We are interested in the mechanisms underlying the development of metastasis, the spread of cancer from one part of the body to another.
Our research focuses on the interaction of cancer cells with the host vasculature and the circulating blood cells. The interactions between tumour cells and the host vasculature are important in the initiation of metastases (secondary cancer) as well as allowing metastatic colony growth later in metastatic progression. Our work has indicated the importance of coagulation and platelets in recruiting myeloid cells to allow the earliest formation of metastatic colonies. Later in metastasis, recruitment of myeloid cells is also essential for colony growth and the formation of blood vessels in the colonies. We are asking how these myeloid cells enable metastatic progression. This work is beginning to identify targets both for detection and for treatment of metastatic lesions.
Figure 1: Tumour cell (green) metastatic to the lung endothelium (red) surrounded by platelets (blue).
Tumour vascularity is essential for the response of cancers to radiation therapy. During therapy, hypoxia (low oxygen) is highly detrimental to effective radiation therapy. Hypoxia is of course determined by tumour vascularity and oxygen consumption. We have begun to develop strategies to reduce hypoxia during radiation by identifying agents that lead to better blood vessel formation, also called vascular normalisation, and strategies to reduce tumoural oxygen consumption. These strategies would be expected to generate tumours that are less hypoxic and more responsive to radiation therapy. Clinical trials are underway based on this work.
The final outcome of radiation therapy is also affected by tumour regrowth at the end of therapy. We have shown that inhibition of vascular regrowth leads to enhanced efficacy of radiation therapy. We are currently exploring the mechanisms that tumours treated with radiation use to stimulate vascular growth and the means to interfere with this growth.
Figure 2: Tumour cell (blue) clot (red) formation, triggered by expression of Tissue Factor, promotes the recruitment of a population of monocytes/macrophages (green) that enhance tumour cell survival. This is a phenomenon that occurs at the very early stages of metastasis and it is also observed during the formation of premetastatic niches.
Ruth Muschel has been Deputy Director of the CRUK/MRC Oxford Institute of Radiation Oncology and Professor of Molecular Pathology at the University of Oxford since 2005. She obtained MD and PhD degrees at Albert Einstein College of Medicine, New York City and completed her specialty training in anatomic pathology at Columbia University and the National Cancer Institute in Bethesda. She continued on staff at the NCI before taking an academic position at the University of Pennsylvania, where she advanced to the rank of Professor.
Kersemans V, Kannan P, Beech JS, Bates R, Irving B, Gilchrist S, Allen PD, Thompson J, Kinchesh P, Casteleyn C, Schnabel J, Partridge M, Muschel RJ, Smart SC. Improving In Vivo High-Resolution CT Imaging of the Tumour Vasculature in Xenograft Mouse Models through Reduction of Motion and Bone-Streak Artefacts. PLoS One. 2015 Jun 5
Gordon-Weeks AN, Lim SY, Yuzhalin AE, Jones K, Muschel R. Macrophage migration inhibitory factor: A key cytokine and therapeutic target in colon cancer. Cytokine Growth Factor Rev. 2015 Apr 7.
Lim SY, Gordon-Weeks A, Allen D, Kersemans V, Beech J, Smart S, Muschel RJ. Cd11b(+) myeloid cells support hepatic metastasis through down-regulation of angiopoietin-like 7 in cancer cells. Hepatology. 2015 Apr 8.
Tiwana GS, Prevo R, Buffa FM, Yu S, Ebner DV, Howarth A, Folkes LK, Budwal B, Chu KY, Durrant L, Muschel RJ, McKenna WG, Higgins GS. Identification of vitamin B1 metabolism as a tumor-specific radiosensitizing pathway using a high-throughput colony formation screen. Oncotarget. 2015 Mar 20
Jon Buzzelli, Postdoctoral Researcher
Yunhong Cao, Laboratory Manager
Jianzhao Chen, Clinical Research Training Fellow
Ana Maria Gil-Bernabe, Postdoctoral Researcher
Alex Gordon-Weeks, Visitor, Clinical Lecturer
Jaehong Im, Senior Research Fellow
Keaton Jones, Clinical Research Training Fellow
Jakob Kaeppler, DPhil Student
Pavitra Kannan, Postdoctoral Researcher
Serena Lucotti, Postdoctoral Researcher
Ceren Yalaz, DPhil Student
Arseniy Yuzhalin, DPhil Student