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

基本信息

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
项目类别：
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

项目摘要

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）是最难治愈的人类癌症之一。这是一种侵袭性肿瘤其特点是快速生长、转移进展和初始反应，随后几乎不变对治疗的抵抗。迄今为止的研究尚未解决不同遗传和表观遗传程序的影响程度驱动 SCLC 并为其致死率做出贡献。我们整合了最大、最多样化的库存之一全球范围内源自患者的 SCLC 异种移植模型，其离体培养系统可维持与匹配的原发性 SCLC 肿瘤的转录保真度，以识别不同的动态表型状态个体肿瘤内的功能属性有所不同。我们发现人类 SCLC 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 状态受到多价细胞可塑性的高度调控，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，这种疾病的护理标准化疗优先杀死特定的癌细胞状态。在此提案中，我们假设了解 SCLC 瘤内异质性的各个方面将：1）有助于我们理解癌症异质性的一个尚未明确表征的方面； 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) 深入了解 SCLC 的生物学和临床行为； 4）拼命前进对于这种顽固性疾病，需要新的表观遗传重编程治疗策略。我们的团队研究人员拥有多种相关计算、实验和转化方法的专业知识该提案包括人源体内和离体模型系统、单细胞 RNA 测序、批量遗传和表达分析、单细胞荧光追踪以及数学和统计建模。我们的综合方法旨在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，恶性细胞个体发生程序（SA1）的特征及其可塑性 (SA2)，以及旨在通过表观遗传重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独特的科学画布。