The Cancer Target Discovery and Development Network at UCSF

加州大学旧金山分校癌症靶标发现和开发网络

• 批准号: 10210200
• 负责人: Sourav Bandyopadhyay
• 金额: $ 102.67万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-10 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10210200
• 关键词: Address; Area; Automobile Driving; CRISPR screen; CRISPR/Cas technology; Cataloging; Cell Communication; Cells; Characteristics; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Critical Pathways; Data; Development; Dominant-Negative Mutation; Drug resistance; Evolution; Fibroblasts; Funding; Gene Combinations; Genes; Genetic; Genetic Epistasis; Genotype; Goals; Growth; Heterogeneity; Human; Individual; Joints; Lesion; Libraries; Link; Maintenance; Malignant Neoplasms; Mammalian Cell; Maps; Mediating; Methodology; Methods; Mining; Mission; Molecular; Molecular Target; Mutation; Neoplasm Metastasis; Oncogenes; Pathway interactions; Patients; Phenotype; Program Development; Protocols documentation; Reagent; Recurrence; Research; Research Project Grants; Resistance; Role; Synthetic Genes; System; Systems Biology; Technology; The Cancer Genome Atlas; Therapeutic; Tissues; Variant; acquired drug resistance; anticancer research; base; cancer cell; cancer genome; cancer initiation; cancer type; cell behavior; cell type; gain of function; gene interaction; genome sequencing; genomic data; high throughput screening; improved; innovation; macrophage; new therapeutic target; novel; novel therapeutics; programs; resistance mechanism; screening; small molecule therapeutics; therapy resistant; tool; tumor; tumor growth; tumor heterogeneity; tumor microenvironment

PROJECT SUMMARY Our general strategy is to take advantage of novel tools and methodologies that we have developed during our first CTD^2 funding period- more specifically pioneering and applying CRISPR based technologies to aid the discovery and characterization of novel cancer targets and their modulators– using innovative high throughput screening methods. Our end goal is to uncover optimal combinations of perturbagens with the potential to eliminate all cancer cells, despite their clonal heterogeneity and environmental context. One goal is to elucidate new molecular targets with the goal to overcome acquired drug resistance. We build upon an exciting system allowing us to quantitate genotypic and phenotypic cell heterogeneity for hundreds of thousands of single cancer cells. We propose a battery of therapeutic small molecule screens to identify candidate driver genes associated with drug resistance and with recurrent mutations from TCGA, TARGET, CGCI, ICGC and related initiatives. The overall goal is to identify synthetic gene combinations necessary for clinical resistance and related to inter- and intra-tumor heterogeneity. We will develop and apply methodologies for the identification of genes influencing heterotypic cell-cell interactions in tumors. Tumor evolution is a challenging area of research, largely due to the complexity of cell types and behaviors. In this aim, high-throughput screens will be performed to identify non-cell autonomous synthetic lethal and synthetic viable interactions relevant to tumor microenvironment interactions. These studies will include primary T-effector/cancer cell interactions to identify new therapeutic targets and cancer associated macrophage and fibroblast/cancer cell screens to identify genes mediating therapeutic resistance. These systems are made possible by using a currently unpublished screening platform that may help to identify genes important for cancer initiation, maintenance, and possibly metastasis. Since we will use primary and cancer tissue, our unique platform will recapitulate as much as possible the characteristics of tumors in patients and address an important challenge in cancer research. We have developed a novel means to establish genetic epistatic interactions in mammalian cells and will expand upon our efforts to generate specific libraries to map the subset of targets identified in the above screens. In this aim, we will address targets and mechanisms by delineating where targets act in the pathway by probing cancer-defining molecular interdependencies, using the novel targets and screening systems described above. The end goal is to uncover the optimal combination of perturbagens with the potential to eliminate all cancer cells, despite their clonal heterogeneity.

