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

胰腺癌在胰腺中发展，但癌细胞侵袭性地扩散到我们身体的远处，这一过程被称为转移，在那里它们可以形成转移肿瘤。胰腺癌最常扩散到肝脏。我们和其他人已经证明，在胰腺癌转移过程中，大量的免疫细胞，即巨噬细胞，在转移部位聚集，这些巨噬细胞促进肝脏播散性癌细胞的有效转移生长。因此，靶向巨噬细胞的促肿瘤功能是一种很有前途的抗击胰腺癌的新策略。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，但对其在肿瘤转移中的作用了解较少。我们的新发现表明，吞噬作用促进了胰腺癌肝转移，但其潜在的分子机制尚不清楚。这项由迪门资助的博士项目将探索吞噬作用是否以及如何在巨噬细胞中诱导转移促进功能。它将使用许多不同的尖端技术，包括基因编辑、随后定量质谱分析的Lyso-IP、3D共培养模型和共聚焦显微镜。此外，我们使用了转移性胰腺癌的小鼠模型，将体外实验的结果转化为体内实验。博士生还将受益于我们与皇家利物浦大学医院和克莱特布里奇癌症中心的临床同事的密切合作，使这一博士项目在癌症患者样本中获得的结果得到验证。我们提供：您将加入利物浦大学分子和临床癌症医学系充满活力的癌症研究实验室，该实验室由Michael Schmid教授(一级主管)和Ainhoa Mielgo博士(三级主管)运营。这个团队长期以来一直对研究癌症中的肿瘤微环境感兴趣。你们的副导师将是纽卡斯尔大学的马蒂亚斯·特罗斯特教授。马蒂亚斯·特罗斯特是纽卡斯尔大学应用定量蛋白质组学研究巨噬细胞中溶酶体隔间的著名专家。你将从每个团队的资深研究人员那里学习必要的技能，以确保高质量的培训，你将每周与你的主管会面，讨论该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获益并接触尖端技术的绝佳机会。我们期望：希望你是一个有创新精神的人，有兴趣将你的研究技能应用到一个具有挑战性的项目中。申请者必须拥有相关学科(如癌症生物学、分子生物学和/或生物医学)的一等或二等以上荣誉学位，并具有一定的实验室工作经验。你应该有很强的攻读博士学位的积极性，并且能够成为团队中的一员。你还将被期望在同行评议的杂志上发表你的结果。胰腺癌仍然是一种高度致命的癌症，目前的治疗方法无效。因此，为这种致命疾病开发成功的治疗方法是很重要的。在疾病进展的早期，胰腺癌细胞从胰腺扩散到身体的远处器官，特别是肝脏。我们和其他研究小组之前发现，播散性胰腺癌细胞的生长伴随着免疫细胞的聚集和纤维化反应。巨噬细胞在肝脏的突起中含量非常丰富。巨噬细胞通常是抵御感染和损伤的主要防御细胞，本质上是“吞噬”癌细胞和可能对身体有害的微生物，并招募更专业的免疫细胞。在正常组织中，巨噬细胞在一个称为

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