RNA-Binding Proteins as Molecular Integrators that Control the Response of HGSOC to Ant-Cancer Therapies

RNA 结合蛋白作为分子整合剂控制 HGSOC 对抗癌疗法的反应

• 批准号: 10524771
• 负责人: CHRISTOPHER B BURGE
• 金额: $ 52.58万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-07 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10524771
• 关键词: Address; Antimitotic Agents; Antineoplastic Agents; Antitumor Response; Ants; Area; Biological Models; CRISPR interference; CRISPR-mediated transcriptional activation; Cancer Patient; Cell Line; Chemoresistance; Cisplatin; Clinical; Collection; Combined Modality Therapy; Communities; Computer Analysis; Cytotoxic agent; DNA Damage; DNA Sequence; DNA-dependent protein kinase; Data; Data Set; Defect; Development; Diagnosis; Disease; Disease Resistance; Drug resistance; Epithelium; Excision; Foundations; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Goals; Hematopoietic Neoplasms; Histologic; Human; Immunotherapy; In Vitro; Laboratories; Limes; Link; Malignant Neoplasms; Malignant neoplasm of ovary; Measures; Mediating; Medical; Messenger RNA; Microtubules; Mitotic; Molecular; Mutation; Non-Small-Cell Lung Carcinoma; Operative Surgical Procedures; Outcome Study; Ovarian Carcinoma; Paclitaxel; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphorylation Site; Phosphotransferases; Platinum; Platinum Compounds; Poly(ADP-ribose) Polymerase Inhibitor; Protein Kinase; Proteins; RNA Binding; RNA Processing; RNA Stability; RNA interference screen; RNA-Binding Proteins; Recurrence; Regulation; Relapse; Research Personnel; Resistance; Role; Serous; Signal Pathway; Solid Neoplasm; TP53 gene; Technology; Therapeutic; Treatment Protocols; United States; Woman; Work; Xenograft Model; Xenograft procedure; bioinformatics pipeline; brca gene; cancer cell; cancer drug resistance; cancer therapy; chemotherapy; cytotoxic; differential expression; experimental study; frontier; genome wide screen; genome-wide; homologous recombination; improved; in vivo; molecular targeted therapies; mouse model; mutant; ovarian neoplasm; p38 Mitogen Activated Protein Kinase; patient derived xenograft model; posttranscriptional; prevent; protein function; recombinational repair; resistance mechanism; resistance mutation; response; screening; standard of care; success; taxane; therapeutic development; therapy resistant; transcriptome sequencing; tumor; upstream kinase; web-based tool

Project Summary Ovarian carcinoma is the fifth deadliest cancer among women in the United States. In spite of advances in surgical resection and platinum-taxane combination therapy over the past several decades, cure rates remain relatively low (~30%) and a majority of women diagnosed with advanced ovarian cancer will die with drug-resistant disease within 5 years. The long-term goal of this project, “RNA-Binding Proteins as Molecular Integrators that Control the Response of HGSOC to Anti-Cancer Therapies”, is to identify specific RNA-binding proteins that, together with their upstream protein kinase regulators, control the resistance and sensitivity of high-grade serous ovarian cancers to these clinically used first line anti-cancer therapies. The project involves: (1) a detailed computational analysis that queries pre-existing publically available RNA expression data using RNA-BP recognition motifs to identify specific RNA binding proteins whose mRNA targets are up- or down- regulated in ovarian cancer patients with chemo-sensitive versus chemo-resistant tumors; and (2) an independent CRISPR-interference and CRISPR-activation genome-wide screen for RNA-BPs whose manipulation alters the resistance and sensitivity of ovarian cancer cells to platinum and taxane agents in vitro, and in vivo using cell line xenografts and human PDX ovarian cancer mouse models. The RNA-BPs identify by these two complimentary approaches, together with a collection of RNA-BPs that we have already identified in previous experiments and preliminary data, are then directly validated for their effects on drug resistance in these model systems, and the identity of their bound RNAs and their effects on gene expression determined using CLIP technologies and RNA-Seq. In selected cases the importance of specific phosphorylation sites on RNA-BP function is examined to further elucidate the molecular basis for anti-cancer drug resistance through pathway-specific regulation of RNA-BP action. The project builds on a broad foundation of expertise and related work from all of the co-Investigators laboratories. Expected outcomes from the studies include the identification of specific RNA-BPs and upstream regulatory kinase pathways whose targeting can prevent or reverse the resistance of ovarian cancers to current clinically used front-lime therapeutics; the elucidation of new molecular circuits that control gene expression in cancers after chemotherapy treatment; and the creation of a suite of web-based tools available to the entire scientific community that can be used to query any set of differentially expressed genes for RNA-BP-based regulation, particularly in a form that is optimized for analysis of new and existing cancer patient RNA expression datasets.

