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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要和摘要：前列腺癌（PCA）是美国男性最常见的癌症。腔组织学是PCA的标志。激素治疗有效地靶向腔细胞，但抗性不可避免地发生。在一半的PCA病例中，ERG癌蛋白过表达。前列腺ERG表达小鼠概括了人类PCA中看到的腔内程序的入侵，从而提出了临床上相关的研究PCA的模型。但是，ERG驱动腔命运和侵入性的分子机制 PCA仍然不清楚，这可能会揭示出新的治疗范例。项目目标：到阐明ERG驱动的腔内命运和PCA入侵的机制和脆弱性。初步数据： 1）假基细胞（具有混合物基础/腔标记物谱）而不是腔细胞是最多的伪基细胞 PCA中的增生和与入侵相关的种群； 2）全基因组CRISPR屏幕显示ERG 通过减轻芳基 - 氢化碳受体（AHR）信号传导来刺激腔命运，该信号提供可毒品脆弱性。中央假设：ERG刺激祖细胞状态，以伪基质细胞为特征，这可以维持PCA的入侵和管腔输出。拟议的项目利用创新的鼠标和器官模型，全基因组筛查数据和患者样品以检验该假设。具体目的：1）确定ERG驱动的PCA中伪基细胞的发光祖细胞和致癌潜力； 2）定义 AHR和其他屏幕候选者如何将谱系输出作为ERG的机制和脆弱性调节功能; 3）在人PCA中表征伪基态。影响：这项工作的成功将为1）进步机械理解，2）确定ERG驱动的PCA的新型漏洞，最常见的PCA 亚型和3）提供具有广泛适用性的工具和方法，可用于研究癌症中的命运选择。这项工作将在MSKCC的协作和足智多谋的研究环境下进行。我有最近开发了用于快速PCA建模的CRISPR编辑工具（Proc Natl Acad Sci），这对于至关重要推进拟议的工作。我的长期职业目标是建立一个独立的研究团队专注于对PCA的机械理解，以制定新的治疗策略。我已经开发了一个详细的职业计划，以获得领导，管理，指导，授予写作和科学的技能通讯。我将在Charles Sawyers博士的指导下工作，Charles Sawyers博士是PCA研究的领导者杰出的受训者的杰出记录。此外，我已经组装了咨询委员会将与我合作，并提供包括Drs在内的科学和职业发展培训。迈克尔·沉（Prostate Lineage规范），Yu Chen（ERG Biology），Gary Perdew（AHR Biology），Anuradha Gopalan（患者样本评估）和Christina Leslie（计算生物学）。我的研究和职业发展计划，以及我的导师，顾问和MSKCC的卓越学术环境将为我在转化前列腺癌研究方面的独立性提供了坚实的基础。