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，对覆盖内脏器官和内腹壁的腹膜了解甚少，尤其是其作为转移前小生境的能力。重要的是，目前尚不清楚为什么有些患者发生腹膜转移，而另一些则没有。腹膜内衬的间皮细胞作为游离转移癌细胞侵袭的基本屏障。越来越多的证据表明，当间皮细胞遇到癌细胞时，它们经历细胞间连接丧失和与基底膜的粘附性差的转变，导致屏障功能缺陷。这个令人兴奋的项目旨在使用系统生物学方法研究腹膜转移患者腹膜的结构和功能。还将分析来自接受常规非癌症手术患者的对照样本。空间转录组学、蛋白质组学和详细成像将确定接种转移性癌细胞的腹膜的独特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附着和侵袭至关重要，将开发一种腹膜转移的3D共培养模型系统，该系统复制了患者的发现。这个创新项目的建议产出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志物，并为新的治疗策略提供靶点。监督团队是各自领域的专家，具有互补的多学科技能，包括癌细胞生物学，腹膜疾病建模，病理学和手术。培训环境是特殊的，临床和学术研究都有最先进的核心设施提供出色的技术支持。

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.