Finding new insights into cancer metastasis: Linking cell migration to metabolic energy flux

寻找癌症转移的新见解：将细胞迁移与代谢能量通量联系起来

• 批准号: MR/R017255/1
• 负责人: Laura Machesky
• 金额: $ 35.13万
• 依托单位: University of Glasgow
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR017255%2F1
• 关键词: Finding; new; insights; into; cancer

The vast majority of deaths due to cancer are caused by recurrence or spread around the body, termed as metastasis. Surgery and chemotherapy can often be used to remove a primary tumour, but if cancer spreads to other parts of the body, treatment options are more limited. Cells move out of the primary tumour when nutrients are scarce and this is how they spread around the body. Pancreatic cancer is one of the worst types of cancer for metastasis and recurrence and only limited treatments are currently available. Our aim is to use pancreatic cancer cells to discover new ways to target this disease and stop it spreading.Tumours typically grow rapidly and consume a large amount of energy to fuel this growth. Consequently, tumour cells have adapted ways to produce more energy and obtain alternative food sources to normal cells. To identify metabolic regulators that were tightly coupled with cell shape and cytoskeletal organisation, we performed a high content imaging based siRNA screen against 494 genes known to be metabolic regulators. Two mouse KPC PDAC cell lines (A and B, both KRasG12D and p53R172H) were independently screened to maximise reliability. We identified the top 10% of hits consistent between the two cell lines showing abnormal shape and impaired in migration but not growth rate, suggesting multiple pathways connecting migration and metabolism. Our screen has uncovered two main functional categories connecting migration to metabolism- mitochondrial (OXPHOS) related (Group 1) or glycolytic related (Group 2).In this project, we will focu on those two main classes of hits and perform cell biological analysis on the candidates to determine the mechanisms by which they affect energy production/consumption and cell migration. Our experiments will focus on how cells couple energy production and nutrient uptake with migration and invasion. Our goal is to identify 1-2 key pathways connecting these processes that could be targetted in vivo in the future to develop new therapeutic angles against pancreatic ductal adenocarcinoma. The outcomes that we expect from this project include:Uncovering key molecular pathways regulating the coupling between mitochondrial energy production and cell migration and invasion.Developing a coherent model for how the actin cytoskeleton scaffolds the vacuolar V-ATPase and glycolytic enzymes to regulate the pH balance when cells are glycolytic.Understanding how integrin trafficking couples with V-ATPase trafficking to regulate tumour cell invasion and maintenence of pH homeostasis by mechanosensing.Modeling how these genes affect invasion into a reconstituted tumour environment, simulating the process of cancer cells migrating out from the primary tumour.Determination of which key aspects of cell migration regulate energy production and consumption so that these can be therapeutically targetted, first for pancreatic cancer, and then for other cancers that also spread through metastasis.

由于癌症造成的绝大多数死亡是由复发引起的或在体内散布，称为转移。手术和化学疗法通常可用于去除原发性肿瘤，但是如果癌症扩散到人体其他部位，则治疗方案将受到更大的限制。当营养稀缺时，细胞从原发性肿瘤中移出，这就是它们在体内散布的方式。胰腺癌是转移和复发的癌症最糟糕的类型之一，目前只能使用有限的治疗方法。我们的目的是使用胰腺癌细胞来发现靶向这种疾病并阻止其扩散的新方法。图通常会迅速生长，并消耗大量能量来促进这种生长。因此，肿瘤细胞具有生产更多能量并获得正常细胞的替代食品来源的方法。为了鉴定与细胞形状和细胞骨架组织紧密结合的代谢调节剂，我们针对494个基因进行了高含量成像的siRNA筛选，该基因已知是代谢调节剂。独立筛选了两种小鼠KPC PDAC细胞系（A和B，KRASG12D和P53R172H），以最大程度地提高可靠性。我们确定了两种细胞系之间一致的命中率的前10％，表现出异常形状和迁移速度受损但没有增长，这表明多种途径连接了迁移和代谢。我们的屏幕发现了将迁移与新陈代谢 - 线粒体（OXPHOS）相关（第1组）或糖酵解相关的两个主要功能类别（第2组）。在该项目中，我们将重点关注这两种主要类别的命中率和细胞生物学分析，并在候选者上确定能源生产/消费型和细胞迁移的机制。我们的实验将集中于细胞如何将能量产生和养分吸收与迁移和侵袭。我们的目标是确定连接这些过程的1-2个关键途径，这些过程将来可以在体内靶向，以开发针对胰腺导管腺癌的新治疗角度。我们从该项目中期望的结果包括：揭示关键分子途径，以调节线粒体能量生产与细胞迁移和入侵之间的耦合。开发一个相干模型，以使肌动蛋白细胞骨架如何与真空液相关的v-atpase和glycolycolighttic seplys condike segrance condike segrance condike segrance condike ph ph per sepligntions condike per consection。 V-ATPase trafficking to regulate tumour cell invasion and maintenence of pH homeostasis by mechanosensing.Modeling how these genes affect invasion into a reconstituted tumour environment, simulating the process of cancer cells migrating out from the primary tumour.Determination of which key aspects of cell migration regulate energy production and consumption so that these can be therapeutically targetted, first for pancreatic cancer, and then for other cancers这也通过转移传播。

项目成果

CYRI/ Fam49 Proteins Represent a New Class of Rac1 Interactors.

• DOI: 10.1080/19420889.2019.1643665
• 发表时间: 2019-01-01
• 期刊: Communicative & integrative biology
• 作者: Whitelaw, Jamie A;Lilla, Sergio;Machesky, Laura M
• 通讯作者: Machesky, Laura M

The Arp2/3 complex is crucial for colonisation of the mouse skin by melanoblasts.

• DOI: 10.1242/dev.194555
• 发表时间: 2020-11-15
• 期刊: Development (Cambridge, England)
• 作者: Papalazarou V;Swaminathan K;Jaber-Hijazi F;Spence H;Lahmann I;Nixon C;Salmeron-Sanchez M;Arnold HH;Rottner K;Machesky LM
• 通讯作者: Machesky LM

CYRI-A limits invasive migration through macropinosome formation and integrin uptake regulation.

• DOI: 10.1083/jcb.202012114
• 发表时间: 2021-09-06
• 期刊: The Journal of cell biology
• 作者: Le AH;Yelland T;Paul NR;Fort L;Nikolaou S;Ismail S;Machesky LM
• 通讯作者: Machesky LM

Image-based Quantification of Macropinocytosis Using Dextran Uptake into Cultured Cells

利用培养细胞摄取的葡聚糖对巨胞饮作用进行基于图像的定量

• DOI: 10.21769/bioprotoc.4367
• 发表时间: 2022
• 期刊: BIO-PROTOCOL
• 影响因子: 0.8
• 作者: Le A

CYRI-B mediated macropinocytosis drives metastasis via lysophosphatidic acid receptor uptake

CYRI-B 介导的巨胞饮作用通过溶血磷脂酸受体摄取驱动转移

• DOI: 10.1101/2022.11.23.517689
• 发表时间: 2022
• 作者: Nikolaou S