High-grade serous ovarian cancer: exploiting a living biobank to delineate mechanisms underlying disease-specific chromosome instability

高级别浆液性卵巢癌:利用活生物库来描述疾病特异性染色体不稳定的机制

基本信息

  • 批准号:
    MR/X008088/1
  • 负责人:
  • 金额:
    $ 84.17万
  • 依托单位:
  • 依托单位国家:
    英国
  • 项目类别:
    Research Grant
  • 财政年份:
    2023
  • 资助国家:
    英国
  • 起止时间:
    2023 至 无数据
  • 项目状态:
    未结题

项目摘要

25 years ago, our understanding of cancer genomics underwent a paradigm shift when it was discovered that cancer cell karyotypes are in a state of constant flux due to underlying chromosome instability (CIN), ie continuous gain and loss of chromosomes and/or acquisition of structural rearrangements. And indeed, it is now widely accepted that CIN is a major driver of tumour heterogeneity, phenotypic adaptation and drug resistance.In the last two decades, we have learnt a great deal about the molecular mechanisms responsible for chromosome replication and segregation, as well as the associated cell cycle checkpoint controls. However, oncogenic mutations in genes directly involved in these processes are extremely rare, meaning our understanding of the basic principles governing the acquisition of CIN, how it drives tumorigenesis and alters trajectories in the face of selective pressures remains more limited. Thus we aim to understand these principles in order to exploit CIN as a therapeutic target.Despite intense efforts, multiple factors have hindered progress. Mechanistic studies typically focus on a limited number of established cancer cell lines, due to experimental tractability, yet they tend to have limited clinical annotation, do not reflect disease heterogeneity, and lack pre-/post- treatment counterparts. Moreover, outgrowth of fitter subclones best suited for long-term cell culture yields relatively stable karyotypes. Additional confounding factors are genetic drift due to extensive in vitro propagation, and a tumour-site agnostic philosophy that ignores the possibility of disease-specific CIN pathways. Another limitation is the lack of non-transformed, karyotypically-stable model systems that represent the cell-of-origin to recapitulate CIN pathways.While cancer sequencing projects can analyse large cohorts of clinically annotated samples, reliance on archival biopsies results in stromal contamination, single-cell approaches are technically challenging, and testing emerging hypotheses with functional experiments is impossible. While sequencing spatially resolved biopsies allows reconstruction of evolutionary trajectories, longitudinal cohorts of matched chemo-naïve, on-treatment and relapse samples are less common. Moreover, isolating progenitors of drug-resistant clones is impossible.Therefore, to define the basic principles governing how CIN drives tumorigenesis and drug resistance, we now propose a fundamentally fresh approach with several key benefits to address the limitations that have hindered progress to date. Importantly, we will take a disease-specific approach, focusing on high-grade serous ovarian cancer (HGSOC), where CIN is the key driver and acquired drug resistance the key clinical challenge.Firstly, we will exploit our living biobank of patient-derived ovarian cancer models (OCMs), possibly the largest and most diverse collection of primary HGSOC cell cultures. OCMs are early passage, purified tumour fractions that possess the hallmarks and heterogeneity of HGSOC. Coupled with a cell culture system that enables extensive proliferative potential, OCMs are amenable to multi-omics, including single-cell omics, high-resolution cell biology studies and drug-sensitivity profiling. As the biobank matures, we are assembling longitudinal cohorts, ie OCMs derived from biopsies taken before, during and after chemotherapy.Secondly, as HGSOC originates from fallopian tube epithelial cells, we have established the FNE1 model system of these cells. FNE1 cells are non-transformed and karyotypically stable, but we have shown that introducing HGSOC-specific genetic lesions is sufficient to induce CIN, yielding karyotypes similar to those of our patient-derived models.And thirdly, to isolate the progenitors of drug-resistant descendants, we will combine a state-of-the-art barcode-based lineage tracing technology with our longitudinal OCMs to study clonal dynamics in response to chemotherapy.
25年前,当我们发现癌细胞核型由于潜在的染色体不稳定性(CIN)而处于不断变化的状态时,我们对癌症基因组学的理解发生了范式转变,即染色体的不断增加和减少和/或结构重排的获得。事实上,现在人们普遍认为CIN是肿瘤异质性、表型适应和耐药性的主要驱动因素。在过去的二十年中,我们已经了解了染色体复制和分离的分子机制,以及相关的细胞周期检查点控制。然而,直接参与这些过程的基因中的致癌突变极为罕见,这意味着我们对控制CIN获得的基本原理,它如何驱动肿瘤发生以及面对选择压力时改变轨迹的理解仍然有限。因此,我们的目的是了解这些原理,以便利用CIN作为治疗靶点。尽管作出了巨大努力,但多种因素阻碍了进展。由于实验的可追溯性,机制研究通常集中在有限数量的已建立的癌细胞系上,但它们往往具有有限的临床注释,不能反映疾病异质性,并且缺乏治疗前/治疗后的对照。此外,最适合长期细胞培养的fitter亚克隆的生长产生相对稳定的核型。其他的混杂因素是由于广泛的体外繁殖引起的遗传漂变,以及肿瘤部位不可知论的哲学,忽视了疾病特异性CIN途径的可能性。另一个限制是缺乏非转化的、核型稳定的模型系统来代表起源细胞来概括CIN途径。虽然癌症测序项目可以分析大量临床注释样本,但依赖档案活检会导致间质污染,单细胞方法在技术上具有挑战性,并且用功能实验来测试新出现的假设是不可能的。虽然测序空间解决活检允许重建进化轨迹,纵向队列匹配chemo-naïve,治疗和复发样本不太常见。此外,分离耐药克隆的祖细胞是不可能的。因此,为了确定控制CIN如何驱动肿瘤发生和耐药性的基本原则,我们现在提出了一种具有几个关键优点的全新方法,以解决迄今为止阻碍进展的限制。重要的是,我们将采取疾病特异性方法,重点关注高级别浆液性卵巢癌(HGSOC),其中CIN是关键驱动因素,获得性耐药是关键的临床挑战。首先,我们将利用我们的患者衍生卵巢癌模型(ocm)活生物库,这可能是最大和最多样化的原代HGSOC细胞培养集合。ocm是早期传代、纯化的肿瘤组分,具有HGSOC的特征和异质性。加上具有广泛增殖潜力的细胞培养系统,ocm适用于多组学,包括单细胞组学,高分辨率细胞生物学研究和药物敏感性分析。随着生物库的成熟,我们正在收集纵向队列,即从化疗前、化疗中和化疗后的活检中提取的ocm。其次,由于HGSOC来源于输卵管上皮细胞,我们建立了输卵管上皮细胞的FNE1模型系统。FNE1细胞未转化,核型稳定,但我们已经证明,引入hgsoc特异性遗传病变足以诱导CIN,产生与患者来源模型相似的核型。第三,为了分离耐药后代的祖细胞,我们将结合最先进的基于条形码的谱系追踪技术和我们的纵向ocm来研究对化疗反应的克隆动力学。

