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Characterisation of the signalling pathways involved in cell invasion downstream of extra centrosomes

中心体外细胞侵袭下游信号通路的表征

基本信息

批准号：
MR/M010414/1
负责人：
Susana Godinho
金额：
$ 59.43万
依托单位：
Queen Mary University of London
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2015
资助国家：
英国
起止时间：
2015 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FM010414%2F1
关键词：
Characterisation signalling pathways involved cell

项目摘要

Despite the progress, cancer is still a serious challenge in medicine. Identifying the differences between tumour and normal cells is imperative to understand the disease and to develop novel selective therapeutic strategies. The presence of extra copies of a cellular organelle called centrosome is a unique feature of tumours. Indeed, the presence of extra centrosomes in tumour cells has been recognized since the late 1800s and was then proposed to be cause of malignancy. Yet, to date how centrosome amplification contributes to tumour progression is still unclear. Our recent work demonstrates that the presence of extra centrosomes can induce cell invasion in cells similarly to overexpression of known oncogenes. This finding highlights the importance that these organelles play in tumour progression. In addition, since cell invasion is one of the first steps required for metastatic dissemination of tumour cells, responsible for 90% of human cancer deaths, understanding this process is crucial. In this research proposal we aim to determine how centrosome amplification induces cell invasion. We will use a combination of approaches to identify the signalling alterations that occur as a result of centrosome amplification. Next, we will investigate the signalling alterations that are important for invasion using sophisticated 3-D cell culture models that closely mimic the real tissues. Our results will be also validated in human breast cancer samples from patients. This is essential to establish the relevance of our findings to cancer. Importantly, this strategy has the potential for the development of novel biomarkers to identify tumours containing extra centrosomes in the clinic. This is important because we previously showed that cells with extra centrosomes have unique survival requirements and can be selectively killed. Based on our previous observations, new drugs that kill cells with extra centrosomes have been recently developed. Thus, our work will not only contribute to understand the role of centrosomes amplification in tumour progression and invasion but could also have a major impact in the clinic.

尽管取得了进展，癌症仍然是医学上的一个严峻挑战。识别肿瘤细胞和正常细胞之间的差异对于了解疾病和开发新的选择性治疗策略至关重要。称为中心体的细胞器的额外副本的存在是肿瘤的一个独特特征。事实上，自 1800 年代末以来，人们就认识到肿瘤细胞中存在额外的中心体，并随后提出这是恶性肿瘤的原因。然而，迄今为止，中心体扩增如何促进肿瘤进展仍不清楚。我们最近的工作表明，额外中心体的存在可以诱导细胞中的细胞侵袭，类似于已知癌基因的过度表达。这一发现强调了这些细胞器在肿瘤进展中的重要性。此外，由于细胞侵袭是肿瘤细胞转移扩散所需的首要步骤之一，而肿瘤细胞导致 90% 的人类癌症死亡，因此了解这一过程至关重要。在这项研究提案中，我们的目标是确定中心体扩增如何诱导细胞侵袭。我们将使用多种方法的组合来识别由于中心体扩增而发生的信号改变。接下来，我们将使用高度模仿真实组织的复杂 3D 细胞培养模型来研究对侵袭很重要的信号传导改变。我们的结果还将在患者的人类乳腺癌样本中得到验证。这对于确定我们的研究结果与癌症的相关性至关重要。重要的是，该策略具有开发新型生物标志物的潜力，以在临床上识别含有额外中心体的肿瘤。这很重要，因为我们之前表明具有额外中心体的细胞具有独特的生存要求并且可以被选择性杀死。根据我们之前的观察，最近开发出了杀死具有额外中心体的细胞的新药物。因此，我们的工作不仅有助于了解中心体扩增在肿瘤进展和侵袭中的作用，而且还可能对临床产生重大影响。

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）

Centrosome amplification fine-tunes tubulin acetylation to differentially control intracellular organization

中心体扩增微调微管蛋白乙酰化以差异控制细胞内组织

DOI：
10.1101/2022.10.17.512471
发表时间：
2022
期刊：
影响因子：
0
作者：
Monteiro P
通讯作者：
Monteiro P

Structural Centrosomal Abnormalities Push Cells toward Invasion.

DOI：
10.1016/j.devcel.2018.04.016
发表时间：
2018-05
期刊：
Developmental cell
影响因子：
11.8
作者：
Pedro Monteiro;S. Godinho
通讯作者：
Pedro Monteiro;S. Godinho

Loss of E-cadherin provides tolerance to centrosome amplification in epithelial cancer cells.

DOI：
10.1083/jcb.201704102
发表时间：
2018-01-02
期刊：
The Journal of cell biology
影响因子：
0
作者：
Rhys AD;Monteiro P;Smith C;Vaghela M;Arnandis T;Kato T;Leitinger B;Sahai E;McAinsh A;Charras G;Godinho SA
通讯作者：
Godinho SA

Oxidative Stress in Cells with Extra Centrosomes Drives Non-Cell-Autonomous Invasion.

DOI：
10.1016/j.devcel.2018.10.026
发表时间：
2018-11-19
期刊：
Developmental cell
影响因子：
11.8
作者：
Arnandis T;Monteiro P;Adams SD;Bridgeman VL;Rajeeve V;Gadaleta E;Marzec J;Chelala C;Malanchi I;Cutillas PR;Godinho SA
通讯作者：
Godinho SA

The principles of spindle bipolarity

主轴双极原理