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

尽管取得了进展，但癌症仍然是医学界的一个严峻挑战。识别肿瘤细胞和正常细胞之间的差异对于了解这种疾病和开发新的选择性治疗策略是必不可少的。一种称为中心体的细胞器的额外拷贝的存在是肿瘤的一个独特特征。事实上，自19世纪末以来，人们就已经认识到肿瘤细胞中存在额外的中心体，并被认为是恶性肿瘤的原因。然而，到目前为止，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侵袭，类似于已知癌基因的过度表达。这一发现突显了这些细胞器在肿瘤进展中发挥的重要性。此外，由于细胞侵袭是肿瘤细胞转移扩散的首要步骤之一，导致90%的人类癌症死亡，因此了解这一过程至关重要。在这项研究方案中，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确定中心体扩增导致的信号变化。接下来，我们将使用复杂的3D细胞培养模型来研究对侵袭至关重要的信号变化，这种细胞培养模型非常接近真实组织。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，这一策略具有开发新的生物标记物的潜力，以在临床上识别包含额外中心体的肿瘤。这一点很重要，因为我们之前已经证明，带有额外中心体的细胞有独特的生存要求，可以选择性地被杀死。根据我们之前的观察，最近已经开发出了用额外的中心体杀死细胞的新药。因此，我们的工作不仅有助于理解中心体扩增在肿瘤进展和侵袭中的作用，而且可能在临床上产生重大影响。

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.