Gloria Echeverria Lab

Our goal: Tackling the molecular evolution of triple negative breast cancer therapy resistance and metastasis

Cancers are ecosystems of diverse tumor and stroma cell subpopulations each capable of having a variety of roles in tumor progression. While the existence of this complex intra-tumor heterogeneity has been thoroughly documented, its functional repercussions are not well understood. We investigate the genomic and metabolic evolution of triple negative breast cancers (TNBCs) as they resist therapies and metastasize to secondary organs. We leverage state-of-the-art technologies in clinically relevant experimental models of TNBC to discover impactful mechanisms. Our ultimate goal is to improve clinical outcomes of women living with TNBC.

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.

Investigating chemotherapy resistance in TNBC: Tumor cell plasticity, metabolic evolution, and tumor-stroma relationships

Using PDX models as a discovery platform, we elucidated mechanisms of chemoresistance in TNBC mediated by tumor cell plasticity rather than clonal selection (Echeverria et al., PMID: 30996079). Leveraging state-of-the-art barcode-mediated clonal tracking and genomic technologies, we discovered that residual tumors surviving chemotherapy treatment maintain extensive intra-tumor heterogeneity and adopt unique phenotypic features, some of which were found to functionally contribute to residual tumor cell survival. Namely, residual tumor cells adopt a unique metabolic profile enabling them to survive. These data provide a robust foundation with which to delineate the contributions of phenotypic and metabolic intra-tumor heterogeneity to therapy resistance in TNBC (detailed in ‘Projects’).

Evolution of multi-organ metastases in TNBC: Selection of genomic lineages & phenotypic plasticity

In relapsed TNBC patients, tumor cells have frequently spread to multiple different visceral organs. The origins and mechanisms driving multi-organ metastasis in TNBC remain unclear. By implementing cutting-edge in vivo monitoring of subclonal dynamics in PDX models, we discovered that an extremely low-abundance primary tumor subclone navigates the metastatic cascade and comprises the bulk of metastatic tumor cells in the three most common sites of human TNBC metastasis (Echeverria et al., PMID: 30498242). Future research will be aimed at identifying properties harbored within this metastatic subpopulation, allowing it to seed and outgrow in diverse metastatic microenvironments (detailed in ‘Projects’).