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

Descrizione del progetto

Dinamiche delle cellule staminali tumorali nel carcinoma mammario BRCA2-deficiente

Le mutazioni germinali eterozigoti nei geni di suscettibilità al cancro del seno (BRCA) 1 o 2 predispongono al cancro al seno, alle ovaie, al pancreas e alla prostata. Negli ultimi anni sono state accumulate prove significative sulle vulnerabilità specifiche dei tumori BRCA1/2 deficienti che hanno portato allo sviluppo di terapie mirate, tra cui gli inibitori della poli (ADP-ribosio) polimerasi (PARP). Studi recenti suggeriscono che le cellule BRCA2-deficienti possono acquisire capacità metastatica e d’insorgenza dei tumori. Il progetto BRCAstem, finanziato dall’UE, intende studiare la relazione tra le cellule staminali tumorali e la risposta agli inibitori PARP e alle radiazioni ionizzanti nelle linee cellulari tumorali e negli xenotrapianti derivati da pazienti privi di BRCA2. Questo studio svelerà i meccanismi che guidano la plasticità cellulare in modelli di inattivazione del BRCA2 e valuterà l’impatto delle cellule staminali tumorali sulla risposta dei tumori con mutazioni di BRCA alle attuali terapie mirate.

Obiettivo

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.

Coordinatore

THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
Contribution nette de l'UE
€ 224 933,76
Indirizzo
WELLINGTON SQUARE UNIVERSITY OFFICES
OX1 2JD Oxford
Regno Unito

Mostra sulla mappa

Regione
South East (England) Berkshire, Buckinghamshire and Oxfordshire Oxfordshire
Tipo di attività
Higher or Secondary Education Establishments
Collegamenti
Costo totale
€ 224 933,76