Uncovering the basis and implications of lineage plasticity in breast cancer

揭示乳腺癌谱系可塑性的基础和影响

基本信息

批准号：
10357013
负责人：
Todd W Miller
金额：
$ 37.95万
依托单位：
DARTMOUTH COLLEGE
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：
2022-01-01 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10357013
关键词：
Address Adjuvant Adjuvant Chemotherapy Attenuated Automobile Driving Basal Cell Biological Breast Cancer Cell Breast Carcinoma Cells Cessation of life Chromatin Clinical Coupled Cyclic AMP-Dependent Protein Kinases Data Disease Progression Event GTP-Binding Protein alpha Subunits, Gs Gene Expression Profiling Genes Genetic Genetically Engineered Mouse Habitats Heterogeneity Knock-in Mouse Label Malignant Neoplasms Metastatic to Modeling Mouse Mammary Tumor Virus Mutation Neoplasm Metastasis Pattern Population Primary Neoplasm Process Publishing Recurrence Regimen Relapse Resistance development Role SOX4 gene Testing Therapeutic Uses Treatment Protocols Tumor-Associated Process Work base cancer cell chemotherapy combinatorial conventional therapy genetic evolution genome-wide in vivo insight malignant breast neoplasm molecular subtypes neoplastic cell novel novel strategies response trait transcriptome treatment response tumor tumor growth tumor heterogeneity tumor initiation tumor microenvironment tumor progression tumorigenesis

项目摘要

Tumorigenesis involves the accumulation of genetic aberrations, leading to the emergence of distinct clonal subpopulations. Studies that have tracked the evolution of genetic events within and between these clonal populations have provided deep insights into the process of tumorigenesis and response to therapy. Despite these advances, the process of metastasis, which is responsible for over 90% of cancer-related deaths, remains poorly understood. The majority of studies that compare genetic aberrations between the primary tumor and metastases find few alterations that are unique to the metastatic clone. Indeed, there are no known recurrent genetic drivers of metastasis. In contrast to primary tumor initiation and establishment, my own future research directions hypothesize that the process of metastasis does not rely on the further acquisition of novel genetic alterations beyond those needed to form primary tumor cells, but is instead driven by alterations to the chromatin landscape, presenting itself in the form of cellular plasticity and a reprogrammed cell state. We have uncovered evidence of a luminal- to-basal transition (LBT) in breast cancers of the luminal B molecular subtype. The LBT is essential for tumor progression as tumors that do not exhibit this plasticity show attenuated metastatic ability and are more sensitive to chemotherapy. Based on these data we hypothesize that the acquisition of tumor cell plasticity that allows breast cancer cells to stray from their lineage-of-origin is an essential first step to initiating the metastatic cascade and disease progression. This increased plasticity likely propels cells into a state that is highly adaptive to new habitats and responsive to interactions with components of the tumor microenvironment, all of which are critical to the process of metastasis. We propose to test this by elucidating the effects of the LBT in luminal B breast cancers by assessing the stability of the cells that undergo the transition, their tumor-initiating capacity and metastatic potential (aim 1). We will further uncover the mechanisms driving the transition by studying the role of Sox4 in the emergence of the basal cells of luminal origin, tracking its expression and determining its genome-wide occupancy to reveal changes to its target gene repertoire during metastatic progression (aim 2). We then propose to test the principle of tumor differentiation as a potential adjuvant to chemotherapy by either combinatorial activation of Gαs R201C/fl and chemotherapy administration, or by sequential activation of Gαs R201C/fl followed by chemotherapy administration.

肿瘤发生涉及遗传畸变的积累，导致出现不同的克隆亚群。跟踪遗传事件进化的研究在这些克隆人群之间，有深刻的见解对肿瘤发生和对治疗的反应。尽管有这些进展，但转移过程，造成90％以上与癌症相关的死亡的原因仍然很少了解。这大多数研究比较原发性肿瘤和转移之间的遗传像差的研究找到很少的转移克隆独特的改动。确实，没有已知的转移的遗传驱动因素。与原发性肿瘤倡议和建立相反，我自己未来的研究方向假设转移的过程不依赖超出形成原发性肿瘤所需的新遗传改变的进一步获取细胞，而是由对染色质景观的改变驱动，以形式出现细胞塑性和重编程的细胞状态。我们发现了腔的证据腔体B分子亚型的乳腺癌中的基本过渡（LBT）。 LBT是对于不存在这种可塑性的肿瘤的必不可少的肿瘤进展至关重要转移能力，对化学疗法更敏感。基于这些数据，我们假设肿瘤细胞可塑性的获取使乳腺癌细胞从其原始谱系是启动转移性级联和疾病的重要第一步进展。这种增加的可塑性可能会将细胞驱动到高度适应的状态新的栖息地和对与肿瘤微环境组成部分相互作用的反应其中对于转移过程至关重要。我们建议通过阐明 LBT通过评估经历的细胞的稳定性在腔内B乳腺癌中的影响过渡，它们的肿瘤发射能力和转移潜力（AIM 1）。我们将进一步通过研究Sox4在出现中的作用来揭示推动过渡的机制腔源的基本细胞，跟踪其表达并确定其全基因组在转移性进展过程中揭示其靶基因库的变化的占用率（AIM 2）。然后，我们建议测试肿瘤分化的原理，以调整 GαSR201C/FL的组合激活和化学疗法给药的化学疗法，或通过连续激活GαSR201C/FL，然后进行化学疗法给药。