Our tools: patient-derived xenografts (PDX) models of TNBC, tractable experimental models of minimally manipulated human tumor specimens
To unravel the biologies of resistance and metastasis, it is essential to use experimental model systems that capture the complex intra-tumor heterogeneity inherent to human TNBC. Our laboratory achieves this by using orthotopic PDX models in vivo (mice) and ex vivo (PDX tumor-derived organoid cultures). We use these PDX models as a primary discovery platform as well as experimental system. As diagrammed above, we have developed methodologies enabling us to readily manipulate PDX, making these a tractable and robust system with which to experimentally perturb human TNBC cells. These PDX studies are complemented by studies in human TNBC cell lines as well as immune-competent genetically engineered mouse models of breast cancer. A key aspect of our approach is evaluation of experimental findings in data derived directly from human TNBC biopsies.
PDX models of TNBC have been shown to recapitulate genomic and transcriptomic features of originating patient biopsies. Importantly, we have shown that these PDX models capture the complex drug treatment responses as well as metastatic phenotypes of patients’ tumors. Thus, we are leveraging these models to discover and mechanistically understand features of tumor cell subpopulations that functionally drive therapy resistance and metastasis.
Foundation projects that exemplify the capabilities of these models and form the basis for many of the future research projects in our laboratory are outlined below.