Breast cancer stem cells and their cellular origin

描述（由申请人提供）：我的长期职业目标是成为一名独立的科学家，主要专注于了解癌症的遗传学和细胞起源，并将其与癌症干细胞（CSC）表型联系起来。这项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？具体来说，我建议使用一种新的小鼠模型，人类乳腺癌发起的染色体易位来研究这一点。该模型的独特之处在于它提供了在癌症演变早期识别受影响细胞群体的机会。该提案的具体目标包括使用这种易位引发的乳腺癌模型来1。纯化癌症的靶细胞并表征其在初始癌基因表达后的最早分子变化。2.鉴定、分离和表征癌症干细胞。3.研究几个受影响的基因/途径中遗传/表观遗传变化对癌症干细胞表型的贡献。4.在分子水平上与人类乳腺癌进行跨物种比较。在不久的将来，我将继续我目前在这种小鼠模型上的工作，以识别和表征这种类型癌症的靶细胞。我还将开始在这个模型中识别CSC，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/R 00奖将使我能够在Stuart Orkin博士的指导下获得干细胞生物学，实体肿瘤生物学和生物信息学/计算生物学方面的额外培训。儿童医院和达纳法伯癌症研究所的血液学和肿瘤学培训计划汇集了两家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，这将有助于顺利过渡到独立。在独立阶段，我将继续在这个模型中对CSC进行研究，并将它们与它们衍生的细胞和它们分化的肿瘤细胞进行比较。更重要的是，我将确定和验证可能有助于CSC表型的其他突变/途径，并评估其作为人类乳腺癌新治疗靶点的潜力。总之，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.