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.

建议：确定调控乳腺肿瘤转移的miRNAs和基因网络 摘要 转移是乳腺癌患者死亡的主要原因。然而，分子机制 潜在的肿瘤起始和转移尚不清楚。我们最近发现了肿瘤起始细胞(TICs) 来自人类乳腺肿瘤1，2。抽搐携带干细胞的某些特性，对常规 癌症治疗，并参与肿瘤转移。如何有效地针对痉挛或开始转移的肿瘤 细胞(MICs)因此成为最具推动力的问题之一。20-内源单链小RNA 长度为22个核苷酸，称为microRNAs(miRNAs，miRs)，已成为强有力的调节因子 肿瘤进展3-15。在这个项目中，我们的目标是描述调节人类乳腺癌的新型miRs。 启动和转移，并确定其靶基因。然后，在我们未来的工作中，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，如新的癌症生物标志物或治疗。 由于基因的原因，以前的大多数转移模型在完全代表人类肿瘤方面的能力有限。 培养中积累的人类癌细胞系的变化，小鼠肿瘤模型的遗传差异 与人类肿瘤相比，并绕过了通过血液接种进行转移的自然步骤。这 Project将利用我们最近建立的人在鼠之间的乳腺癌模型，这些模型是 从临床肿瘤标本中提取，并在以下情况下发生自发性肺或淋巴结转移 小鼠乳房脂肪垫原位移植。密切监测乳腺肿瘤的发生和发展 在体内转移方面，我们还用光学记者转导原代癌细胞，并改善了 通过非侵入性生物发光成像对体内10个细胞的检测灵敏度。MIR更稳定， 对分析方案的抵抗力超过mRNAs，因此成为有希望的新型癌症生物标记物。此外， 它们是内源性的小RNA，与复合药物相比毒性很小；因此有希望 将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起始和转移的了解与多学科领域的知识相结合。 改善临床医学和减少癌症的学科技术(如化学和生物工程) 死亡率。 转录 因素 活体内 肿瘤起源 转移 未来1 新型miRNAs 1 未来2 离体 肿瘤生长 细胞侵袭 目标差异化 基因抗药性 临床前 生物标志物 治疗学 2. 目标示意图：(1)表征和验证miRNA候选函数，(2) 确定miRNA靶标及其在BTIC和转移中的重要性，(未来1)转录 转录因子对miRNAs的调控，以及(未来2)miRNAs的临床前研究 以及作为乳腺癌新生物标记物和/或治疗靶点的基因。