项目成果

期刊论文数量(1)
专著数量(0)
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会议论文数量(0)
专利数量(0)

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Stephen Taylor其他文献

A Hausdorff measure classification of polar sets for the heat equation
热方程极集的豪斯多夫测度分类
The long shadows cast by the field: violence, trauma, and the ethnographic researcher
该领域投下的长长的阴影:暴力、创伤和民族志研究者
  • DOI:
  • 发表时间:
    2019
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Stephen Taylor
  • 通讯作者:
    Stephen Taylor
A quantitative investigation of electron detrapping in SiO2 under Fowler–Nordheim stress
Fowler-Nordheim 应力下 SiO2 中电子去俘获的定量研究
  • DOI:
    10.1063/1.350452
  • 发表时间:
    1992
  • 期刊:
  • 影响因子:
    3.2
  • 作者:
    J. Zhang;Stephen Taylor;W. Eccleston
  • 通讯作者:
    W. Eccleston
Can Virtual Replace In-person Coaching? Experimental Evidence on Teacher Professional Development and Student Learning in South Africa
虚拟辅导可以取代面对面辅导吗?
FITC-lectin avidity of Cryptococcus neoformans cell wall and capsular components
新型隐球菌细胞壁和荚膜成分的 FITC-凝集素亲合力
  • DOI:
    10.1080/15572536.2005.11832989
  • 发表时间:
    2004
  • 期刊:
  • 影响因子:
    2.8
  • 作者:
    A. J. Foster;R. Bird;S. Kelly;K. Nishimura;David A. Poyner;Stephen Taylor;Stephen N. Smith
  • 通讯作者:
    Stephen N. Smith

