Phenotype Heterogeneity and Dynamics in SCLC

异质性是癌症的普遍特征，是进展和治疗失败的关键。无论是遗传还是 非遗传因素、细胞与细胞、细胞与微环境的相互作用是肿瘤细胞表型变异的重要原因。 因此，异质性是一个复杂的多尺度问题，很难用简化论的方法来研究，但却很好。 适合系统思维的。对异质性的机械的、系统层面的理解将催生 癌症治疗策略的基本进展。主要挑战包括相关肿瘤细胞的定义 从单细胞行为和相互作用中产生的表型、表型动态以及有效的靶向 战略。在我们的中心，我们将使用系统生物学方法来应对这些挑战，重点是 小细胞肺癌(SCLC)，其中肿瘤内异质性的影响尤其引人注目。因此， 小细胞肺癌，虽然在组织病理学上与经典的“小蓝圆细胞”形态相同，但 由表型亚群组成(例如，肿瘤增殖细胞；Hes1细胞；CD44细胞) 合作形成与药物治疗相适应的肿瘤生态系统。在SCLC基因工程小鼠中 模型(GEMM)和患者肿瘤，累积的遗传改变(例如，MYC扩增，缺口 突变)可能会影响表型组成和药物敏感性，强调两者的联合作用 遗传和非遗传来源。我们建议的中心的总体目标是从系统层面理解 小细胞肺癌表型异质性对药物逃避的影响，这将为新的治疗方法开辟道路 战略。在两个高度集成的项目中，我们将结合实验和数学建模来 生成SCLC表型空间的全面蓝图，识别复杂表型动态 潜在的治疗耐药性。项目1将使用高维细胞术和转录组数据来 确定人类和GEMM核心小细胞肺癌的表型，它们对基因组改变偏差的易感性，以及它们的药物 反应可塑性。项目2将研究由细胞-细胞和分泌因子启动的小细胞肺癌表型动力学。 小细胞肺癌肿瘤生态系统中的外切体，使用驱动肿瘤侵袭性的细胞种群动力学模型。 项目将得到单细胞生物学和数据分析共享资源的支持，该资源配备了大量的 最先进的单细胞技术调色板，包括质量细胞术、scRNA-Seq和多维 数据分析。该中心将设在范德比尔特大学，斯坦福大学的一个卫星站点将提供 备受推崇的SCLC GEMM。实验系统将包括人类和GEMM SCLC细胞系，以及 肿瘤。我们的中心调查人员在SCLC和/或系统中有合著出版物的跟踪记录 生物学。行政核心将在整个中心提供领导和沟通，而 外联核心将促进合作，传播关于小细胞肺癌和癌症的知识和工具 异质性。我们希望实验和建模之间的迭代将带来系统级别的 了解小细胞肺癌肿瘤的异质性，课程一般适用于任何癌症类型。

Heterogeneity is a pervasive feature of cancer, central to progression and therapy failure. Both genetic and nongenetic factors, cell-cell and cell-microenvironment interactions contribute to tumor cell phenotypic variation. Thus, heterogeneity is a complex multiscale problem difficult to study by reductionist approaches but well suited to systems thinking. A mechanistic, system-level understanding of heterogeneity would spawn fundamental advances in cancer treatment strategies. Major challenges include definition of relevant tumor cell phenotypes, phenotype dynamics emergence from single-cell behavior and interactions, and effective targeting strategies. In our Center, we will use systems biology approaches to tackle these challenges, focusing on small cell lung cancer (SCLC), in which the impact of intratumor heterogeneity is particularly compelling. Thus, SCLC tumors, while histo-pathologically homogeneous with classic “small blue round cell” morphology, are comprised of phenotypic subpopulations (e.g., tumor-propagating cells; Hes1+ cells; CD44+ cells) that cooperate to form a tumor ecosystem adaptive to drug treatment. In SCLC genetically engineered mouse models (GEMMs) and patient tumors, accumulated genetic alterations (e.g., MYC amplification, NOTCH mutations) may bias phenotypic compositions and consequent drug sensitivity, underscoring the combined role of genetic and nongenetic sources. The overall goal of our proposed Center is a system-level understanding of the impact of SCLC phenotype heterogeneity in drug evasion, that will open avenues to novel treatment strategies. In two highly integrated Projects, we will combine experimentation with mathematical modeling to generate a comprehensive blueprint of SCLC phenotypic space and identify complex phenotype dynamics underlying treatment resistance. Project 1 will use high-dimensional cytometry and transcriptomics data to define human and GEMM core SCLC phenotypes, their susceptibility to genomic alteration bias, and their drug response plasticity. Project 2 will study SCLC phenotype dynamics initiated by cell-cell and secreted factors or exosomes in SCLC tumor ecosystems, using models of cell population dynamics driving tumor aggressiveness. Projects will be supported by a Single-Cell Biology and Data Analysis Shared Resource equipped with a vast palette of state-of-the-art single-cell technologies, including mass cytometry, scRNA-Seq and multidimensional data analysis. The Center will be located at Vanderbilt University and a satellite site at Stanford contributing highly-regarded SCLC GEMMs. Experimental systems will encompass human and GEMM SCLC cell lines and tumors. Our Center investigators have a track record of co-authored publications in SCLC and/or systems biology. The Administrative Core will provide leadership and communication across the Center while the Outreach Core will promote collaborations and disseminate knowledge and tools on SCLC and cancer heterogeneity. We expect that iteration between experiments and modeling will bring about a system-level understanding of SCLC tumor heterogeneity with lessons generally applicable to any cancer type.