Breast cancer stem cells and their cellular origin

描述(申请人提供)：我的长期职业目标是成为一名独立科学家，主要专注于了解癌症的遗传学和细胞起源，并将这些与癌症干细胞(CSC)表型联系起来。这项提案中描述的研究旨在回答癌症生物学中的一个基本问题：CSC是如何从最初的正常细胞形成的？具体地说，我建议使用一种由染色体易位引发的人类乳腺癌的新小鼠模型来研究这一点。这个模型的独特之处在于，它提供了一个机会，在癌症进化的早期识别受影响的细胞群体。这项建议的具体目的包括使用这种易位启动的乳腺癌模型来1.纯化癌症的靶细胞，并表征它们在最初的癌基因表达后的最早分子变化。2.鉴定、分离和鉴定肿瘤干细胞。3.研究几个受影响基因/途径的遗传/表观遗传变化对肿瘤干细胞表型的贡献。4.在分子水平上与人类乳腺癌进行跨物种比对。在不久的将来，我将继续我目前在这个小鼠模型上的工作，以识别和表征这种类型的癌症的靶细胞。我还将开始在这个模型中识别CSCs，并通过在分子水平上与人类乳腺癌进行跨物种比较来验证该模型。K99/R00奖将允许我在斯图尔特·奥尔金博士的指导下，获得关于干细胞生物学、实体肿瘤生物学和生物信息学/计算生物学的额外培训。儿童医院和Dana Farber癌症研究所的血液学和肿瘤学培训计划汇集了这两个机构以及哈佛癌症中心的资源，并为在指导阶段完成培训提供了良好的环境，这应该有助于平稳过渡到独立。在独立阶段，我将继续我在这个模型中对CSCs的研究，并将它们与它们来源的细胞和它们分化为的大部分肿瘤细胞进行比较。更重要的是，我将确定和验证可能导致CSC表型的其他突变/途径，并评估它们作为人类乳腺癌新治疗靶点的潜力。综上所述，我建议利用一种新的人类乳腺癌小鼠模型作为研究CSCs及其相应的正常靶细胞的范例，以期开发合理的治疗方法来消除癌症。

DESCRIPTION (provided by applicant): My long-term career goal is to become an independent scientist with a primary focus on understanding the genetics and cellular origin of cancer and relating these to the cancer stem cell (CSC) phenotype. The research described in this proposal is designed to answer a fundamental question in cancer biology: how a CSC is formed from an originally normal cell? Specifically, I propose to use a novel mouse model of human breast cancer initiated by chromosomal translocation to study this. This model is unique in that it provides an opportunity to identify the affected population of cells early in the evolution of cancer. The specific aims of this proposal include using this translocation-initiated breast cancer model to 1. purify target cells of the cancer and characterize their earliest molecular changes after the initial oncogene expression. 2. identify, isolate and characterize cancer stem cells. 3. study contributions of genetic/epigenetic changes in several affected genes/pathways to the cancer stem cell phenotype. 4. perform cross-species comparison with human breast cancer at the molecular level. For the immediate future, I will continue my current work on this mouse model to identify and characterize target cells of this type of cancer. I will also start to identify CSCs in this model and validate the model by performing cross-species comparison with human breast cancer at the molecular level. The K99/R00 award would allow me to obtain additional training on stem cell biology, on solid tumor biology, and on bioinformatics/computational biology, under the mentorship of Dr. Stuart Orkin. The training program in hematology and oncology at Children's Hospital and Dana Farber Cancer Institute brings together the resources of both institutions as well as those from Harvard Cancer Center and provides an excellent environment for the completion of training during the mentored phase, which should facilitate a smooth transition to independence. During the independent phase, I will continue my study on CSCs in this model and compare them to the cells from which they derive and the bulk of tumor cells to which they differentiate. More importantly, I will identify and validate additional mutations/pathways that may contribute to the CSC phenotype, and assess their potential as novel therapeutic targets for human breast cancer. In summary, I propose to exploit a novel mouse model of human breast cancer as a paradigm to study CSCs and their corresponding normal target cells, for the purpose of developing rational therapeutics to eliminate cancer.