Implications of metabolic heterogeneity on collective lung cancer cell invasion

代谢异质性对肺癌细胞集体侵袭的影响

• 批准号: 10672179
• 负责人: Adam I. Marcus
• 金额: $ 44.14万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-05 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10672179
• 关键词: 3-Dimensional; Address; Area; Automobile Driving; Biology; Cell Proliferation; Cell Respiration; Cells; Chemicals; Citric Acid Cycle; Consumption; Data; Dependence; Environment; Fostering; G6PD gene; Genetic; Genetic Transcription; Genomics; Glucose; Glucose Transporter; Glycolysis; Goals; Heterogeneity; Hypermethylation; Invaded; KRASG12D; Lead; Lung Adenocarcinoma; Maintenance; Malignant Neoplasms; Malignant neoplasm of lung; Metabolic; Metabolism; Modeling; Molecular; Molecular Analysis; Nature; Neoplasm Metastasis; Oxidative Phosphorylation; PDH kinase; Pentosephosphate Pathway; Phenotype; Population; Proliferating; Publishing; Pyruvate; SLC2A1 gene; Signal Pathway; Technology; Testing; Therapeutic; Tumor Cell Invasion; cancer cell; forging; genomic platform; glucose uptake; image guided; lung cancer cell; neoplastic cell; pharmacologic; pressure; promoter; pyruvate dehydrogenase; spatiotemporal; targeted agent; targeted treatment; tumor; tumor initiation; tumor progression

Project Summary Most studies investigate whole cancer cell populations and rarely address how single cells or sub-populations cooperate to promote their survival and spread. This is especially true in the context of metabolism, where tumors harbor distinct sub-populations of glycolytic and oxidative cells forged in part by microenvironmental pressures. How this metabolic heterogeneity drives tumor invasion and metastasis is an unexplored area and requires approaches that can isolate these specific cancer cell sub-populations. This multi-PI application in lung adenocarcinoma attempts to address this by determining how metabolically heterogeneous cancer cell sub- populations function and cooperate to drive invasion and metastasis. We build upon our published image-guided genomics technology (SaGA) to extract living and phenotypically defined cell sub-populations within collectively invading packs. We used SaGA to deconstruct the lung cancer collective invasion pack, which is comprised of hierarchical groups of invasive leader and proliferative follower cells invading as a cohesive unit. Our published and preliminary data show that follower cells consume twice as much glucose as leaders, and rely on glycolysis and the oxidative pentose phosphate pathway (PPP) to maintain their proliferative state. By simply disrupting the glucose transporter, GLUT1, followers become invasive and take on a leader-like phenotype. In contrast, leaders rely on oxidative phosphorylation (OXPHOS) via pyruvate dehydrogenase (PDH) activity to drive invasion, where disrupting PDH creates a more follower-like phenotype. These data lead to our overarching hypothesis that metabolic heterogeneity sustained by differential GLUT1 and PDH-driven metabolism facilitates lung cancer metastasis by maintaining distinct phenotypes in the collective invasion pack. We propose that this metabolic heterogeneity warrants a co-targeting therapeutic approach that disrupts both metabolic populations to inhibit metastasis. Thus, the objective of this proposal is to 1) elucidate the molecular basis and mechanistic underpinnings of how metabolic heterogeneity drives collective invasion and 2) test if co-targeting different metabolic sub-populations limits metastasis. We propose that these studies will directly impact our understanding of how metabolic heterogeneity sustains cooperativity to promote collective invasion/metastasis.

项目摘要 大多数研究研究了整个癌细胞群体，很少解决单个细胞或亚群 合作以促进其生存和传播。在肿瘤的新陈代谢的背景下尤其如此 藏有糖酵解和氧化细胞的独特亚群，部分由微环境压力锻造。 这种代谢异质性如何驱动肿瘤侵袭和转移是一个未开发的区域，需要 可以分离这些特定癌细胞亚群的方法。该多PI在肺中的应用 腺癌试图通过确定如何代谢异质性癌细胞亚 人群的功能并合作以推动入侵和转移。我们建立在已发表的图像引导的基础上 基因组学技术（SAGA）集体提取生活和表型定义的细胞亚种群 入侵包。我们使用传奇来解构肺癌集体入侵包，该包由 侵入性领导者和增生性追随者细胞的分层群体入侵，作为一个内聚单元。我们出版了 和初步数据表明，自动细胞消耗的葡萄糖是铅的两倍，并依靠糖酵解 以及氧化戊糖磷酸途径（PPP）以维持其增殖状态。通过简单地破坏 葡萄糖转运蛋白Glut1的追随者变得侵入性并采用了领导者样表型。相比之下， 领导者通过丙酮酸脱氢酶（PDH）活性依赖氧化磷酸化（OXPHOS） 入侵，破坏PDH会产生更像追随者的表型。这些数据导致我们的总体 差分GLUT1和PDH驱动的代谢促进的代谢异质性促进的假设促进 通过在集体入侵包中维持不同的表型，肺癌转移。我们提出这一点 代谢异质性需要一种共同靶向的治疗方法，破坏了这两个代谢种群 抑制转移。因此，该提案的目的是1）阐明分子基础和机械基础 代谢异质性如何驱动集体入侵和2）测试是否共同靶向不同的基础 代谢亚群限制了转移。我们建议这些研究将直接影响我们的理解 代谢异质性如何维持合作性以促进集体入侵/转移。