Abstract
Most triple negative breast cancers (TNBCs) are aggressively metastatic with a high degree of intra-tumoral heterogeneity (ITH), but how ITH contributes to metastasis is unclear. Here, clonal dynamics during metastasis were studied in vivo using two patient-derived xenograft (PDX) models established from the treatment-naive primary breast tumors of TNBC patients diagnosed with synchronous metastasis. Genomic sequencing and high-complexity barcode-mediated clonal tracking reveal robust alterations in clonal architecture between primary tumors and corresponding metastases. Polyclonal seeding and maintenance of heterogeneous populations of low-abundance subclones is observed in each metastasis. However, lung, liver, and brain metastases are enriched for an identical population of high-abundance subclones, demonstrating that primary tumor clones harbor properties enabling them to seed and thrive in multiple organ sites. Further, clones that dominate multi-organ metastases share a genomic lineage. Thus, intrinsic properties of rare primary tumor subclones enable the seeding and colonization of metastases in secondary organs in these models.
Highlights
Most triple negative breast cancers (TNBCs) are aggressively metastatic with a high degree of intra-tumoral heterogeneity (ITH), but how ITH contributes to metastasis is unclear
Tumor cells from the breast of a patient with treatmentnaive TNBC, with synchronous metastasis detected at the time of diagnosis, were isolated by fine needle aspiration (FNA) and were engrafted into the pre-humanized mammary fat pads (MFPs) of NOD/SCID mice to generate the patient-derived xenograft (PDX) model Patient-In-Mouse (PIM)001-P (Fig. 1a)
Genomic sequencing studies have been performed on metastases isolated from patients who received therapy prior to metastatic sampling and are not directly comparable to our study
Summary
Most triple negative breast cancers (TNBCs) are aggressively metastatic with a high degree of intra-tumoral heterogeneity (ITH), but how ITH contributes to metastasis is unclear. A high-complexity library of 50 million unique barcodes was employed to simultaneously label and track the fates of individual tumor cells in vivo in two independent PDX models of treatment-naive TNBC. This high-resolution approach, combined with whole-exome sequencing (WES) and targeted deep sequencing, affords the opportunity to characterize the clonal architecture of primary tumors and their matched metastases in multiple organs. Genomic sequencing reveals reproducible enrichment of a shared set of mutations in lung, liver, and brain metastases and identifies candidate mutational drivers of metastasis These data highlight the limitations of bulk primary tumor profiling to capture the biological properties of subclones that contribute to metastatic lesions
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