Investigating the Role of Emergent Oscillations of Hypoxia Inducible Factor-1 alpha Activity in Cancer Growth and Progression

研究缺氧诱导因子 1 α 活性的紧急振荡在癌症生长和进展中的作用

• 批准号: 10630068
• 负责人: Kshitiz Gupta
• 金额: $ 48.66万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10630068
• 关键词: Automobile Driving; Autophagocytosis; Bioinformatics; Biological; Breast Cancer Model; Bypass; Cancer Prognosis; Cell Cycle Arrest; Cell Proliferation; Cell Survival; Cells; Circadian Rhythms; Complex; Computer Models; Data; Environment; Exhibits; Feedback; Frequencies; Gene Expression; Generations; Genes; Genetic Transcription; Glycolysis; Growth; Heterogeneity; Homologous Gene; Hybrids; Hypoxia; Hypoxia Inducible Factor; Image; Invaded; Label; Link; Malignant Neoplasms; Mediating; Metabolic; Methods; Molecular; Molecular Chaperones; Mus; Neoplasm Metastasis; Outcome; Oxygen; Pathway interactions; Phenotype; Population; Proliferating; Property; Regulation; Role; Signal Transduction; Stress; Stromal Invasion; Testing; Transcriptional Regulation; Tumor Cell Invasion; Tumorigenicity; Vascularization; Xenograft procedure; biological adaptation to stress; cancer cell; cancer stem cell; cofactor; extracellular; fitness; gene product; gene regulatory network; hypoxia inducible factor 1; in vivo; mathematical model; mouse model; novel; response; single cell sequencing; spatiotemporal; stemness; transcription factor; transcriptomics; tumor; tumor growth; tumor hypoxia; tumor microenvironment; tumor progression; tumorigenesis; tumorigenic

ABSTRACT Hypoxia influences nearly all steps in the metastatic cascade, and is an independent adverse indicator for cancer prognosis. Cellular response to hypoxia is tightly regulated, and is mediated by hypoxia-inducible factors (HIFs), with HIF-1 being the ubiquitously expressed homologue. Canonical response to hypoxia involves stabilization of HIF-1α, which acts as a key transcriptional factor, regulating the expression of more than 1000 gene products indirectly, influencing key steps in cancer progression. However, we discovered that the population response to hypoxia is more complex than the canonically understood response, with a small subpopulation displaying oscillations in HIF-1α stabilization and transcriptional activity in a lactate dependent manner. Lactate is a byproduct of glycolysis, which is itself increased due to HIF-1α activity, and can cause degradation of HIF-1α by chaperone mediated autophagy, driving oscillations. Owing to the centrality of HIF- 1α in transcriptional regulation in hypoxic tumors, oscillations in HIF-1α in a subset of cells could have profound consequences in gene expression, and cancer progression. Our preliminary data show that oscillatory hypoxic input can drive large scale transcriptomic changes, resulting in increased metabolic activity, cell proliferation, as well as altered regulation of pathways related to circadian rhythms, and invasion. These data suggest that possibly emergent oscillations in HIF-1α activity may provide a selective advantage to these cells to escape hypoxia induced stress response. Our preliminary data present a strong rationale to investigate this emergent phenotype in cancer populations, the mechanisms driving these oscillations and the phenotypic consequence of these oscillations. Furthermore, many of the genes responded to oscillating hypoxia as a qualitatively different signal, suggesting presence of regulatory motifs, incoherent feedforward loops (IFFLs) which could distinguish between oscillatory and sustained HIF-1α signal. Using an integrated approach involving computational modeling, bioinformatics, and experimentation, we will systematically identify and validate these IFFLs, as well as the co-factors necessary to form these IFFLs along with HIF-1α. Our aim will not only shed light on the fundamental regulatory mechanisms of decoding of oscillatory signaling in cancer, but also provide a targeting strategy to contain the phenotypic consequences of emergent HIF-1α oscillations. Finally, we will test the consequence of emergent HIF-1α oscillations in vivo in a mouse model of breast cancer tumorigenesis, and test if oscillating HIF-1α confers increased tumorigenicity, proliferation, and survival. Our proposed method will facilitate mechanistically understanding the genesis of oscillations, generation of phenotypic heterogeneity in cancer, as well as understand and target the consequence of this emergent subpopulation in influencing cancer progression.

摘要 缺氧几乎影响了转移级联反应中的所有步骤，并且是癌症的独立不良指标 预后细胞对缺氧的反应受到严格的调节，并由缺氧诱导因子介导 HIF-1是广泛表达的同源物。典型的缺氧反应包括 HIF-1α作为一个关键的转录因子，调节超过1000个基因的表达， 基因产物间接影响癌症进展的关键步骤。然而，我们发现， 群体对缺氧的反应比规范理解的反应更复杂， 在乳酸依赖性细胞中显示HIF-1α稳定性和转录活性振荡的亚群 方式乳酸盐是糖酵解的副产物，其本身因HIF-1α活性而增加，并可能导致 通过分子伴侣介导的自噬降解HIF-1α，驱动振荡。由于HIF-1 α的重要性， 在缺氧肿瘤中，HIF-1α在转录调控中的作用，在一个细胞亚群中HIF-1α的振荡可能具有深远的意义。 基因表达和癌症进展的后果。我们的初步数据表明，振荡缺氧 输入可以驱动大规模的转录组变化，导致代谢活性增加，细胞增殖， 以及改变与昼夜节律相关的途径的调节和侵入。这些数据表明 HIF-1α活性可能出现的振荡可能为这些细胞提供选择性优势， 缺氧诱导应激反应。 我们的初步数据提供了一个强有力的理由来研究癌症人群中出现的这种表型， 驱动这些振荡的机制和这些振荡的表型后果。此外，委员会认为， 许多基因对振荡缺氧的反应是一种性质不同的信号，表明存在着 调节基序，不相干前馈回路（IFFL），可以区分振荡和 持续的HIF-1α信号。使用包括计算建模、生物信息学和 通过实验，我们将系统地识别和验证这些IFFL，以及必要的辅助因素， 与HIF-1α一起形成这些IFFL沿着。我们的目标不仅将揭示基本的监管 癌症中振荡信号的解码机制，而且还提供了一种靶向策略， HIF-1α振荡的表型后果。最后，我们将测试紧急的后果， 在乳腺癌肿瘤发生的小鼠模型中体内HIF-1α振荡，并测试振荡HIF-1α是否赋予 增加的致瘤性、增殖和存活。我们提出的方法将有助于机械 了解振荡的起源，癌症表型异质性的产生，以及 了解并针对这一新兴亚群在影响癌症进展方面的后果。