Analysis of how quantitative cellular network variation impacts tumor progression

分析定量细胞网络变化如何影响肿瘤进展

• 批准号: 8754209
• 负责人: Pamela K Kreeger
• 金额: $ 229.5万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8754209
• 关键词: Address; Biomimetics; Cancer Biology; Cancer cell line; Cell model; Cells; Chemotherapy-Oncologic Procedure; Data; Development; Disease; Drug Targeting; Environment; Epithelial Cells; Epithelium; Genes; In Vitro; Information Systems; Malignant neoplasm of ovary; Mammalian Oviducts; Modeling; Multivariate Analysis; Mutation; Ovarian; Ovary; Pathway interactions; Patients; Pattern; Peritoneum; Platinum; Process; Proteins; Relative (related person); Research; Resistance; Series; Serous; Signal Transduction; Staging; Structure; Surface; Survival Rate; System; Systems Biology; Techniques; Therapeutic; Variant; cell behavior; gain of function; improved; in vivo; innovation; neoplastic cell; novel; novel therapeutics; programs; protein expression; protein function; public health relevance; treatment strategy; tumor; tumor progression

DESCRIPTION (provided by applicant): In many tumors, mutations in genes impact protein functions (i.e., loss or gain of function); when these mutations impact proteins in cellular pathways that control key processes such as proliferation and invasion, they provide potential drug targets to slow tumor progression. In contrast, other tumors such as high-grade serous ovarian cancer (HGSOC) do not have a significant number of such mutations, and instead have subtle changes in the relative levels of multiple proteins distributed across the cellular network, setting up cellular networks that are qualitatively the same (i.e., nearly all components are present and have normal functionality) but quantitatively very different. The outlined research program will seek to analyze this new paradigm in order to address the hypothesis that at each stage of progression in HGSOC (i.e., fallopian tube  ovary, ovary  peritoneum, and platinum-sensitive  platinum-resistant), specific quantitative changes in the cell network influence the likelihood of progression. To address this hypothesis, we propose to analyze cells in in vitro culture systems that mimic the in vivo environment of HGSOC. Primary fallopian tube epithelial cells and immortalized HGSOC cell lines derived from patients with metastatic disease, mimicking early and late stages of HGSOC, will be genetically manipulated to develop panels of cells with quantitative variation in proteins across the cell network. With these cell models, we will determine how different network combinations influence likelihood of successful progression in 1) a novel biomimetic surrogate for the ovarian surface epithelium that mimics the initial breach from the fallopian tube, 2) a model to mimic tumor cell dissemination to the peritoneum, and 3) a chemotherapy regimen that induces platinum resistance. Using multivariate analysis techniques, we will identify patterns in the quantitative protein data that together predict or classify cell behavior. These models will be experimentally validated and analyzed to determine combinations of proteins that influence tumor progression, providing potential co-treatment strategies. In addition to significantly improving our understanding of HGSOC progression and identifying potential therapeutic strategies, this innovative approach can be broadly applied to understand progression in other tumor types that have quantitative as well as qualitative variation in cell networks. Our lab is uniquely suited to carry out this innovative research program as we have extensive expertise in biomimetic culture development, analysis of quantitative data by systems biology models, and ovarian cancer biology.

描述（由申请人提供）：在许多肿瘤中，基因突变影响蛋白质功能（即，功能丧失或获得）;当这些突变影响细胞通路中控制增殖和侵袭等关键过程的蛋白质时，它们提供了减缓肿瘤进展的潜在药物靶点。相比之下，其他肿瘤如高级别浆液性卵巢癌（HGSOC）没有大量的此类突变，而是在分布于细胞网络中的多种蛋白质的相对水平上有细微的变化， 建立定性相同的蜂窝网络（即，几乎所有的组分都存在并且具有正常的功能性），但是在数量上非常不同。概述的研究计划将寻求分析这种新的范式，以解决假设，在HGSOC的每个进展阶段（即，输卵管  卵巢，卵巢  腹膜和铂敏感  铂耐药），细胞网络中的特定数量变化影响进展的可能性。为了解决这一假设，我们建议在体外培养系统中模拟HGSOC的体内环境来分析细胞。将对源自转移性疾病患者的原代输卵管上皮细胞和永生化HGSOC细胞系（模拟HGSOC的早期和晚期）进行遗传操作，以开发跨细胞网络蛋白质定量变异的细胞组。通过这些细胞模型，我们将确定不同的网络组合如何影响以下方面的成功进展的可能性：1）模拟输卵管初始破裂的卵巢表面上皮的新型仿生替代物，2）模拟肿瘤细胞传播到腹膜的模型，以及3）诱导铂耐药的化疗方案。使用多变量分析技术，我们将识别定量蛋白质数据中的模式，这些模式共同预测或分类细胞行为。这些模型将进行实验验证和分析，以确定影响肿瘤进展的蛋白质组合，提供潜在的联合治疗策略。除了显着提高我们对HGSOC进展的理解并确定潜在的治疗策略外，这种创新方法还可以广泛应用于了解细胞网络中具有定量和定性变化的其他肿瘤类型的进展。我们的实验室非常适合开展这项创新的研究计划，因为我们在仿生培养开发，系统生物学模型定量数据分析和卵巢癌生物学方面拥有广泛的专业知识。

项目成果

Quantitative analysis of insulin-like growth factor 2 receptor and insulin-like growth factor binding proteins to identify control mechanisms for insulin-like growth factor 1 receptor phosphorylation.

胰岛素样生长因子2受体和胰岛素样生长因子结合蛋白的定量分析，以鉴定胰岛素样生长因子1受体磷酸化的控制机制。

• DOI: 10.1186/s12918-016-0263-6
• 发表时间: 2016-02-09
• 期刊: BMC systems biology
• 作者: Tian D;Mitchell I;Kreeger PK
• 通讯作者: Kreeger PK

A kinetic model identifies phosphorylated estrogen receptor-α (ERα) as a critical regulator of ERα dynamics in breast cancer.

动力学模型将磷酸化雌激素受体-α (ERα) 确定为乳腺癌 ERα 动力学的关键调节因子。

• DOI: 10.1096/fj.14-265637
• 发表时间: 2015
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Tian,Dan;Solodin,NataliaM;Rajbhandari,Prashant;Bjorklund,Kelsi;Alarid,ElaineT;Kreeger,PamelaK
• 通讯作者: Kreeger,PamelaK

M2 macrophages induce ovarian cancer cell proliferation via a heparin binding epidermal growth factor/matrix metalloproteinase 9 intercellular feedback loop.

• DOI: 10.18632/oncotarget.13474
• 发表时间: 2016-12-27
• 期刊: Oncotarget
• 作者: Carroll MJ;Kapur A;Felder M;Patankar MS;Kreeger PK
• 通讯作者: Kreeger PK

High-grade serous ovarian cancer cell lines exhibit heterogeneous responses to growth factor stimulation.

高级浆液卵巢癌细胞系对生长因子刺激表现出异质反应。

• DOI: 10.1186/s12935-015-0263-4
• 发表时间: 2015
• 期刊: Cancer cell international
• 影响因子: 5.8
• 作者: Bourgeois DL;Kabarowski KA;Porubsky VL;Kreeger PK
• 通讯作者: Kreeger PK