Breast cancer is a vast and heterogeneous disease, classified into subtypes based on the expression of ER, PR, and HER2 receptors. Triple negative breast cancer (TNBC), lacking ER, PR and HER2 expression, remains the subtype the most difficult to treat where intra-tumour heterogeneity is thought to be responsible for treatment resistance. Therefore, the study of heterogeneity is of great interest for the optimisation of novel combinational therapies.
Recent studies using single cell “-omics” experiments in patient samples or patient derived xenografts (PDXs) have shown that both primary tumours and metastases are heterogeneous. In order to better understand the spatio-temporal evolution of malignant clones in vivo, we are using barcoded PDXs in which tumour cells are labelled with genetic tags (or barcodes). In brief, cancer cells from early passage PDXs are infected with lentiviruses containing unique DNA barcodes. As the barcodes are stably integrated into the genome of the cells, they are transmitted to their progenies, allowing to track clonal expansion over time. After infection, barcoded cells are transplanted into the mammary fat pad of immunodeficient mice, and the barcoding repertoire of primary tumours and metastases can be analysed by sequencing.
Our previous results indicated that when primary tumours were dissected into pieces, each piece contained a unique barcode repertoire, underlying the spatial heterogeneity present in primary tumours (Merino, Weber et al., Nat Comm 2019). Interestingly, our recent results suggest that the cellular features associated with tumour growth and migration are not random, and we are currently investigating the molecular mechanisms associated with these features.
In this work, genetic barcoding has been elegantly combined with breast cancer patient-derived xenograft to decipher tumour heterogeneity at a cellular level, highlighting the evolution of a complex clonal landscape during tumour growth and metastatic progression.