Crosstalk between PAK1 signalling and intracellular trafficking

上皮细胞是人体许多不同组织和器官的重要组成部分。它们形成了一层高度粘附的细胞，排列在我们的内部器官和外部，形成我们的皮肤。上皮细胞是生命必需的细胞类型，其结构和功能的改变具有重要的临床意义。由于上皮组织面临许多化学、生物和环境方面的挑战，很大比例的癌症（约85%）起源于上皮细胞。剖析扰乱上皮细胞稳态和功能的致癌驱动因素将突出潜在的治疗步骤，以改善肿瘤进展。广泛的研究集中在理解上皮细胞如何组装成组织以及它们的功能是如何被调节的。决定组织结构的一个关键过程是上皮细胞粘在一起的能力。这种有序的上皮细胞-细胞粘附组织在肿瘤发生、炎症性、慢性和超增生性疾病中受到严重干扰。因此，维持细胞结构对上皮组织的功能是重要的。在这里，我们的目的是研究破坏正常上皮结构和破坏邻近细胞之间接触的分子事件。Rac1和Rabs是两类信号分子，它们控制着看似独立的不同细胞过程：细胞粘附和细胞内运输。我们将研究Rac1和Rab蛋白如何在肿瘤进展过程中结合它们的作用，促进粘附受体（将细胞粘合在一起）从细胞相互接触的部位移除。我们发现一个Rac1的伙伴，激酶PAK1，介导这两个信号分子之间的无缝整合，整合它们在空间和时间上的功能，精确地破坏细胞-细胞接触。PAK1基因在多种癌症中扩增或突变，与更具侵袭性的肿瘤表型和患者的不良预后相关。它也被不同的癌基因激活，如Rac1本身或H-Ras，从而增加了它作为癌症患者治疗药物的意义和影响。我们发现PAK1直接调节Rab调节因子的功能，这反过来可以重定向粘附受体的运输，从而在转化过程中破坏组织内聚和结构。这种分子关系和结果将在患者来源的肿瘤细胞中得到验证，这些肿瘤细胞代表了每个患者的原发肿瘤状态和相应的淋巴结转移。通过了解PAK1调控Rac1和Rab串扰的机制，我们的工作将强调通过延缓良性肿瘤向转移性肿瘤的转变来干扰肿瘤进展的潜在方法。

Epithelial cells are an important component of many different tissues and organs in the body. They form a sheet of highly adherent cells that line all inside our internal organs and externally to form our skin. Epithelial cells are an essential cell type for life, and alterations in their structure and function have important clinical implications. As epithelial tissues face many chemicals, biological and environmental challenges, a high proportion of cancers (about 85%) originates in epithelial cells. Dissecting the oncogenic drivers that perturb epithelial cells homeostasis and function will highlight potential therapeutic steps to ameliorate tumour progression.Extensive research has focused on understanding how epithelial cells assemble themselves as tissues and how their function is regulated. A key process that determines tissue structure is the ability of epithelial cells to stick together and strongly. Such orderly organization of epithelial cell-cell adhesion is severely perturbed during tumorigenesis, in inflammatory, chronic and hyper-proliferative diseases. Thus, maintaining cell architecture is important for the function of epithelial tissues.Here we aim to investigate the molecular events that subvert the normal epithelial architecture and disrupt contacts between neighbouring cells. Rac1 and Rabs are two classes of signalling molecules that control distinct cellular processes that are seemingly independent: cell adhesion and intracellular transport. We will study how Rac1 and Rab proteins combine their efforts during tumour progression to promote the removal of adhesion receptors (that glue cells together) from sites where cells contact each other. We find that a Rac1 partner, the kinase PAK1, mediates a seamless integration between these two signalling molecules to integrate their function in space and time to precisely destroy cell-cell contacts. PAK1 gene is amplified or mutated in various cancers, where it is associated with more aggressive tumour phenotypes and poor outcome for patients. It is also activated by different oncogenes such as Rac1 itself or H-Ras, thereby increasing its significance and impact as therapeutics for cancer patients. We find that PAK1 directly modulate the function of a Rab regulator, which in turn can redirect trafficking of adhesion receptors to destroy tissue cohesion and architecture during transformation. Such molecular relationships and outcome will be validated in patient-derived tumour cells that represent the primary tumour status and the corresponding lymph node metastasis in each patient. By understanding the mechanisms via which Rac1 and Rab cross-talk is regulated by PAK1, our work will highlight potential approaches to interfere with tumour progression, by delaying the transition from benign to metastatic tumours.