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Monitoring cancer stem cell dynamics and therapeutic response in BRCA2-deficient breast tumour cells

Project description

Cancer stem cell dynamics in BRCA2-deficient breast cancer

Heterozygous germline mutations in the breast cancer susceptibility genes (BRCA) 1 or 2 predispose to breast, ovarian, pancreatic and prostate cancers. Significant evidence has accumulated in recent years on vulnerabilities specific to BRCA1/2-deficient tumours leading to the development of targeted therapies including poly(ADP-ribose) polymerase (PARP) inhibitors. Recent studies suggest that BRCA2-deficient cells can acquire metastatic and tumour-initiating capacity. The EU-funded BRCAstem project intends to study the relationship between cancer stem cells (CSCs) and the response to PARP inhibitors and ionising radiation in cancer cell lines and patient-derived xenografts lacking BRCA2. This study will uncover the mechanisms driving cell plasticity in models of BRCA2 inactivation and evaluate CSC impact on the response of BRCA-mutated tumours to current targeted therapies.

Objective

Heterozygous germ line mutations in the breast cancer susceptibility genes (BRCA) 1 or 2 predispose carriers to breast, ovarian, pancreatic and prostate cancers. Significant evidence has accumulated in recent years on vulnerabilities specific to BRCA1/2-deficient tumours, leading to the development of personalized therapies, such as poly-ADP ribose polymerase (PARP) inhibitors. However, tumours develop resistance to these therapies, with tumour heterogeneity and enrichment in cancer stem cell (CSC) sub-population as an underlying resistance mechanism. How the genomic instability intrinsic to BRCA1/2 inactivation impacts on CSC survival and propagation during tumorigenesis and their relevance to the response to therapy has not yet been established. Previous results obtained in the host laboratory show that BRCA2 loss is associated, in the long term (28 days after BRCA2 abrogation), with upregulation of genes involved in metastasis and CSC markers, suggesting BRCA2-deficient cells can acquire metastatic and tumour-initiating capacity. In the current project proposal, we intend to study at single-cell resolution the relationship between CSCs and the response to PARP inhibitors and ionizing radiation (IR) in cancer cell lines and patient-derived xenografts (PDXs) lacking BRCA2 . We will develop a combined single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) experimental approach to characterize BRCA2-deficient CSC subpopulations and to monitor the spatio-temporal dynamics of the CSC signature. This will enable us not only to understand the molecular mechanisms driving cell plasticity in models of BRCA2 inactivation, but also to evaluate the CSC impact on the response of BRCA-mutated tumours to current targeting therapies.

Coordinator

THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
Net EU contribution
€ 224 933,76
Address
WELLINGTON SQUARE UNIVERSITY OFFICES
OX1 2JD Oxford
United Kingdom

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Region
South East (England) Berkshire, Buckinghamshire and Oxfordshire Oxfordshire
Activity type
Higher or Secondary Education Establishments
Links
Total cost
€ 224 933,76