Mutations in the breast cancer susceptibility genes (BRCA) 1 and 2 lead to an increased susceptibility to breast, ovarian, and other types of cancers. In recent years, PARP inhibitors rapidly transformed the treatment of such cancers. As an anti-cancer drug, these inhibitors stop the Poly-ADP Ribose Polymerase (PARP) protein from doing its repair work in cancer cells, leading to cell death. Normally, the BRCA1 and BRCA2 genes play an important role in cell repair (through a process called homologous repair, HR) so that cells are less likely to undergo successful DNA repair if there is a fault in one or both of these genes. In other terms, BRCA1/2-deficient cancer cells already have a compromised DNA repair system, therefore blocking PARP leads to the accumulation of DNA lesions and ultimately to the cancer cells’ death. However, it has been reported that tumours develop resistance to PARP inhibitors, which often entails the emergence of mutations that trigger rewiring of the damage response pathways within the tumour, so that cell death responses to treatment are replaced by cancer cell survival and metastasis. It has also been suggested that resistance can be linked to the propagation of rare, stem-like cells (also known as cancer-initiating or cancer stem cells), responsible for the sustained and uncontrolled growth of malignant tumours and proposed to play significant roles in metastasis and cancer recurrence in DNA repair-deficiency contexts.
In the current project, we propose to study the relationship between the propagation of stem-like cancer cells and the response to PARP in cancer cell lines and tumours models lacking BRCA1/2. The proposed project is based on a combination of interdisciplinary experimental and analytical strategies, at the interface between Molecular Biology (experimental setup and validation), Computational Biology (custom designed analytical tools) and Molecular Medicine (biomarker identification, treatment benchmarking and evaluation). Indeed, our goal is to understand the molecular mechanisms driving the emergence and dynamics of stem-like cells in models of BRCA2 inactivation, but also to evaluate the stem-like cell subpopulations’ impact on the response of BRCA-mutated tumours to current targeting therapies. Our novel approach combining histology information and gene expression analysis will allow to understand both which cell subpopulations are present (before and after treatments) as well as the physical interactions between them, bringing the analysis of intra-tumour heterogeneity to an unprecedented resolution level. Importantly, this work will help design novel biomarkers to stratify patients likely to respond to therapy and thus propose personalized treatment strategies. A gene expression signature indicative of specific cell dynamics within HR-defective tumours may provide new molecular targets for prognosis and treatment, allowing to predict and monitor therapeutic responses in BRCA1/2-deficient breast tumours. Thus, the proposed project is highly translational, directly aiming at improving therapy outcomes for patients with BRCA1/2 and other HR mutations.
