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

点击翻译按钮获取中文摘要

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