Phenotype Heterogeneity and Dynamics in SCLC

异质性是癌症的普遍特征，是癌症进展和治疗失败的核心。无论是遗传还是 非遗传因素、细胞与细胞以及细胞与微环境的相互作用导致肿瘤细胞表型变异。 因此，异质性是一个复杂的多尺度问题，很难通过还原论方法进行研究，但很好 适合系统思维。对异质性的机械的、系统级的理解将会产生 癌症治疗策略的根本性进展。主要挑战包括相关肿瘤细胞的定义 表型、单细胞行为和相互作用产生的表型动力学以及有效靶向 策略。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，重点关注 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， SCLC 肿瘤虽然组织病理学上均质，具有经典的“小蓝色圆形细胞”形态，但 由表型亚群（例如肿瘤增殖细胞、Hes1 细胞、CD44 细胞）组成 合作形成适应药物治疗的肿瘤生态系统。 SCLC 基因工程小鼠 模型（GEMM）和患者肿瘤，积累的基因改变（例如，MYC 扩增、NOTCH 突变）可能会使表型组成和随后的药物敏感性产生偏差，强调了综合作用 遗传和非遗传来源。我们提议的中心的总体目标是系统层面的理解 SCLC 表型异质性对药物逃避的影响，这将为新的治疗开辟途径 策略。在两个高度集成的项目中，我们将把实验与数学建模结合起来 生成 SCLC 表型空间的综合蓝图并识别复杂的表型动态 潜在的治疗抵抗。项目 1 将使用高维细胞计数和转录组学数据 定义人类和 GEMM 核心 SCLC 表型、它们对基因组改变偏差的敏感性及其药物 响应可塑性。项目 2 将研究细胞间和分泌因子引发的 SCLC 表型动力学或 SCLC 肿瘤生态系统中的外泌体，使用驱动肿瘤侵袭性的细胞群动态模型。 项目将得到单细胞生物学和数据分析共享资源的支持，该资源配备有大量的 一系列最先进的单细胞技术，包括质谱流式细胞术、scRNA-Seq 和多维 数据分析。该中心将设在范德比尔特大学和斯坦福大学的卫星站点 备受推崇的 SCLC GEMM。实验系统将涵盖人类和 GEMM SCLC 细胞系 肿瘤。我们中心的研究人员在 SCLC 和/或系统中拥有共同撰写出版物的记录 生物学。行政核心将提供整个中心的领导和沟通，而 Outreach Core 将促进合作并传播有关 SCLC 和癌症的知识和工具 异质性。我们期望实验和建模之间的迭代将带来系统级的 了解 SCLC 肿瘤异质性以及普遍适用于任何癌症类型的经验教训。

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.