Cellular plasticity gives rise to phenotypic equilibrium in small cell lung carcinoma

摘要 小细胞肺癌(SCLC)是人类最难治愈的癌症之一。它是一种侵袭性肿瘤 以快速生长、转移进展和最初反应为特征的，随后几乎不变 对治疗的抗拒。到目前为止，研究还没有解决不同的遗传和表观遗传程序的程度 推动小细胞肺癌并促成其杀伤力。我们合并了最大和最多样化的库存之一 具有体外培养系统的全球小细胞肺癌患者来源的异种移植模型 匹配的原发SCLC肿瘤的转录保真度可以识别不同的和动态的表型状态， 不同肿瘤的功能属性不同。我们发现人类小细胞肺癌肿瘤表现出独特的 处于各种表型(不仅仅是转录)状态的细胞比例的平衡。我们还表明， SCLC的状态受多价细胞可塑性的高度调节，我们测量了这种可塑性的动力学 在单细胞水平上。重要的是，这种疾病的标准护理化疗优先杀死特定的 癌细胞的状态。在这项建议中，我们假设了解小细胞肺癌肿瘤内异质性的各个方面 将：1)有助于我们理解癌症异质性特征不佳的一个方面；2)揭示 单细胞行为中的随机性和/或生态线索促进癌症的表型平衡 人口；3)洞察小细胞肺癌的生物学和临床行为；以及4)拼命前进 这种顽固性疾病需要表观遗传重编程的新治疗策略。我们的团队 研究人员在几种相关的计算、实验和翻译方法方面拥有丰富的专业知识 这一建议包括人体来源的体内和体外模型系统，单细胞RNA测序，散装 基因和表达分析、单细胞荧光跟踪以及数学和统计建模。 我们的综合方法准备好制定和验证统一的蜂窝状态模型和程序 小岛屿发展中国家的多样性。如果成功，恶性细胞个体发生程序(SA1)的特征，它们的可塑性 (SA2)，以及旨在通过表观遗传重新编程对抗可塑性的新疗法的进展(SA3) 将为研究这种高度致命的疾病提供一张独特的科学画布。

ABSTRACT Small cell lung carcinoma (SCLC) is one of the most intractable human cancers to cure. It is an aggressive tumor characterized by rapid growth, metastatic progression, and initial response followed by almost invariable resistance to therapy. Studies to date have not resolved the extent that diverse genetic and epigenetic programs drive SCLC and contribute to its lethality. We combined one of the largest and most diverse inventories of patient-derived xenograft models of SCLC globally with an ex vivo culture system that maintains transcriptional fidelity with matched primary SCLC tumor to identify distinct and dynamic phenotypic states that differ in functional attributes within individual tumors. We show that human SCLC tumors display distinctive equilibria in the proportion of cells in various phenotypic (not merely transcriptional) states. We also show that SCLC states are highly regulated by multivalent cellular plasticity and we measure the kinetics of this plasticity at the single cell level. Importantly, standard of care chemotherapies in this disease preferentially kill specific cancer cell states. In this proposal, we posit that understanding the facets of SCLC's intratumoral heterogeneity will: 1) contribute to our understanding of a poorly characterized aspect of cancer heterogeneity; 2) reveal how stochasticity and/or ecological cues in single-cell behaviors promote phenotypic equilibrium in cancer populations; 3) provide insight into the biological and clinical behavior of SCLC; and 4) advance desperately needed new therapeutic strategies of epigenetic reprogramming in this recalcitrant disease. Our team of investigators have content expertise in several computational, experimental, and translational methods pertinent to this proposal including human-derived in vivo and ex vivo model systems, single-cell RNA sequencing, bulk genetic and expression analysis, single cell fluorescence tracking, and mathematical and statistical modeling. Our integrative approach is poised to formulate and validate a unified model of cellular states and program diversity in SCLC. If successful, the characterization of malignant cell ontogenic programs (SA1), their plasticity (SA2), and the advancement of new therapies designed to combat plasticity by epigenetic reprogramming (SA3) will advance a unique scientific canvas for the study of this highly lethal disease.