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

前列腺癌中 ERG 驱动的管腔命运的机制和脆弱性

• 批准号: 10572836
• 负责人: Weiran Feng
• 金额: $ 17.3万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10572836
• 关键词: ARNT gene; Address; Adenocarcinoma; Advisory Committees; American; Aryl Hydrocarbon Receptor; Basal Cell; Biology; CRISPR screen; Cancer Etiology; Castration; Cells; Cessation of life; Chemicals; Chromatin; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Communication; Computational Biology; Data; Dependence; Development Plans; Dimerization; Environment; Epithelial Cells; Epithelium; Faculty; Foundations; Gene Fusion; Genetic; Genetically Engineered Mouse; Goals; Grant; Histology; Human; In Vitro; Incidence; Invaded; Knowledge; Leadership; Ligands; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Memorial Sloan-Kettering Cancer Center; Mentors; Mentorship; Modeling; Molecular; Mus; Oncogenic; Oncoproteins; Organoids; Output; Pathway interactions; Patients; Population; Positioning Attribute; Proliferating; Prostate; Prostatic; RNA; Receptor Signaling; Research; Residual state; Resistance; S-Phase Fraction; Sampling; Science; Signal Transduction; Solid; Specific qualifier value; Testing; Therapeutic; Training; Work; Writing; androgen deprivation therapy; anticancer research; cancer cell; cancer invasiveness; cancer subtypes; career; career development; clinically relevant; cohort; genome wide screen; genome-wide; hormone therapy; in vivo; innovation; insight; men; mouse model; multidisciplinary; novel; novel therapeutic intervention; overexpression; patient subsets; progenitor; programs; prostate cancer model; research and development; skills; success; tool; transcription factor; translational cancer research; tumor

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.

前列腺癌（PCa）是美国男性最常见的癌症。 管腔组织学是PCa的标志。激素治疗有效地靶向管腔细胞，但耐药性 不可避免地发生。ERG癌蛋白在一半的PCa病例中过表达。前列腺ERG表达 小鼠重现了在人类前列腺癌中观察到的管腔程序的侵袭，因此呈现出临床相关的 模型研究PCa。然而，ERG驱动管腔命运和侵袭性的分子机制是不确定的。 PCa仍不清楚，从中可以揭示新的治疗模式。项目目标： 阐明ERG驱动的管腔命运和PCa侵袭的机制和脆弱性。初步数据： 1)假基底细胞（具有基底/管腔标记物混合物的细胞）而不是管腔细胞是最常见的。 PCa中增殖和侵袭相关群体; 2）全基因组CRISPR筛选显示， 通过减轻芳香烃受体（AHR）信号传导刺激管腔命运，这提供了一种可药用的 易损性.中心假设：ERG刺激祖细胞状态，其特征为假基底细胞， 维持PCa的侵入和腔输出。拟议的项目利用创新的鼠标和 类器官模型、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中假基底细胞的管腔祖细胞和致癌潜力; 2）定义 AHR和其他筛选候选者如何调节作为ERG机制和脆弱性谱系输出 功能; 3）表征人PCa中的伪基础状态。影响：这项工作的成功将1）推进 机制的理解，2）识别ERG驱动的PCa的新漏洞，最常见的PCa 亚型，和3）提供了广泛适用于研究癌症中谱系命运选择的工具和方法。 这项工作将在MSKCC的协作和资源丰富的研究环境下进行。我有 最近开发的用于快速PCa建模的CRISPR编辑工具（Proc Natl Acad Sci），这对于 推进拟议工作。我的长期职业目标是建立一个独立的研究团队， 侧重于PCa的机制理解，以开发新的治疗策略。我开发了一个 详细的职业规划，以获得领导，管理，指导，赠款写作和科学技能 通讯我将在Charles Sawyers博士的指导下工作，他是PCa研究的领导者， 有着出色的培训记录的学员们都能继续担任教职。此外，我还召集了一个顾问团， 委员会将与我合作，并提供科学和职业发展的培训，包括博士。 Michael Shen（前列腺谱系规范）、Yu Chen（ERG生物学）、加里·佩尔杜（AHR生物学）、阿努拉达 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的特殊学术环境将 为我在转化前列腺癌研究中的独立性提供了坚实的基础。