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

细胞可塑性导致小细胞肺癌的表型平衡

• 批准号: 10525950
• 负责人: Mohamed E. Abazeed
• 金额: $ 49.51万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10525950
• 关键词: Affect; Aftercare; Bar Codes; Behavior; Biodiversity; Biological; Biological Assay; Biological Models; Cell Communication; Cell model; Cells; Chemoresistance; Chemotaxis; Clinical; Clinical Trials Design; Coupled; Cues; Cytoplasm; DNA Sequence Alteration; Data; Disease; Ecosystem; Elasticity; Environment; Epigenetic Process; Equilibrium; Equipment and supply inventories; Exhibits; Exposure to; Extinction (Psychology); Fluorescence; Gene Expression; Genetic; Genetic Transcription; Genome; Growth; Heterogeneity; Human; Individual; Investigation; Kinetics; Malignant Epithelial Cell; Malignant Neoplasms; Markov Chains; Measurement; Measures; Membrane; Mesenchymal; Methods; Modeling; Mus; Neuroendocrine Cell; Neuroendocrine Tumors; Outcome; Patients; Pattern; Pharmacotherapy; Phenotype; Population; Population Dynamics; Primary Neoplasm; Registries; Relapse; Reporter; Research Personnel; Resistance; Resources; Role; Sampling; Statistical Models; System; Therapeutic; Time; Transcription Factor 3; Withholding Treatment; base; cancer cell; cancer heterogeneity; cancer survival; cell behavior; cell type; chemotherapy; clinically relevant; combat; discrete time; epigenetic drug; epigenome; experimental study; functional genomics; in vivo; innovation; insight; lung small cell carcinoma; mathematical model; novel therapeutic intervention; novel therapeutics; patient derived xenograft model; prevent; programs; rapid growth; relating to nervous system; response; single-cell RNA sequencing; standard of care; study population; therapy design; therapy resistant; transcription factor; translational model; treatment response; tumor; tumor heterogeneity

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.

抽象的 小细胞肺癌（SCLC）是治愈的最棘手的人类癌症之一。这是一种侵略性肿瘤 以快速生长，转移性进展和初始反应的特征，然后几乎不变 抵抗治疗。迄今为止的研究尚未解决不同遗传和表观遗传学计划的程度 驱动SCLC并促进其杀伤力。我们结合了最大，最多样化的库存之一 全球SCLC的患者衍生的异种移植模型，具有维护的离体培养系统 带有匹配的原发性SCLC肿瘤的转录保真度，以识别不同的动态表型状态 单个肿瘤内的功能属性不同。我们表明人类SCLC肿瘤显示出独特的 在各种表型（不仅是转录）状态下细胞比例的平衡。我们还表明 SCLC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。重要的是，这种疾病中的护理标准化学疗法优先杀死特异性 癌细胞状态。在此提案中，我们认为了解SCLC的肿瘤内异质性的方面 意志：1）有助于我们理解癌症异质性的特征性不佳方面； 2）揭示如何 单细胞行为的随机性和/或生态线索促进癌症的表型平衡 人口； 3）提供有关SCLC的生物学和临床行为的见解； 4）拼命前进 在这种顽固疾病中，需要新的表观遗传重编程的治疗策略。我们的团队 研究人员在几种计算，实验和翻译方法方面具有内容专业知识 该提案包括人体衍生的体内和离体模型系统，单细胞RNA测序，批量 遗传和表达分析，单细胞荧光跟踪以及数学和统计建模。 我们的综合方法有望制定和验证细胞状态和程序的统一模型 SCLC的多样性。如果成功，则表征恶性细胞个体生成程序（SA1），它们的可塑性 （SA2），以及旨在通过表观遗传重编程来对抗可塑性的新疗法的进步（SA3） 将推进独特的科学画布，以研究这种高度致命的疾病。