The Role of Dedifferentiation in Basal like Breast Cancer

去分化在基底样乳腺癌中的作用

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

抽象的成年乳腺由单能祖细胞群维持，这些祖细胞群源自来自胚胎发育专有的多能干细胞。多能性的出现由成人腺体致癌突变引起是恶性乳腺癌的常见过程实现细胞可塑性并促进肿瘤异质性的转化。虽然这些过程对侵袭性未分化乳腺癌带来巨大的治疗挑战例如基底样乳腺癌（BLBC），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 创始人细胞 (BFC) 很可能属于 ER-luminal 谱系，如多个团体，但缺乏证明这一观点的具体证据。在这个提案中，我们寻求识别和描述 BFC 的特征，并揭示负责的机制这些细胞的多能性重新激活。我们假设一个有能力转型的人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对 BLBC 肿瘤进展至关重要的逐步重编程。为了验证这个假设，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) 通过以下方式建立候选 BFC 群体将上皮聚类数据与 RNA 速度和细胞伪时间分析相结合人群，（2）确定可疑的 BFC 簇在乳腺和肿瘤中的作用发育，最后 (3) 确定 BFC 去分化的分子决定因素。分析这些数据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 及其转型和涉及的途径随后的去分化。对 BLBC 中异常去分化的详细了解可能会可用于改善当前和未来 BLBC 治疗的状态以及其他疾病的治疗利用细胞可塑性来抵抗和逃避治疗的侵袭性癌症。下郭文军博士的良好指导和专业知识，我将执行研究和培训计划本提案中概述了。这，结合阿尔伯特提供的培训环境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并发展成为成为细胞生物学家所需的研究和专业技能独立医师科学家。