Mechanisms and vulnerabilities of ERG-driven luminal fate in prostate cancer

项目摘要与摘要：前列腺癌(Pca)是美国男性最常见的癌症。 腔组织学是前列腺癌的一个标志。激素治疗有效地针对腔细胞，但耐药 不可避免地会发生。ERG癌蛋白在一半的PCa中过度表达。前列腺癌组织中ERG的表达 小鼠用人类前列腺癌的腔程序概括了侵袭性，因此提出了一个临床上相关的 模型来研究主成分分析。然而，ERG驱动子宫命运和侵袭性的分子机制 PCA仍不清楚，从中获得的见解可能会揭示新的治疗范例。项目目标： 阐明ERG驱动的腔内命运和PCa侵袭的机制和脆弱性。初步数据： 1)假性基底细胞(具有混合基底/腔标记轮廓的细胞)比腔细胞多 PCa中的增殖和侵袭相关群体；2)全基因组CRISPR筛选显示ERG 通过减轻芳香烃受体(AHR)信号来刺激管腔命运，这提供了一种可药物 脆弱性。中心假设：ERG刺激一种以伪基底层细胞为特征的祖细胞状态， 这支持了前列腺癌的侵袭和腔内输出。建议的项目利用创新的鼠标和 器官模型、全基因组筛选数据和患者样本来验证这一假设。具体目标：1) 确定ERG驱动的PCa中腔前体细胞和假性基底细胞的致癌潜能；2)确定 AHR和其他候选筛选者如何调制谱系输出作为ERG的一种机制和脆弱性 功能；3)表征人主成分分析中的伪基础状态。影响：这项工作的成功将推动1) 机制理解，2)识别ERG驱动的PCA的新脆弱性，最频繁的PCA 3)为研究癌症的世系命运选择提供了具有广泛适用性的工具和方法。 这项工作将在MSKCC的协作和足智多谋的研究环境下进行。我有过 最近开发了用于快速PCA建模的CRISPR编辑工具(Proc Natl Acad Sci)，这将对 推进拟议的工作。我的长期职业目标是建立一个独立的研究团队， 侧重于从机理上理解前列腺癌，以开发新的治疗策略。我已经开发出一种 详细的职业生涯规划，以获得领导、管理、指导、拨款撰写和科学方面的技能 通讯。我将在查尔斯·索耶斯博士的指导下工作，他是PCA研究的领导者， 优秀的实习生晋升到教员职位的记录。此外，我还收集了一份建议 该委员会将与我合作，并提供科学和职业发展方面的培训，包括Dr。 Michael Shenin(前列腺谱)，Yu Chen(ERG生物学)，Gary Perdew(AHR生物学)，Anuradha Gopalan(患者样本评估)和Christina Leslie(计算生物学)。我的研究和事业 发展计划，连同我的导师、顾问和MSKCC卓越的学术环境将 为我在翻译前列腺癌研究方面的独立性提供了坚实的基础。

Project Summary and Abstract: Prostate cancer (PCa) is the most frequent cancer in American men. Luminal histology is a hallmark of PCa. Hormone therapy effectively targets luminal cells, but resistance inevitably occurs. The ERG oncoprotein is overexpressed in half of PCa cases. Prostatic ERG expression in mice recapitulates invasion with a luminal program seen in human PCa, thus presenting a clinically relevant model to study PCa. However, the molecular mechanisms by which ERG drives a luminal fate and invasive PCa remain unclear, insights from which may reveal new treatment paradigms. Project objective: To elucidate the mechanisms and vulnerabilities of ERG-driven luminal fate and PCa invasion. Preliminary data: 1) pseudo-basal cells (those with a mixture basal/luminal marker profile) rather than luminal cells are the most proliferative, and invasion-associated population in PCa; 2) a genome-wide CRISPR screen reveals that ERG stimulates luminal fate by alleviating aryl-hydrocarbon receptor (AHR) signaling, which provides a druggable vulnerability. Central hypothesis: ERG stimulates a progenitor state, characterized as pseudo-basal cells, that sustains invasion and luminal output of PCa. The proposed project leverages innovative mouse and organoid models, genome-wide screen data, and patient samples to test this hypothesis. Specific Aims: 1) determine the luminal progenitor and oncogenic potential of pseudo-basal cells in ERG-driven PCa; 2) define how AHR and other screen candidates modulate lineage output as a mechanism and vulnerability of ERG function; 3) characterize the pseudo-basal state in human PCa. Impact: Success of this work will 1) advance mechanistic understanding, 2) identify novel vulnerabilities of ERG-driven PCa, the most frequent PCa subtype, and 3) provide tools and approaches with wide applicability to studying lineage fate choices in cancer. This work will be performed under the collaborative and resourceful research environment at MSKCC. I have recently developed CRISPR editing tools for rapid PCa modeling (Proc Natl Acad Sci), which will be critical to advance the proposed work. My long-term career goal is to establish an independent research team that focuses on mechanistic understanding of PCa to develop novel therapeutic strategies. I have developed a detailed career plan to obtain skills in leadership, management, mentoring, grant writing, and scientific communications. I will work under the mentorship of Dr. Charles Sawyers, a leader in PCa research with a stellar track record of trainees that went on to faculty positions. In addition, I have assembled an Advisory Committee that will collaborate with me and offer training on science and career development, including Drs. Michael Shen (prostate lineage specification), Yu Chen (ERG biology), Gary Perdew (AHR biology), Anuradha Gopalan (patient sample assessment), and Christina Leslie (computational biology). My research and career development plan, together with my mentor, advisors and the exceptional academic environment at MSKCC will provide a solid foundation for my independence in translational prostate cancer research.