Role of macrophage-mediated efferocytosis in cancer - mechanisms and new therapeutic opportunities

巨噬细胞介导的胞吞作用在癌症中的作用 - 机制和新的治疗机会

• 批准号: 2887777
• 金额: --
• 依托单位: University of Liverpool
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2887777
• 关键词: Role; macrophage; mediated; efferocytosis; cancer

Pancreatic cancer develops in the pancreas, yet cancer cells spread aggressively to distant sites in our body, a process called metastasis, where they can form metastatic tumours. Pancreatic cancer most often spreads to the liver. We and others have shown that during pancreatic cancer metastasis, large numbers of immune cells, known as macrophages, accumulate at the metastatic site and these macrophages promote efficient metastatic outgrowth of disseminated cancer cells in the liver. Thus, targeting tumour promoting functions of macrophages represents a promising new strategy to fight pancreatic cancer. Efferocytosis, or engulfment of apoptotic cells by macrophages, is an essential process in tissue homoeostasis and the resolution of inflammation, but its role in metastasis is less well understood. Our new findings suggest that efferocytosis is promoting pancreatic cancer liver metastasis, however, the underlying molecular mechanisms remain unknown.This DiMeN funded PhD project will explore whether and how efferocytosis induces metastasis promoting functions in macrophages. It will employ a number of different cutting-edge technologies, including gene editing, Lyso-IP with subsequent quantitative mass spectrometry analysis, 3D co-culture models, and confocal microscopy. In addition, we employ mouse models of metastatic pancreatic cancer to translate findings from in vitro assays into an in-vivo scenario. The PhD candidate will also benefit from our close collaborations with clinical colleagues at the Royal Liverpool University Hospital and the Clatterbridge Cancer Centre, allowing the validation of findings obtained during this PhD project in cancer patient samples.We offer:You will join a vibrant cancer research laboratory in the Department of Molecular and Clinical Cancer Medicine, University of Liverpool run by Prof Michael Schmid (primary supervisor) and Dr Ainhoa Mielgo (tertiary supervisor). This team has a long-standing interest in studying the tumour microenvironment in cancer. Your secondary supervisor will be Prof Matthias Trost from the University of Newcastle. Matthias Trost is a renowned expert in applying quantitative proteomics to study lysosomal compartments in macrophages at the University of Newcastle. You will learn the necessary skills from senior researchers of each team to assure high quality training and you will weekly meet with your supervisors to discuss the findings and future directions of the project. This PhD project provides exceptional opportunities for the student to benefit from diverse expertise and to be exposed to cutting edge techniques.We expect:It is expected that you will be an innovative individual with an interest in applying your research skills to a challenging project. Applicants should have a First or Upper Second Class Honours Degree in a relevant subject (i.e. cancer biology, molecular biology, and/or biomedical sciences) and some experience of working in a laboratory. You should be highly motivated to pursue a PhD training and should be able to work as part of a team. You will also be expected to publish your results in a peer-reviewed journal.Pancreatic cancer remains a highly lethal cancer, with ineffective current treatments. It is thus important to develop successful therapies for this deadly disease. Pancreatic cancer cells spread early in the progressing disease from the pancreas to distant organs in the body, particularly to the liver.We and other groups have previously found that the outgrowth of disseminated pancreatic cancer cells is accompanied by the accumulation of immune cells and a fibrotic reaction. Macrophages were found to be highly abundant in outgrowths in the liver.Macrophages typically act as a primary defence against infection and injury, essentially "eating" cancer cells and microbes which may harm the body, and recruiting more specialised immune cells. In normal tissue, macrophages destroy dying cells in a process called

胰腺癌在胰腺中发展，但癌细胞会积极扩散到我们体内的远处部位，这一过程称为转移，在那里它们可以形成转移性肿瘤。胰腺癌最常扩散到肝脏。我们和其他人已经表明，在胰腺癌转移过程中，大量的免疫细胞（称为巨噬细胞）在转移部位积聚，这些巨噬细胞促进肝脏中播散性癌细胞的有效转移生长。因此，靶向巨噬细胞的肿瘤促进功能代表了对抗胰腺癌的有希望的新策略。胞饮作用或巨噬细胞吞噬凋亡细胞是组织内稳态和炎症消退的重要过程，但其在转移中的作用尚不清楚。我们的新发现表明巨噬细胞增多症促进胰腺癌肝转移，然而，潜在的分子机制仍然未知。这个DiMeN资助的博士项目将探索巨噬细胞增多症是否以及如何诱导巨噬细胞的转移促进功能。它将采用许多不同的尖端技术，包括基因编辑，Lyso-IP与随后的定量质谱分析，3D共培养模型和共聚焦显微镜。此外，我们采用转移性胰腺癌的小鼠模型将体外试验的结果转化为体内情况。博士候选人还将受益于我们与皇家利物浦大学医院和Clatterbridge癌症中心的临床同事的密切合作，允许在癌症患者样本中验证该博士项目期间获得的发现。我们提供：您将加入利物浦大学分子和临床癌症医学系的一个充满活力的癌症研究实验室，由Michael Schmid教授（主要导师）和Ainhoa Mielgo博士（三级导师）管理。该团队长期以来一直对研究癌症中的肿瘤微环境感兴趣。你的二级导师将是来自纽卡斯尔大学的Matthias Trost教授。Matthias Trost是纽卡斯尔大学应用定量蛋白质组学研究巨噬细胞溶酶体区室的著名专家。您将从每个团队的高级研究人员那里学习必要的技能，以确保高质量的培训，并且您将每周与您的主管会面，讨论项目的发现和未来方向。这个博士项目为学生提供了从不同的专业知识中受益并接触尖端技术的绝佳机会。我们期望：预计您将成为一个创新的个人，有兴趣将您的研究技能应用于具有挑战性的项目。申请人应具有相关学科（即癌症生物学，分子生物学和/或生物医学科学）的一级或二级以上荣誉学位，并具有在实验室工作的经验。你应该有很高的动力去追求博士学位的培训，应该能够作为团队的一部分工作。胰腺癌是一种高致死率的癌症，目前的治疗方法效果不佳。因此，为这种致命的疾病开发成功的治疗方法非常重要。胰腺癌细胞在疾病进展的早期从胰腺扩散到身体的远端器官，特别是肝脏。我们和其他小组以前发现，扩散的胰腺癌细胞的生长伴随着免疫细胞的积累和纤维化反应。研究发现，巨噬细胞在肝脏中的副产物非常丰富。巨噬细胞通常作为对抗感染和损伤的主要防御，基本上是“吃掉”可能伤害身体的癌细胞和微生物，并招募更专门的免疫细胞。在正常组织中，巨噬细胞通过一种称为