Variability of Cellular Responses to Growth Factors and Drugs During Tumorgenesis

肿瘤发生过程中细胞对生长因子和药物反应的变异性

• 批准号: 8181539
• 负责人: Gregoire Altan-Bonnet
• 金额: $ 165.27万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8181539
• 关键词: Adopted; Affect; Breast Cancer Cell; Cancer Biology; Cancer cell line; Cell Line; Cells; Clinical; Complement; Dependence; Growth Factor; Individual; Interleukin-6; Lead; Malignant Neoplasms; Measures; Mediator of activation protein; Mesenchymal; Mesenchymal Cell Neoplasm; Modeling; Monitor; Mus; Normal Cell; Pathway interactions; Pharmaceutical Preparations; Population; Process; Protocols documentation; Resistance; Signal Transduction; Stat3 Signaling Pathway; Stochastic Processes; Stromal Cells; Systems Biology; Testing; Therapeutic; Translating; autocrine; base; biochemical model; cancer cell; cancer therapy; cytokine; design; experience; extracellular; fitness; improved; in vivo; inhibitor/antagonist; malignant breast neoplasm; mathematical model; melanoma; mouse model; neoplastic cell; paracrine; research study; response; tumor; tumor progression; tumorigenesis

During tumorigenesis, cancer cells as well as healthy cells depend upon growth factors produced in an autocrine and paracrine manner to maintain their proliferafion and differenfiafion. Hence there exists a "tug-ofwar" for growth factors between a tumor and the surrounding non-cancer cells, and the fitness of each individual cell must be defined by this competifion at the populafion level. Importantly, cancer cells on the leading edge of tumors are characterized as being chemo-resistant, have enhanced metastatic potential and are extremely efficient at forming new tumors [6]. We have determined that cancer cells and adjacent stromal cells express high levels of the growth factor IL-6 and activated Stat3 which are hypothesized to be the principal mediators of both tumorigenesis and metastafic progression. In this proposal, we focus on the IL-6/pStat3 pathway in melanoma and breast cancer cells, whose proliferation and differenfiafion crifically depends on pStat3 signals. In the context of understanding tumor dynamics, especially during drug treatment, the intraclonal competifion for growth factors within a genefically-idenfical populafion of cells will be investigated. An understanding of the resulfing phenotypic diversity of tumor cells will lead to improved therapeufic intervenfions eradicafing tumor populafions. Specifically, we will (1) characterize the variable response of tumor cells to growth factors and targeted inhibitors: (2) design a mathemafical framework to predict the consequences of cellular diversity and identify the opfimum therapeutic intervenfion that maximizes the chance of eradicafing the tumor; and (3) validate the predictions of the mathemafical framework in cell lines and murine models. This project fully leverages our expertise in cancer biology and clinical experience (Bromberg), single cell profiling and biochemical modeling (Altan-Bonnet), and mathemafical modeling (Michor). We will dissect how the IL-6 pathway can generate phenotypic variability in tumors, which drives their progression and causes resistance to targeted therapies [7- 13]. Based on our models, we will identify and test the opfimal therapeufic protocol for treafing these cancers.

在肿瘤发生期间，癌细胞和健康细胞取决于在 自分泌和旁分泌方式维持其增殖和不同的方式。因此存在“拔河” 对于肿瘤和周围的非癌细胞之间的生长因子以及每个肿瘤的适应性 必须在人群级别上通过这种竞争来定义单个单元。重要的是，癌细胞上 肿瘤的前缘被描述为具有化学性，具有增强的转移潜力，并且 在形成新肿瘤方面非常有效[6]。 我们已经确定癌细胞和邻近的基质细胞表达高水平的生长因子IL-6 和激活的STAT3，假设是肿瘤发生和转移的主要介体 进展。在此提案中，我们专注于黑色素瘤和乳腺癌细胞中的IL-6/PSTAT3途径， 其增殖和不同的法律依赖于PSTAT3信号。在理解的背景下 肿瘤动力学，尤其是在药物治疗期间 将研究细胞的基因叶片人群。对重硫表型的理解 肿瘤细胞的多样性将导致改善治疗性介入肿瘤人群。 具体而言，我们将（1）表征肿瘤细胞对生长因子的可变响应并靶向 抑制剂：（2）设计一个数学框架，以预测细胞多样性的后果并确定 最大化肿瘤的机会的OPF最大性治疗性介入。 （3）验证 细胞系和鼠模型中数学框架的预测。这个项目完全利用了我们的 癌症生物学和临床经验（BROMBERG），单细胞分析和生化建模方面的专业知识 （Altan-Bonnet）和数学模型（Michor）。我们将剖析IL-6途径如何产生 肿瘤中的表型变异性，可驱动其进展并引起对靶向疗法的抗性[7- 13]。基于我们的模型，我们将识别和测试用于捕获这些癌症的Opfimal Therapeufic方案。