Modelling triple negative breast cancer with stem cells-derived organoids for the development of targeted therapy

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The aim of this research project is to develop a novel in vitro stem cell model to study triple negative breast cancer (TNBC) initiation and progression. TNBC represents a real clinical challenge as this type of breast cancer is aggressive, it tends to affect young women and cannot be treated with current therapies. TNBC is highly metastatic and associated with poor clinical outcome and survival. Therefore, it is critical to dissect the molecular mechanisms responsible for the origin and progression of this breast cancer subtype in order to progress the discovery of novel biomarkers for early detection and effective treatment.This project addressed this unmet clinical need by focusing on modelling TNBC to study how oncogenic mutations can drive the development of TNBC and how they cooperate to instruct the tumour microenvironment to allow metastatic spread. To this end, we will create a complex in vitro model by reprogramming normal breast cells harbouring genetic mutations found in primary and metastatic TNBC into induced pluripotent stem cells (iPSCs) followed by directed differentiation into 3D mammary organoids. These TBNBC organoids will resemble mutated tumours in vivo and uniquely allow a genetically-defined modelling of early stages of the disease, that is not accessible using patient-derived tumours, as well as standardized analysis of the effect of specific mutations in tumour evolution. By combining the epigenetic reprogramming strategy with the introduction of specific mutations, the model is an ideal platform to study the developmental contexts that are required for tumorigenesis induced by specific mutations during differentiation. Our vision is also to address 3Rs concerns together with unmet clinical needs in cancer research by leading the field of cancer iPSC and delivering an animal-free isogenic platform for breast cancer modelling which will be instrumental for the discovery of cancer biomarkers for the development of novel targeted therapies.