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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。追踪遗传事件进化的研究这些克隆群体之间的关系提供了对克隆过程的深刻见解肿瘤发生和对治疗的反应。尽管取得了这些进展，但转移过程 90%以上的癌症相关死亡是由这种疾病造成的，但人们对其仍知之甚少。这大多数研究比较原发肿瘤和转移瘤之间的遗传畸变发现转移克隆特有的一些改变。确实，目前还没有已知的转移的复发性遗传驱动因素。与原发性肿瘤的发生和建立相反，我自己未来的研究方向假设转移过程不依赖于进一步获得超出形成原发肿瘤所需的新基因改变细胞，而是由染色质景观的改变驱动，以以下形式呈现：细胞可塑性和重新编程的细胞状态。我们发现了发光体的证据—— 管腔 B 分子亚型乳腺癌中的基底细胞转变 (LBT)。小比特是对于肿瘤进展至关重要，因为不表现出这种可塑性的肿瘤会减弱转移能力强，对化疗更敏感。根据这些数据我们假设肿瘤细胞可塑性的获得使乳腺癌细胞偏离了它们的定位起源谱系是启动转移级联和疾病的重要第一步进展。这种可塑性的增加可能会促使细胞进入一种高度适应的状态新的栖息地以及对与肿瘤微环境成分的相互作用做出反应，所有这些其中对于转移过程至关重要。我们建议通过阐明来测试这一点通过评估经历过 LBT 的细胞的稳定性，研究 LBT 对管腔 B 型乳腺癌的影响转变、肿瘤启动能力和转移潜力（目标 1）。我们将进一步通过研究 Sox4 在出现的过程中的作用来揭示驱动转变的机制腔起源的基底细胞，跟踪其表达并确定其全基因组占用率以揭示其靶基因库在转移进展过程中的变化（目标 2）。然后，我们建议测试肿瘤分化的原理作为潜在的佐剂通过 Gαs R201C/fl 的组合激活和化疗给药进行化疗，或依次激活 Gαs R201C/fl，然后进行化疗。