Deciphering the role of Six2 in regulating cancer stem cell properties and promoting late-stage metastasis in breast cancer.

解读 Six2 在调节癌症干细胞特性和促进乳腺癌晚期转移中的作用。

• 批准号: 10242740
• 负责人: Michael UJ Oliphant
• 金额: $ 9.31万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10242740
• 关键词: Affect; Bioinformatics; Biological; Biological Assay; Biology; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Patient; Breast cancer metastasis; Cancer Biology; Candidate Disease Gene; Cell Lineage; Cells; Cessation of life; Communication; Complement; Complex; Data; Dedications; Development; Diagnosis; Disease; Education; Educational process of instructing; Engineering; Environment; Epithelial; Family; Future; Future Generations; Genes; Genetic Transcription; Goals; Homeobox; Human; In Vitro; Kidney; Laboratories; Left; Maintenance; Malignant Neoplasms; Measures; Mediating; Mediator of activation protein; Mentors; Metastatic Neoplasm to the Lung; Metastatic to; Microscopy; Molecular; National Cancer Institute; Neoplasm Metastasis; Pathway interactions; Phenotype; Positioning Attribute; Prevention; Primary Neoplasm; Process; Property; Regulation; Research; Research Personnel; Research Project Grants; Resources; Role; Sampling; Scientist; Site; Study models; Surface; System; Technical Expertise; Techniques; Testing; Therapeutic; Time; Tissues; Training; Translational Research; Work; base; cancer cell; cancer stem cell; cancer subtypes; experimental study; human model; improved; in vitro Model; in vivo; in vivo Model; interest; large datasets; live cell microscopy; malignant breast neoplasm; mammary; member; migration; mouse model; neoplastic cell; nephrogenesis; nephron progenitor; novel; overexpression; pre-doctoral; progenitor; programs; self-renewal; single cell analysis; skills; small hairpin RNA; stem; stem cell biomarkers; stem cell population; stem cells; stemness; targeted treatment; therapeutic target; therapeutically effective; transcription factor; transcriptome sequencing; triple-negative invasive breast carcinoma; tumor; tumor initiation; tumor progression; virtual

Project Summary. The vast majority of breast cancer-related deaths are not caused by the primary tumor, but rather by metastases. Current studies mainly focus on the prevention of the early stages of metastasis. However, since tumor cells have likely left the primary tumor at diagnosis, inhibiting early stages of metastasis may not be the most effective way to inhibit metastatic burden. Therefore, an emphasis on developing therapeutics against late-stage metastasis is essential for improving survival in breast cancer patients. To better understand this complex process, I am examining the role of the developmental transcription factor Six2 in promoting metastatic burden. Six2 is a member of the Six family of transcription factors that are not only critical for development, but also for tumor progression and metastasis. Six2 is unique because it specifically affects the later stages of breast cancer metastasis, demonstrating its potential as a therapeutic target to decrease metastatic burden. My studies thus far have revealed novel roles for Six2 in breast cancer. I have shown that Six2 upregulates the expression of numerous stem cell-related genes, including a master regulator of stemness, Sox2. Six2 also increases the mammary stem cell population, as well as tumor-initiation in vivo. My data demonstrate for the first time that cancer cells may hijack Six2 to perform its developmental stem cell roles out of context, and that this role of Six2 may contribute to its ability to induce metastatic outgrowth. In this F99/K00 proposal, I outline a strategy to complete my dissertation studies, as well as how I will prepare to move on to a postdoctoral position. In Aim 1, I will describe my current findings regarding the role of Six2 in regulating stem cell phenotypes to promote late-stage metastasis. In Aim 2, I will outline my research strategy to complete my predoctoral studies, which will use stage-specific in vitro/in vivo models in combination with a comprehensive bioinformatics-driven candidate gene approach to continue to examine the role of Six2 in the later stages of metastasis. This approach will lead to the discovery of additional downstream effectors that could be targeted therapeutically to inhibit metastatic burden. Lastly, Aim 3 outlines my plans for postdoctoral research, and how I will identify an ideal postdoctoral mentor who will provide additional training in in vivo microscopy, single-cell analysis approaches and in vitro/ex vivo tissue-specific microenvironment engineering to examine other aspects of late-stage metastasis including how the microenvironment regulates the activity of metastasis-initiating cells (MICs). In addition, I will seek out an environment in which translational research is encouraged, as well as my continued commitment to academics and teaching. My current and future training, along with my dedication to cancer biology education and mentoring, is well aligned with the goals of the National Cancer Institute of providing opportunities and resources that allow current scientists to conduct cutting-edge research, while also inspiring future generations of cancer researchers.

项目摘要。绝大多数乳腺癌相关死亡不是由原发肿瘤引起的， 而不是转移。目前的研究主要集中在转移早期的预防上。 然而，由于肿瘤细胞在诊断时可能已经离开原发肿瘤，抑制了早期转移， 可能不是抑制转移负荷的最有效方法。因此，强调发展 针对晚期转移的治疗对于提高乳腺癌患者的存活率是必不可少的。到 为了更好地理解这个复杂的过程，我正在研究发育转录因子Six 2的作用 促进转移负荷。Six 2是Six转录因子家族的一员， 这不仅对发展至关重要，而且对肿瘤进展和转移也至关重要。Six 2是独一无二的，因为它 影响乳腺癌转移的后期阶段，证明其作为治疗靶点的潜力， 减少转移负担。到目前为止，我的研究揭示了Six 2在乳腺癌中的新作用。我有 Six 2上调了许多干细胞相关基因的表达，包括一个主调节因子， Sox2. Six 2还增加了乳腺干细胞群，以及体内肿瘤起始。 我的数据首次证明癌细胞可以劫持Six 2来执行其发育干细胞 Six 2的这种作用可能有助于其诱导转移性生长的能力。 在这个F99/K 00建议中，我概述了完成论文学习的策略，以及我将如何 准备去做博士后在目标1中，我将描述我目前的研究结果， Six 2在调节干细胞表型促进晚期转移中的作用。在目标2中，我将概述我的研究 战略，以完成我的博士前研究，这将使用特定阶段的体外/体内模型相结合 通过全面的生物信息学驱动的候选基因方法，继续研究Six 2在以下方面的作用： 转移的后期阶段。这种方法将导致发现额外的下游效应物， 可以在治疗上靶向抑制转移负荷。最后，目标3概述了我的博士后计划 研究，以及我将如何确定一个理想的博士后导师谁将提供额外的培训，在体内 显微镜、单细胞分析方法和体外/离体组织特异性微环境工程 研究晚期转移的其他方面，包括微环境如何调节 转移起始细胞（MIC）。此外，我将寻找一个环境中，翻译研究是 鼓励，以及我对学术和教学的持续承诺。我现在和将来的训练， 沿着我对癌症生物学教育和指导的奉献精神， 国家癌症研究所提供的机会和资源，让目前的科学家进行 前沿研究，同时也激励了未来几代癌症研究人员。