The Role of Dedifferentiation in Basal like Breast Cancer

去分化在基底样乳腺癌中的作用

• 批准号: 10723094
• 负责人: Jessie Larios-Valencia
• 金额: $ 5.27万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-28 至 2026-09-27
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10723094
• 关键词: Ablation; Adult; Aggressive Clinical Course; BRCA1 gene; Biology; Breast; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Treatment; Candidate Disease Gene; Cell Transplantation; Cells; Chromatin; Complement 3a; DNA Binding; Data; Data Analyses; Development; Embryo; Embryonic Development; Enhancers; Environment; Epithelial Cells; Epithelium; Future; Gene Expression; Genes; Genetic; Genetic Engineering; Genetic Transcription; Gland; Goals; Heterogeneity; Homeostasis; Human; Hyperplasia; Lesion; Literature; Malignant - descriptor; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Maps; Medicine; Mentorship; Modeling; Molecular; Multipotent Stem Cells; Mus; Mutation; Oncogenic; Paper; Pathway interactions; Physicians; Population; Precancerous Conditions; Predisposition; Prevalence; Process; Prognosis; Proliferating; RNA; Research; Resolution; Role; Scientist; TP53 gene; Testing; Therapeutic; Training; Transcription Factor AP-1; Transitional Cell; Transplantation; Tumor Promotion; Tumor Suppressor Proteins; Undifferentiated; Up-Regulation; Women' s Health; Work; cancer subtypes; college; effective therapy; experimental study; follow-up; gene regulatory network; improved; in vivo; malignant breast neoplasm; mammary; mortality; mouse model; novel; premalignant; progenitor; single-cell RNA sequencing; skills; stem cell biology; stem cells; synergism; targeted treatment; therapy resistant; triple-negative invasive breast carcinoma; tumor; tumor heterogeneity; tumor progression; tumorigenesis

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.

抽象的 成年乳腺由衍生的一能祖细胞维持 从多元干细胞独有到胚胎发育。多能力的出现 由成人腺体的致癌突变引起的是恶性乳腺癌的常见过程 能够促进细胞塑性并促进肿瘤异质性的转化。虽然这些 过程对侵略性未分化的乳腺癌提出了巨大的治疗挑战 例如基底样乳腺癌（BLBC），这是最常见的三重阴性乳腺癌 （TNBC），成年乳腺中细胞可塑性的基础机制保持较差 理解。 BLBC创始人细胞（BFC）可能是eR腔谱系，如 多个小组，但是缺乏证明这种概念的具体证据。在这个建议中，我们 寻求识别和表征BFC并发现负责的机制 这些细胞中的多稳定重新激活。我们假设转型能力 单位腔祖先通过保守的途径获得多履行，或产生 多能进行的后代对BLBC肿瘤进展至关重要。 为了检验该假设，我进行了增生乳腺的单细胞RNA测序 C3/TAG BLBC小鼠肿瘤模型中的腺体到（1）建立候选BFC种群 将上皮聚类数据与RNA速度和细胞的伪颞分析相结合 种群，（2）确定可疑BFC簇在乳腺和肿瘤中的作用 开发，最后（3）确定了BFC中去分化的分子决定因素。 来自对这些数据的分析以及后续谱系追踪实验的发现将揭示 迄今为止最高决议的BFC以及其转型涉及的途径和 随后的去分化。对BLBC中异常去分化的详细理解可能 对于改善当前和未来的BLBC治疗状态以及其他治疗 利用细胞可塑性来治疗耐药性和逃避的侵略性癌症。在 我将执行研究和培训计划的著名指导和专业知识 在此提案中概述了。这与阿尔伯特提供的培训环境相结合 爱因斯坦医学院将使我能够为乳腺癌和STEM的领域做出贡献 细胞生物学并发展成为一种必要的研究和专业技能 独立的医师科学家。