Stephen Taylor的其他文献

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{{ truncateString('Stephen Taylor', 18)}}的其他基金

WoU-MMA: Mapping the host galaxies of low-frequency gravitational-wave sources
WoU-MMA:绘制低频引力波源的主星系图
  • 批准号:
    2307719
  • 财政年份:
    2023
  • 资助金额:
    $ 84.17万
  • 项目类别:
    Standard Grant
CAREER: Unveiling the Nanohertz GW Discovery Landscape by Broadening Participation In Multi-Messenger Astrophysics
职业生涯:通过扩大多信使天体物理学的参与来揭示纳赫兹引力波发现景观
  • 批准号:
    2146016
  • 财政年份:
    2021
  • 资助金额:
    $ 84.17万
  • 项目类别:
    Continuing Grant
WoU-MMA: Multi-messenger Titans: Probing The Dynamics & Environments Of Supermassive Binary Black Holes
WoU-MMA:多信使泰坦:探索动态
  • 批准号:
    2007993
  • 财政年份:
    2020
  • 资助金额:
    $ 84.17万
  • 项目类别:
    Standard Grant
Cultural Heritage 360
文化遗产360
  • 批准号:
    AH/V005596/1
  • 财政年份:
    2020
  • 资助金额:
    $ 84.17万
  • 项目类别:
    Research Grant
Non-genetic heterogeneity in response to anti-mitotic chemotherapeutics
抗有丝分裂化疗药物反应的非遗传异质性
  • 批准号:
    MR/L006839/1
  • 财政年份:
    2014
  • 资助金额:
    $ 84.17万
  • 项目类别:
    Research Grant
Digital Multi-channel Tibial Implants in Orthopedic Medicine
数字化多通道胫骨植入物在骨科医学中的应用
  • 批准号:
    TS/G002320/1
  • 财政年份:
    2009
  • 资助金额:
    $ 84.17万
  • 项目类别:
    Research Grant
Hawaii-Vancouver Education, Assessment, and Articulation Planning Visit: Vancouver, Canada, July-August 2009
夏威夷-温哥华教育、评估和衔接规划访问:加拿大温哥华,2009 年 7 月至 8 月
  • 批准号:
    0938979
  • 财政年份:
    2009
  • 资助金额:
    $ 84.17万
  • 项目类别:
    Standard Grant
Microengineering of Quadrupole Mass Spectrometers using RP techniques
使用 RP 技术的四极杆质谱仪微工程
  • 批准号:
    EP/F008848/1
  • 财政年份:
    2007
  • 资助金额:
    $ 84.17万
  • 项目类别:
    Research Grant
The role of Cenp-F and Nudel in chromosome segregation
Cenp-F 和 Nudel 在染色体分离中的作用
  • 批准号:
    BB/E015034/1
  • 财政年份:
    2007
  • 资助金额:
    $ 84.17万
  • 项目类别:
    Research Grant
Research Experiences for Undergraduates in Chemistry at Hope College
希望学院化学专业本科生的研究经历
  • 批准号:
    9619667
  • 财政年份:
    1997
  • 资助金额:
    $ 84.17万
  • 项目类别:
    Continuing Grant

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Decoding the impact of single cell mutational processes in triple negative breast cancer and high grade serous ovarian cancer
解读单细胞突变过程对三阴性乳腺癌和高级别浆液性卵巢癌的影响
  • 批准号:
    477662
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  • 批准号:
    10603092
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