Implications of metabolic heterogeneity on collective lung cancer cell invasion

项目摘要 大多数研究调查的是整个癌细胞群体，很少涉及单个细胞或亚群如何 合作促进它们的生存和传播。尤其是在新陈代谢的背景下，肿瘤 港湾有不同的糖酵解和氧化细胞亚群，部分是由微环境压力形成的。 这种代谢的异质性如何驱动肿瘤的侵袭和转移是一个未知的领域，需要 可以分离这些特定癌细胞亚群的方法。多点PI在肺部的应用 腺癌试图通过确定代谢异质性的癌细胞亚群如何解决这个问题。 人口的功能和合作推动了侵袭和转移。我们建立在我们出版的形象指导下 基因组学技术(SAGA)提取集体内活的和表型定义的细胞亚群 入侵的狼群。我们使用SAGA解构了肺癌集体侵袭包，它包括 侵袭性先导细胞和增殖性跟随者细胞作为一个凝聚力单元入侵的层级组织。我们出版的 初步数据显示，跟随者细胞消耗的葡萄糖是领先者的两倍，并依赖糖酵解 和氧化戊糖磷酸途径(PPP)来维持它们的增殖状态。通过简单地扰乱 葡萄糖转运蛋白GLUT1，追随者变得侵袭性，并呈现出领先者样的表型。相比之下， 领导者依赖通过丙酮酸脱氢酶(PDH)活性的氧化磷酸化(OXPHOS)来推动 侵袭，破坏PDH产生更像追随者的表型。这些数据导致了我们最重要的 GLUT1和PDH驱动的差异代谢维持代谢异质性的假说 通过在集体侵袭包中保持不同的表型来实现肺癌转移。我们建议这一点 代谢异质性需要联合靶向治疗方法，扰乱两种代谢群体 以抑制肿瘤转移。因此，这一提议的目的是1)阐明分子基础和机制 代谢异质性如何推动集体侵袭的基础，以及2)测试共同目标是否不同 新陈代谢亚群限制转移。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作性以促进集体侵袭/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.