(MRC DTP) The role of the lung microenvironment in regulating metastatic colonisation by breast cancer

The metastatic spread of breast cancer cells and their colonisation of important organs such as the lungs is the cause of death in 95% of breast cancer. Symptomatic lung metastases are also associated with poorer quality of life (increased morbidity) in breast cancer patients. We recently studied the bone metastatic microenvironment (Eyre et al., Nature Communications, in press, see above) and discovered cytokines and other secreted factors determine the interactions between metastatic breast cancer cells and the bone microenvironment. These factors are very important for the colonisation and tumour outgrowth at the metastatic site. In the current proposed project, we intend to apply the same paradigm to the lung microenvironment using the following objectives:

1. To determine and quantitate important factors secreted by the lung microenvironment that stimulate breast cancer colony-forming activity.
2. To use human breast cancer patient-derived xenograft (PDX) tumour models in immune-deficient mice to determine if the same factors are important in vivo and to quantify their expression.
3. To test inhibitors of, and/or genetically delete these pathways in PDX models to prevent lung metastases.

Briefly, we will establish cultures of lung epithelial cells and whole tissues from which the secreted factors will be extracted and tested on patient-derived breast cancer cells to determine whether they stimulate stem cell activity using the mammosphere colony assay established in our lab (Shaw et al., JMGBN, 2012). The secreted factors will be identified using cytokine arrays and RNAseq, as previously established for bone metastases, and the candidates will be tested individually and in combination for their stimulatory activity. The importance of these signalling pathways, in vivo, will be corroborated using PDX tumours established in our lab to undergo spontaneous lung metastasis (Eyre et al., JMGBN, 2016; Byrne et al., Nature Reviews Cancer, 2017). We will upregulate (gene overexpression) or delete (shRNA/CRISPR) genes in relevant pathways to discover their effect on the lung metastatic process in the in vivo microenvironment. Finally, we will use available small molecule or biological (antibody) inhibitor drugs to test preclinically for their efficacy in preventing secondary breast cancer in the lungs.

The outcome will be the discovery of new important pathways involved in lung metastasis of breast cancer by using human tissue and tumours. These pathways may be targetable by existing drugs or novel drugs in development and be translatable to the clinic, via clinical drug development, to improve the therapeutic options for breast cancer patients at risk of secondary breast cancer.

https://www.research.manchester.ac.uk/portal/en/researchers/robert-clarke(f73e5839-de76-4e2a-b2fb-f93ab86553be).html

Entry Requirements:
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.