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

项目摘要。绝大多数与乳腺癌相关的死亡不是由原发肿瘤引起的，而是 而是通过转移。目前的研究主要集中在早期转移的预防上。 然而，由于肿瘤细胞很可能在确诊时离开了原发肿瘤，从而抑制了早期的转移 可能不是抑制转移性负担的最有效方法。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至关重要。至 为了更好地理解这一复杂的过程，我正在研究发育转录因子SIX2的作用 在促进转移性负担方面。SIX2是六个转录因子家族的成员，它们不仅是 对发育至关重要，但对肿瘤的进展和转移也是至关重要的。SIX2是独特的，因为它特别 影响乳腺癌转移的后期，显示其作为治疗靶点的潜力 减少转移性负担。到目前为止，我的研究揭示了SIX2在乳腺癌中的新角色。我有过 研究表明，SIX2上调了许多干细胞相关基因的表达，包括一个主调节因子 茎，索克斯2。SIX2还增加了乳腺干细胞的数量，以及体内肿瘤的启动。 我的数据首次表明，癌细胞可能劫持SIX2来执行其发育干细胞 SIX2的这种作用可能有助于其诱导转移性生长。 在这份F99/K00提案中，我概述了完成我的论文研究的策略，以及我将如何 准备好进入博士后岗位吧。在目标1中，我将描述我目前关于 SIX2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 完成我的博士前研究的战略，将结合使用特定阶段的体外/体内模型 用全面的生物信息学驱动的候选基因方法继续检测SIX2在 转移的后期。这种方法将导致发现额外的下游效应器 可以被靶向治疗以抑制转移负担。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，他将在体内提供额外的培训 显微镜、单细胞分析方法和体外/体外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血管活性。 转移起始细胞(MICs)。此外，我将寻找一种翻译研究的环境 受到鼓舞，以及我对学术和教学的持续承诺。我现在和未来的训练， 以及我对癌症生物学教育和指导的奉献精神，与 国家癌症研究所提供机会和资源，使当前的科学家能够进行 前沿研究，同时也激励着未来几代癌症研究人员。

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.