Measuring, Modeling and Controlling Heterogeneity

摘要-总体 测量，建模和控制癌症系统生物中心的总体目标- ogy联盟（M2 CH-CSBC中心）将通过以下措施改善三阴性乳腺癌（TNBC）的管理： 制定系统水平的战略，以防止出现耐药的癌症亚群， 治疗我们假设，异质性所产生的表观基因组的不稳定性固有的癌细胞和双， 来自癌细胞所处的外部微环境的反向信号是耐药的根本原因。我们 将学习内在和外在因素如何影响分化状态，增殖和治疗再 通过癌细胞系的实验操作和计算建模，3D工程在TNBC中的反应， 需要的多细胞系统、异种移植物和临床标本。我们将部署单细胞组学和成像 允许定量评估分子、细胞和结构异质性的技术。我们将 使用计算模型来解释这些数据，这些计算模型定义了异构环境中的控制网络和结构， 系统以及治疗抗性和敏感性状态之间的转换。这将是一个住宿- 在三个相关项目和三个核心中实现。项目1将侧重于测量和管理阻力- 与癌细胞固有的异质性相关。项目2将侧重于确定耐药相关的信号- 从微环境和减轻这些信号对治疗反应的影响。项目 3将空间系统生物学方法应用于TNBC标本及其多细胞型模型，以研究TNBC的生物学特性。 涵盖影响细胞内在可塑性和微环境信号传导方式的分子控制网络， 称为复杂组织中的治疗反应。所有三个项目将包括5个核心细胞系的分析 （HCC 1143、HCC 1599、MDA-MB-468、SUM 149 PT和HCC 1806）、5种患者来源的培养物和6种FDA批准的培养物。 经证实的途径靶向药物（阿法替尼、鲁索洛替尼、曲美替尼、BYL 719、卡博替尼和依维莫司）。的 计算网络发现，数据集成，空间系统分析和建模方法是 在所有项目中相同，并用于整合整个M2 CH-CSBC中心的工作。多元一体化 提出了用于识别候选异质性控制网络的计算策略。这些包括 分析现有的基因组，表观基因组，药理学反应，和代谢组学特征的初级， Ry肿瘤及其模型。成像管理和分析核心将提供基础设施， 图像分析，将实现有效的图像数据管理，图像特征的定量分析， 使用多尺度光学和电子显微镜生成的图像和元数据的可视化。一个外联 核心将使教育材料，实验和计算工具和数据提供给CSB 联盟，CSBC/PS-ON协调中心和更广泛的科学界。一个 行政核心是M2 CH-CSBC中心的组织、集成和评估中心。

ABSTRACT - Overall The overall goal of the Measuring, Modeling and Controlling Heterogeneity Center in the Cancer Systems Biol- ogy Consortium (M2CH-CSBC Center) is to improve management of triple negative breast cancer (TNBC) by developing systems level strategies to prevent the emergence of cancer subpopulations that are resistant to treatment. We postulate that heterogeneity arising from epigenomic instability intrinsic to cancer cells and di- verse signals from extrinsic microenvironments in which cancer cells reside are root causes of resistance. We will learn how intrinsic and extrinsic factors influence differentiation state, proliferation and therapeutic re- sponse in TNBC through experimental manipulation and computational modeling of cancer cell lines, 3D engi- neered multicellular systems, xenografts and clinical specimens. We will deploy single cell `omic and imaging technologies that allow quantitative assessment of molecular, cellular, and structural heterogeneity. We will interpret these data using computational models that define control networks and structures in heterogeneous systems as well as transitions between states of therapeutic resistance and sensitivity. This will be accom- plished in three related Projects and three Cores. Project 1 will focus on measuring and managing resistance- associated heterogeneity intrinsic to cancer cells. Project 2 will focus on identifying resistance-associated sig- nals from the microenvironment and on mitigating effects from these signals on therapeutic response. Project 3 will apply spatial systems biology approaches to TNBC specimens and multicell type models thereof to dis- cover molecular control networks that influence how cell intrinsic plasticity and microenvironment signaling al- ter therapeutic responses in complex tissues. All three Projects will include analysis of 5 core cell lines (HCC1143, HCC1599, MDA-MB-468, SUM149PT, and HCC1806), 5 patient derived cultures, and 6 FDA ap- proved, pathway-targeted drugs (afatinib, ruxolotinib, trametinib, BYL719, cabozantinib, and everolimus). The computational network discovery, data integration, spatial systems analysis and modeling approaches are the same in all Projects and serve to integrate the work of the overall M2CH-CSBC Center. Multiple integrative computational strategies are proposed to identify candidate heterogeneity control networks. These include analysis of existing genomic, epigenomic, pharmacologic response, and metabolomic characteristics of prima- ry tumors and models thereof. An Imaging Management and Analysis Core will provide infrastructure and image analytics that will enable efficient image data management, quantitative analysis of image features, and visualization of images and metadata generated using multiscale light and electron microscopy. An Outreach Core will make educational materials, experimental and computational tools and data available to the CSB Consortium, to the CSBC/PS-ON Coordinating Center and to the broader scientific community. An Administrative Core serves as the organization, integration, and evaluation hub of the M2CH-CSBC Center.