The Role of Dedifferentiation in Basal like Breast Cancer

摘要 成人乳腺由单能祖细胞群体维持，这些祖细胞群体是从 从多能干细胞到胚胎发育。多能性的出现 由成人腺体中的致癌基因突变引起的是恶性乳腺癌的常见过程 能够实现细胞可塑性并促进肿瘤异质性的转化。尽管这些 对侵袭性未分化乳腺癌的治疗提出了巨大的挑战 例如基底细胞样乳腺癌(BLBC)，这是最常见的三阴性乳腺癌 (TNBC)，成人乳腺细胞可塑性的机制仍然很差。 明白了。BLBC创始细胞(BFC)很可能是内质网血统，如以下所述 然而，缺乏具体的证据来证明这一概念。在这项提案中，我们 寻求确定和描述BFC的特征并发现负责 这些细胞的多能性重新激活。我们假设一次转变能胜任 单能的流明祖细胞通过保守的途径获得多能性或产生 对BLBC肿瘤进展至关重要的多能子代进行逐步重编程。 为了验证这一假设，我对增生性乳腺进行了单细胞RNA测序 C3/Tag BLBC小鼠肿瘤模型中的腺体以(1)通过以下方法建立候选BFC群体 将上皮聚类数据与RNA速度和细胞假时相分析相结合 人群，(2)确定可疑的BFC簇在乳腺和肿瘤中的作用 最后(3)确定BFC中去分化的分子决定因素。 对这些数据的分析和后续的血统追踪实验的结果将揭示 到目前为止最高分辨率的BFC以及涉及到它的转换和 随后的去分化。对BLBC异常去分化的详细了解可能会 有助于改善目前和未来BLBC治疗的状态，并有助于治疗其他 利用细胞的可塑性来抵抗和逃避治疗的侵袭性癌症。在.之下 经过证明的郭文俊博士的指导和专业知识，我将执行研究和培训计划 在这项提案中概述了。这一点，再加上阿尔伯特提供的训练环境 爱因斯坦医学院将允许我在乳腺癌和干细胞领域做出贡献 细胞生物学，并发展必要的研究和专业技能 独立的医生兼科学家。

ABSTRACT The adult mammary gland is maintained by unipotent progenitor populations which are derived from multipotent stem cells exclusive to embryonic development. The emergence of multipotency caused by oncogenic mutations in adult glands is a common process in malignant breast cancer transformation that enables cellular plasticity and promotes tumor heterogeneity. Although these processes pose immense therapeutic challenges for aggressive undifferentiated breast cancers such as Basal-like Breast Cancer (BLBC), the most common Triple Negative Breast Cancer (TNBC), the mechanisms underlying cellular plasticity in the adult mammary gland remain poorly understood. The BLBC founder cell (BFC) is likely of the ER- luminal lineage as suggested by multiple groups, however concrete evidence to prove this notion is lacking. In this proposal, we seek to identify and characterize the BFC and to uncover mechanisms responsible for multipotency reactivation in these cells. We hypothesize that a transformation competent unipotent luminal progenitor acquires multipotency through a conserved pathway or gives rise to multipotent progeny that undergo stepwise reprogramming essential for BLBC tumor progression. To test this hypothesis, I have performed single cell RNA sequencing of hyperplastic mammary glands in the C3/Tag BLBC mouse tumor model to (1) establish candidate BFC populations by integrating epithelial clustering data with RNA velocity and pseudotemporal analysis of cell populations, (2) determine the role of suspected BFC clusters in mammary gland and tumor development, and finally (3) identify the molecular determinants of dedifferentiation in the BFC. Findings from the analysis of this data and from follow up lineage tracing experiments will reveal the BFC in the highest resolution to date as well as pathways involved in its transformation and subsequent dedifferentiation. A detailed understanding of aberrant dedifferentiation in BLBC may be useful for improving the state of current and future BLBC treatments and for treatment of other aggressive cancers that employ cellular plasticity for treatment resistance and evasion. Under the proven mentorship and expertise of Dr. Wenjun Guo, I will execute the research and training plan outlined in this proposal. This, combined with the training environment provided by the Albert Einstein College of Medicine will allow me to contribute to the fields of breast cancer and stem cell biology and to develop the research and professional skills necessary to become an independent physician-scientist.