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.

摘要 成年乳腺由单能祖细胞群维持， 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突变引起的是恶性乳腺癌中的常见过程， 这种转化使细胞具有可塑性并促进肿瘤异质性。虽然这些 这一过程对侵袭性未分化乳腺癌提出了巨大的治疗挑战 如基底样乳腺癌（BLBC），最常见的三阴性乳腺癌 （TNBC），成年乳腺细胞可塑性的机制仍然很差 明白BLBC创始者细胞（BFC）可能是ER-管腔谱系，如 多个群体，但缺乏证明这一概念的具体证据。在本提案中，我们 寻求确定和描述BFC的特点，并发现负责 这些细胞中的多能性再激活。我们假设一个有能力的变形 单能管腔祖细胞通过保守途径获得多能性或产生 多能后代经历BLBC肿瘤进展所必需的逐步重编程。 为了验证这一假设，我进行了单细胞RNA测序， 在C3/Tag BLBC小鼠肿瘤模型中的腺体，以（1）通过以下方式建立候选BFC群体： 整合上皮聚类数据与RNA速度和细胞的伪时间分析 （2）确定疑似BFC簇在乳腺和肿瘤中的作用 最后（3）确定BFC去分化的分子决定因素。 这些数据的分析和后续谱系追踪实验的结果将揭示 迄今为止最高分辨率的BFC以及参与其转化的途径， 随后的脱分化。详细了解BLBC的异常去分化可能 可用于改善当前和未来BLBC治疗的状态以及用于治疗其他 利用细胞可塑性来抵抗和逃避治疗的侵袭性癌症。下 在郭文俊博士的指导和专业知识的基础上，我将执行研究和培训计划 在这份提案中。这与阿尔伯特提供的培训环境相结合， 爱因斯坦医学院将允许我为乳腺癌和干细胞领域做出贡献 细胞生物学和发展必要的研究和专业技能，成为一个 独立的物理学家和科学家