Tumour associated macrophages in breast cancer: New targets for therapy

Breast cancer is the most frequent cancer in women with 1 in 8 getting this disease in their lifetime. Outcomes for this disease have improved dramatically over the last ten years due to early detection and neo-adjuvant therapy. Unfortunately however, for women with metastatic disease survival has not changed significantly for 30-years and this aspect of disease accounts for 95% of breast cancer deaths. This means that current therapies including biologics are inadequate.

Cancers consist not only of malignant epithelial cells but also a plethora of normal diploid cells including resident ones for example adipocytes in breast cancer, and a wide range of innate and adaptive immune cells [1]. Among these immune cells macrophages are the most abundant. Clinical data has correlated an increased density of tumour-associated macrophages (TAMs) with markers of poor prognosis in a wide-range of cancers. Studies from my lab and others have shown that macrophages promote tumour progression to malignancy by accelerating progression from benign tumours to invasive adenocarcinomas and enhancing metastasis [2,3]. Our studies and others have shown that TAMs promote many steps in tumour progression including angiogenesis, cancer cell invasion and intravasation [4-7]. TAMs also limit the efficacy of various forms of anti-cancer therapies including chemo- and radio-therapy [8]. Recently evidence has accumulated that TAMs are immunosuppressive as their depletion can result in activation of T cells for example in the response to chemotherapy, or after their repolarization to an activated state that also enhanced T cell activity [9]. These cells therefore play important roles in enhancing the tumour’s malignant phenotype.

The majority of these studies have been performed in primary tumour models. Given the poor outcome for patients my lab has recently focused on metastatic breast cancer to the lung. We have shown recruitment at the metastatic site of metastasis-associated-macrophages (MAMs) that promote tumour-cell extravasation and subsequent survival and growth. We demonstrated that these MAMs are recruited from circulating monocytes by tumour-derived CCL2 acting via its receptor CCR2 expressed on these monocytes [10]. This recruitment results in a chemokine cascade that through CCL3 signalling to CCR1 results in the delivery of a a survival signal to the tumour cells and thus enhances their successful extravasation and subsequent metastatic growth [11]. These recruited monocytes suppress T cytotoxicity. MAMs in turn upregulate FLK1 (VEGFR1) that in response to VEGFA signals to an inflammatory gene expression programme centered on CSF1 [12]. Importantly, we have recently shown that IL4 is a master regulator of these activities. Genetic ablation of any of these pathways dramatically inhibits metastatic seeding and persistent growth.

All these studies have been performed in mouse models. Recently we have extended them to humans identifying the transcriptomes of cancer monocytes and breast cancer TAMs. We have also developed unique methods to study human macrophages and assays in which to interrogate their function. These methods give us unique insights into human cancer biology. In this project the student will use these in vitro methods to establish assays for macrophage regulated immunosuppression, angiogenesis and invasion and identify signaling pathways responsible for the macrophage activities.

The Little France Campus – interdisciplinary research
The MRC Centre for Reproductive Health (CRH) is located on the ground floor of the Queen’s Medical Research Institute on the University of Edinburgh’s Medical Campus at Little France in Edinburgh. The MRC CRH enjoys close collaborative links with the other Centres on the Little France Campus including the MRC Centre for Inflammation Research (MRC CIR); the British Heart Foundation Centre of Excellence in Cardiovascular Science (BHF CVS), the Clinical Research Imaging Centre (CRIC) and the MRC Centre for Regenerative Medicine (CRM). The campus has a large thriving postgraduate community.

www.ed.ac.uk/centre-reproductive-health

How to Apply
Please submit:
• a curriculum vitae
• a ’statement of purpose’ - outlining your reasons for undertaking this programme of study and how you see it affecting your career plan
• arrange for references to be sent by 2 academic referees from their professional email accounts by application deadline using the format available to download from the link below
www.dropbox.com/s/8obexb7grnfdsqx/CRH%20Reference%20form.docx?dl=0.

The closing date to apply for these studentships is Thursday 18 January 2018. Interviews will be held in Edinburgh on 6 February 2018.
Applications should be sent to [Email Address Removed]. Due to annual leave over the festive period, correspondence will be delayed until after 8 January 2018.