Breast tumors consist of various sub-populations of cells or clones, each exhibiting distinct cellular and molecular features. Certain cancer clones can be more 'aggressive' than others within specific tumor microenvironments (TMEs), leading to metastatic progression and resistance to treatment. Identifying the particular genes and pathways that are disrupted in these aggressive cancer cells is crucial for designing novel and targeted treatment approaches.
To accomplish this, we optimised the use of a lentiviral-based barcoding technique (Berthelet, J., et.al., Sci Adv 2021, Serrano, A., et.al., Nat Rev Cancer 2022) where cancer cells from cell lines and patient-derived xenografts are tagged with optical barcodes and transplanted into the mammary fat pads of immunodeficient mice. Upon resection of tumours and collection of metastatic organs at the experimental endpoint, we analysed clonal fate and fitness using flow cytometry and imaging. The subsequent molecular characterisation of individual clones was determined by bulk and single-cell RNA sequencing. We also leverage the use of these barcoded models to investigate the mechanisms of innate and acquired resistance to Sacituzumab Govitecan (SG), a drug recently approved for the treatment of patients with advanced breast cancer.
Our studies revealed unique gene signatures and pathways associated with preferential organ tropism (in the lungs, liver and brain TMEs) and SG resistance. This comprehensive analysis, being currently validated using autopsy samples and patient databases, will support the design of new predictive markers and targeted therapies for metastatic breast cancer.