项目总结 我们的总体战略是利用我们在 第一个CTD^2资助期--更具体地说，开创和应用基于CRISPR的技术，以帮助 利用创新的高通量发现和表征新的癌症靶点及其调节剂 筛查方法。我们的最终目标是发现最优的微扰剂组合 消灭所有癌细胞，尽管它们具有克隆异质性和环境背景。 一个目标是阐明新的分子靶点，目标是克服获得性耐药性。我们建造 在一个令人兴奋的系统上，允许我们量化数百个 成千上万个单一的癌细胞。我们提出了一组治疗性小分子筛查来识别 候选驱动基因与耐药性和TCGA、TARGET CGCI、ICGC及相关倡议。总的目标是确定合成的基因组合 临床耐药与肿瘤内和肿瘤内的异质性有关。 我们将开发和应用鉴定影响异型细胞的基因的方法。 肿瘤中的相互作用。肿瘤进化是一个极具挑战性的研究领域，很大程度上是由于细胞的复杂性。 类型和行为。为此，将进行高通量筛查，以识别非细胞自治 与肿瘤微环境相关的合成致命性和合成活性相互作用。这些 研究将包括主要T效应分子/癌细胞的相互作用，以确定新的治疗靶点和癌症 相关的巨噬细胞和成纤维细胞/癌细胞筛选以确定介导治疗耐药的基因。 这些系统是通过使用目前未发布的筛查平台来实现的，该平台可能有助于 确定对癌症的发生、维持和可能的转移有重要作用的基因。因为我们将使用主服务器 和癌组织，我们独特的平台将尽可能多地概括肿瘤的特征 并解决癌症研究中的一个重要挑战。 我们已经开发出一种新的方法来建立哺乳动物细胞和意志中的遗传上位性相互作用 扩展我们为生成特定库以映射上述确定的目标子集所做的努力 屏幕。在这个目标中，我们将通过描绘靶标在路径中的作用位置来解决靶标和机制 通过使用新的靶点和筛查系统来探测定义癌症的分子相互依赖关系 如上所述。最终目标是发现具有潜在的微扰的最佳组合 消灭所有癌细胞，尽管它们具有克隆异质性。

项目成果

Integration of Tumor Genomic Data with Cell Lines Using Multi-dimensional Network Modules Improves Cancer Pharmacogenomics.

• DOI: 10.1016/j.cels.2018.10.001
• 发表时间: 2018-11-28
• 期刊: Cell systems
• 影响因子: 9.3
• 作者: Webber JT;Kaushik S;Bandyopadhyay S
• 通讯作者: Bandyopadhyay S

Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition.

• DOI: 10.1038/nature24297
• 发表时间: 2017-11-09
• 期刊: Nature
• 影响因子: 64.8
• 作者: Hangauer MJ;Viswanathan VS;Ryan MJ;Bole D;Eaton JK;Matov A;Galeas J;Dhruv HD;Berens ME;Schreiber SL;McCormick F;McManus MT
• 通讯作者: McManus MT

High-Throughput CRISPR Screening Identifies Genes Involved in Macrophage Viability and Inflammatory Pathways.

• DOI: 10.1016/j.celrep.2020.108541
• 发表时间: 2020-12-29
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Covarrubias S;Vollmers AC;Capili A;Boettcher M;Shulkin A;Correa MR;Halasz H;Robinson EK;O'Briain L;Vollmers C;Blau J;Katzman S;McManus MT;Carpenter S
• 通讯作者: Carpenter S

miR-200 deficiency promotes lung cancer metastasis by activating Notch signaling in cancer-associated fibroblasts.

• DOI: 10.1101/gad.347344.120
• 发表时间: 2021-08-01
• 期刊: Genes & development
• 影响因子: 10.5
• 作者: Xue B;Chuang CH;Prosser HM;Fuziwara CS;Chan C;Sahasrabudhe N;Kühn M;Wu Y;Chen J;Biton A;Chen C;Wilkinson JE;McManus MT;Bradley A;Winslow MM;Su B;He L
• 通讯作者: He L

A Single-Chain Photoswitchable CRISPR-Cas9 Architecture for Light-Inducible Gene Editing and Transcription.

• DOI: 10.1021/acschembio.7b00603
• 发表时间: 2018-02-16
• 期刊: ACS chemical biology
• 影响因子: 4
• 作者: Zhou XX;Zou X;Chung HK;Gao Y;Liu Y;Qi LS;Lin MZ
• 通讯作者: Lin MZ