Defining the pre-metastatic niche for colorectal cancer dissemination

结直肠癌是死亡的主要原因，通常与腹部腹膜转移有关。然而，覆盖内脏和腹壁的腹膜却知之甚少，尤其是在其作为转移前小生境的能力方面。重要的是，目前尚不清楚为什么一些患者会发生腹膜转移，而另一些患者则不会。排列在腹膜上的间皮细胞对自由转移的癌细胞的侵袭起着必不可少的屏障作用。越来越多的证据表明，当间皮细胞遇到癌细胞时，它们会经历一种过渡，细胞间连接丢失，与基底膜的粘附性差，导致屏障功能缺陷。这个激动人心的项目旨在用系统生物学的方法研究腹膜转移患者腹膜的结构和功能。还将对接受常规非癌症手术的患者的对照样本进行分析。空间转录组学、蛋白质组学和详细成像将确定种植有转移性癌细胞的腹膜独特的基因和蛋白质表达谱。为了确定哪些分子和关键信号通路对癌细胞的附着和侵袭至关重要，将开发一个复制患者发现的腹膜转移的3D共培养模型系统。这一创新项目的拟议成果将阐明与腹膜转移相关的潜在生物学机制，并可能有助于识别疾病的早期生物标记物，并为新的治疗策略提供靶点。监督团队是各自领域的专家，拥有互补的多学科技能，包括癌细胞生物学、腹膜疾病建模、病理学和外科手术。培训环境出类拔萃，拥有临床和学术研究经验，并拥有最先进的核心设施提供的出色技术支持。

Colorectal cancer is a major cause of mortality and commonly associated with peritoneal metastasis in the abdomen. However, the peritoneum that covers internal organs and inner abdominal wall is poorly understood especially in terms of its ability to act as a premetastatic niche. Importantly, it is not clear why some patients develop peritoneal metastasis while others do not. Mesothelial cells that line the peritoneum act as an essential barrier to the invasion of free metastatic cancer cells. Mounting evidence suggests that when mesothelial cells encounter cancer cells, they undergo a transition with loss of intercellular junctions and poor adhesion to the basement membrane resulting in a defective barrier function. This exciting project aims to investigate the structure and function of the peritoneum of patients with peritoneal metastasis using a systems biology approach. Control samples will also be analysed from patients undergoing routine non-cancer surgery. Spatial transcriptomics, proteomics and detailed imaging will determine the unique gene and protein expression profile of peritoneum seeded with metastatic cancer cells. To define which molecules and key signalling pathways are essential to cancer cell attachment and invasion, a 3D co-culture model system of peritoneal metastasis will be developed that replicates findings from patients. Proposed outputs from this innovative project will elucidate the underlying biological mechanisms associated with peritoneal metastasis and may help identify early biomarkers of disease and offer targets for novel treatment strategies. The supervisory team are experts in their field with complementary multidisciplinary skillsets encompassing cancer cell biology, peritoneal disease modelling, pathology and surgery. The training environment is exceptional with both clinical and academic research exposure with excellent technical support from state-of-the-art core facilities.