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

基本信息

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

项目摘要

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.

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
影响因子：
0
作者：
Whitelaw, Jamie A;Lilla, Sergio;Machesky, Laura M
通讯作者：
Machesky, Laura M

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
影响因子：
0
作者：
Le AH;Yelland T;Paul NR;Fort L;Nikolaou S;Ismail S;Machesky LM
通讯作者：
Machesky LM

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)
影响因子：
0
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

The cell pushes back: The Arp2/3 complex is a key orchestrator of cellular responses to environmental forces.