Identifying a network of microRNAs and genes that regulate breast tumor metastasis

识别调节乳腺肿瘤转移的 microRNA 和基因网络

• 批准号: 9459147
• 负责人: Huiping Liu
• 金额: $ 19.73万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9459147
• 关键词: Identifying; network; microRNAs; genes; regulate

Proposal: Identifying a network of miRNAs and genes that regulate breast tumor metastasis Abstract Metastasis is the major cause of death in breast cancer patients. However, the molecular mechanisms underlying tumor initiation and metastasis are not clear. We have recently identified tumor initiation cells (TICs) from human breast tumors 1,2. TICs carry certain properties of stem cells, are more resistant to conventional cancer therapies, and are involved in tumor metastasis. How to effectively target TICs or metastasis initiating cells (MICs) thus becomes one of the most propelling questions. Endogenous single strand small RNAs of 20- 22 nucleotides in length, known as microRNAs (miRNAs, miRs), have emerged to be powerful regulators of tumor progression 3-15. In this project, we aim to characterize novel miRs that regulate human breast cancer initiation and metastasis and identify their target genes. Then in our future endeavors, we will examine miR regulation mechanisms at the transcriptional level and further translate our understanding to clinical applications, such as novel cancer biomarkers or therapeutics. Most previous metastasis models are limited in their ability to fully represent human tumors, due to genetic changes accumulated in culture for human cancer cell lines, genetic differences in mouse tumor models compared to human tumors, and bypassing the natural steps of metastasis via bloodstream inoculations. This project will take advantage of our recently established human-in-mouse breast cancer models, which are derived from clinical tumor specimens and develop spontaneous lung or lymph node metastases upon orthotopic transplantation into mouse mammary fat pads. To closely monitor breast tumor initiation and metastasis in vivo, we have also transduced primary cancer cells with optical reporters and improved the detection sensitivity to 10 cells in vivo via non-invasive bioluminescence imaging. MiRs are more stable and resistant to analysis protocols than mRNAs, thus serving as promising novel cancer biomarkers. Furthermore, they are endogenous small RNAs with little toxicity compared to compound drugs; therefore hold the promise to be developed as innovative cancer therapeutics. Our long-term goal is to combine our understanding of tumor initiation and metastasis with knowledge in multi- disciplinary technology (such as chemistry and bioengineering) to improve clinical medicine and reduce cancer mortality. Transcription Factors In vivo Tumor initiation metastasis Future 1 Novel miRNAs 1 Future 2 In vitro Tumor growth Cell invasion Target Differentiation Genes Drug-resistance Preclinical Biomarkers Therapeutics 2 A schematic figure of aims: (1) to characterize and validate miRNA candidate functions, (2) to identify miRNA targets and their importance in BTICs and metastasis, (Future 1) transcriptional regulation of miRNAs by transcriptional factors, and (Future 2) preclinical studies of miRNAs and genes serving as novel biomarkers and/or therapeutic targets for breast cancer.

提案：识别调节乳腺肿瘤转移的 miRNA 和基因网络 抽象的 转移是乳腺癌患者死亡的主要原因。然而，分子机制 潜在的肿瘤发生和转移尚不清楚。我们最近发现了肿瘤起始细胞（TIC） 来自人类乳腺肿瘤1,2。 TIC 具有干细胞的某些特性，对传统疗法更具抵抗力 癌症治疗，并参与肿瘤转移。如何有效靶向 TIC 或转移起始点 因此，细胞（MIC）成为最紧迫的问题之一。 20-的内源性单链小RNA 长度为 22 个核苷酸的 microRNA（miRNA、miR）已成为强大的调节因子 肿瘤进展3-15。在这个项目中，我们的目标是表征调节人类乳腺癌的新型 miR 起始和转移并确定其靶基因。那么在我们未来的努力中，我们将研究 miR 转录水平的调控机制，并进一步将我们的理解转化为临床 应用，例如新型癌症生物标志物或治疗方法。 由于遗传因素，大多数先前的转移模型在完全代表人类肿瘤的能力方面受到限制。 人类癌细胞系培养物中积累的变化、小鼠肿瘤模型中的遗传差异 与人类肿瘤相比，并绕过通过血流接种转移的自然步骤。这 该项目将利用我们最近建立的人鼠乳腺癌模型，该模型是 源自临床肿瘤标本，并在发生后发生自发性肺或淋巴结转移 原位移植到小鼠乳腺脂肪垫中。密切监测乳腺肿瘤的发生和 为了实现体内转移，我们还用光学报告基因转导了原代癌细胞，并改善了 通过非侵入性生物发光成像检测体内 10 个细胞的灵敏度。 MiR 更稳定 比 mRNA 更能抵抗分析方案，因此可以作为有前途的新型癌症生物标志物。此外， 是内源性小RNA，与复合药物相比毒性较小；因此信守诺言 被开发为创新的癌症疗法。 我们的长期目标是将我们对肿瘤发生和转移的理解与多学科知识结合起来。 学科技术（例如化学和生物工程）以改善临床医学并减少癌症 死亡。 转录 因素 体内 肿瘤起始 转移 未来1 新型 miRNA 1 未来2 体外 肿瘤生长 细胞侵袭 目标差异化 基因耐药性 临床前 生物标志物 疗法 2 目标示意图：(1) 表征和验证 miRNA 候选功能，(2) 识别 miRNA 靶标及其在 BTIC 和转移中的重要性，（Future 1）转录 转录因子对miRNA的调控，以及（未来2）miRNA的临床前研究 以及作为乳腺癌新生物标志物和/或治疗靶点的基因。