Implications of metabolic heterogeneity on collective lung cancer cell invasion

项目摘要 大多数研究调查了整个癌细胞群，很少涉及单个细胞或亚群如何 共同促进它们的生存和传播。这在新陈代谢的背景下尤其如此， 含有糖酵解和氧化细胞的不同亚群，部分是由微环境压力造成的。 这种代谢异质性如何驱动肿瘤侵袭和转移是一个未探索的领域，需要 可以分离这些特定癌细胞亚群的方法。这种多PI在肺部的应用 腺癌试图通过确定代谢异质性癌细胞亚群如何来解决这一问题。 群体起作用并合作驱动侵袭和转移。我们建立在我们发布的图像引导 基因组学技术（佐贺）提取活的和表型定义的细胞亚群， 入侵的共生体我们使用佐贺来解构肺癌集体入侵包，该包由以下内容组成 作为内聚单位侵入的侵入性领导细胞和增殖性跟随细胞的等级组。我们的出版 初步数据显示，跟随细胞消耗的葡萄糖是领导细胞的两倍， 和氧化戊糖磷酸途径（PPP）来维持它们的增殖状态。通过简单地破坏 葡萄糖转运蛋白GLUT 1的跟随者变得具有侵入性并呈现出领导者样表型。与此相反， 领导者依靠氧化磷酸化（OXPHOS）通过丙酮酸脱氢酶（PDH）活性来驱动 侵袭，其中破坏PDH产生更像追随者的表型。这些数据导致我们的总体 假设由不同GLUT 1和PDH驱动的代谢维持的代谢异质性有助于 通过在集体侵袭包中维持不同的表型来防止肺癌转移。我们建议， 代谢异质性保证了一种共靶向治疗方法， 以抑制转移。因此，本建议的目的是1）阐明分子基础和机制 代谢异质性如何驱动集体入侵的基础和2）测试共同靶向是否不同 代谢亚群限制了转移。我们认为这些研究将直接影响我们对 代谢异质性如何维持协同性以促进集体侵袭/转移。

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.