; Blood Vessels; Breast cancer metastasis; Cancer Patient; Cause of Death; Cells; Cessation of life; Clinical Trials; Critical Pathways; Data; Development; Disease; Event; Genes; Genetic; Genetic Models; Genetic screening method; Germ-Line Mutation; Glycoproteins; Human; Immune; Immunotherapy; Inherited; Laboratory Study; Malignant Neoplasms; Mediating; MicroRNAs; Molecular; Mus; Neoplasm Metastasis; Optics; Patients; Physiological; Prevention; Process; Signal Transduction; Solid; Therapeutic; colorectal cancer metastasis; driver mutation; effective therapy; genetic variant; innovation; insight; melanoma; mouse model; prevent; response; reverse genetics; standard of care; targeted treatment; translational potential; tumor

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 我的实验室研究导致转移形成的分子改变， 癌症死亡的过程和主要原因。长期以来，人们一直认为转移是由 体细胞转移驱动突变-假设的改变，尚未确定。通过表明 在转移性肿瘤中，特异性microRNA的水平发生改变，并确定它们的靶基因，我的实验室 确定并表征了转移形成的关键途径和过程。通过研究 一个这样的靶向转移基因的种系变异，我们发现转移潜能也可以预先 肿瘤形成的日期和遗传-揭示了一个意想不到的遗传基础， 转移，开辟了该领域的新方向。具体来说，我们确定了两个常见的人类 分泌性糖蛋白ApoE的种系变体促进或抑制黑色素瘤的转移， 数据表明这一原则可能适用于其他癌症。发现ApoE信号传导控制血管 和免疫相互作用以及细胞侵袭性共同促成转移形成。 这些见解具有重大的转化潜力，并形成了临床试验的基础， “转移靶向治疗”的概念验证，其中多个转移消退反应是 在标准护理和免疫疗法治疗失败的晚期患者中观察到。 展望未来，我们将使用ApoE的等位基因变体作为强大的遗传切入点，以了解ApoE的基因突变。 转移形成的潜在分子事件，我们将定义ApoE信号是如何被 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 将我们的反向遗传学和小鼠建模方法应用于其他癌症和基因， 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， 询问小鼠和人转移瘤的生理、遗传建模和筛选方法 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， 治疗和预防。