项目摘要 卵巢癌是美国女性中第五大致命癌症。尽管取得了进步， 在过去的几十年里，手术切除和铂-紫杉烷联合治疗的治愈率 仍然相对较低（~30%），大多数被诊断患有晚期卵巢癌的女性将死于 5年内出现耐药疾病。该项目的长期目标是“RNA结合蛋白作为分子生物学的基础”。 控制HGSOC对抗癌疗法的反应的整合剂”，是为了鉴定特异性RNA结合 这些蛋白质与其上游蛋白激酶调节剂一起，控制了对 高级别浆液性卵巢癌与这些临床上使用的一线抗癌疗法相比。该项目涉及： (1)一个详细的计算分析，查询预先存在的生物学上可用的RNA表达数据，使用 RNA-BP识别基序，以识别其mRNA靶点上调或下调的特异性RNA结合蛋白。 在具有化学敏感性肿瘤与化学抗性肿瘤的卵巢癌患者中调节;和（2） 独立CRISPR干扰和CRISPR激活全基因组筛选RNA-BP， 操作改变了体外卵巢癌细胞对铂和紫杉烷试剂的抗性和敏感性， 以及使用细胞系异种移植物和人PDX卵巢癌小鼠模型的体内研究。RNA-BP识别 通过这两种互补的方法，以及我们已经确定的一系列RNA-BP， 在先前的实验和初步数据中，然后直接验证它们对耐药性的影响， 这些模型系统，以及它们结合的RNA的特性和它们对基因表达的影响， 使用CLIP技术和RNA-Seq.在选定的情况下， RNA-BP功能的检查，以进一步阐明抗癌药物耐药性的分子基础，通过 RNA-BP作用的途径特异性调节。该项目建立在广泛的专业知识基础上， 所有合作研究者实验室的相关工作。这些研究的预期成果包括： 鉴定特异性RNA-BP和上游调节激酶途径，其靶向可以预防或 逆转卵巢癌对目前临床上使用的前沿疗法的耐药性;阐明 控制化疗后癌症基因表达的新分子电路; 提供给整个科学界的一套基于网络的工具，可用于查询任何一组 用于基于RNA-BP的调控的差异表达基因，特别是以优化的形式用于分析 新的和现有的癌症患者RNA表达数据集。

项目成果

MAPKAP Kinase-2 Drives Expression of Angiogenic Factors by Tumor-Associated Macrophages in a Model of Inflammation-Induced Colon Cancer.

• DOI: 10.3389/fimmu.2020.607891
• 发表时间: 2020
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Suarez-Lopez L;Kong YW;Sriram G;Patterson JC;Rosenberg S;Morandell S;Haigis KM;Yaffe MB
• 通讯作者: Yaffe MB

Microenvironmental IL-6 inhibits anti-cancer immune responses generated by cytotoxic chemotherapy.

• DOI: 10.1038/s41467-021-26407-4
• 发表时间: 2021-10-28
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Bent EH;Millán-Barea LR;Zhuang I;Goulet DR;Fröse J;Hemann MT
• 通讯作者: Hemann MT

Functional genomics reveals an off-target dependency of drug synergy in gastric cancer therapy.

功能基因组学揭示了胃癌治疗中药物协同作用的脱靶依赖性。

• DOI: 10.1101/2023.10.07.561351
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Leylek,Ozen;Honeywell,MeganE;Lee,MichaelJ;Hemann,MichaelT;Ozcan,Gulnihal
• 通讯作者: Ozcan,Gulnihal

Multi-pathway DNA-repair reporters reveal competition between end-joining, single-strand annealing and homologous recombination at Cas9-induced DNA double-strand breaks.

• DOI: 10.1038/s41467-022-32743-w
• 发表时间: 2022-09-08
• 期刊: Nature communications
• 影响因子: 16.6

Early Immune Changes Support Signet Ring Cell Dormancy in CDH1-Driven Hereditary Diffuse Gastric Carcinogenesis.

早期免疫变化支持 CDH1 驱动的遗传性弥漫性胃癌中印戒细胞休眠。

• DOI: 10.1158/1541-7786.mcr-23-0122
• 发表时间: 2023
• 期刊: Molecular cancer research : MCR
• 作者: Green,BenjaminL;Gamble,LaurenA;Diggs,LaurenceP;Nousome,Darryl;Patterson,JesseC;Joughin,BrianA;Gasmi,Billel;Lux,StephanieC;Samaranayake,SarahG;Miettinen,Markku;Quezado,Martha;Hernandez,JonathanM;Yaffe,MichaelB;Davis,Jere
• 通讯作者: Davis,Jere