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

尽管取得了进展，癌症仍然是医学上的一个严重挑战。识别肿瘤细胞和正常细胞之间的差异对于理解疾病和开发新的选择性治疗策略至关重要。肿瘤的一个独特特征是存在一个叫做中心体的细胞器的额外拷贝。事实上，自19世纪末以来，肿瘤细胞中额外中心体的存在就已被认识到，并被认为是恶性肿瘤的原因。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，额外的中心体的存在可以诱导细胞入侵细胞类似的过度表达已知的癌基因。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性传播所需的第一步，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。我们将使用一种方法的组合，以确定发生的信号改变，作为中心体扩增的结果。接下来，我们将使用精密的三维细胞培养模型来研究对侵袭很重要的信号改变，该模型非常接近于真实的组织。我们的结果也将在来自患者的人类乳腺癌样本中得到验证。这对于确定我们的发现与癌症的相关性至关重要。重要的是，这种策略有可能开发新的生物标志物，以识别临床上含有额外中心体的肿瘤。这一点很重要，因为我们之前已经证明，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。基于我们以前的观察，最近已经开发出了杀死具有额外中心体的细胞的新药。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。

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.