High-resolution clonal mapping of multi-organ metastasis in triple negative breast cancer

Most triple negative breast cancers (TNBCs) are aggressively metastatic with a high degree of intratumoral heterogeneity. We employed patient-derived xenograft models established from the breast tumors of patients with treatment-naïve metastatic TNBC to study clonal dynamics during metastasis. Genomic sequencing coupled with high-complexity barcode-mediated clonal tracking revealed robust alterations in clonal architecture between primary tumors and corresponding metastases that were deterministic rather than stochastic. The presence of numerous rare subclones in each metastatic lesion demonstrated that polyclonal seeding occurred and that heterogeneous populations of low-abundance clones were maintained in metastases. An identical population of subclones was enriched in lung, liver, and brain metastases, demonstrating that primary tumor clones harbor properties enabling them to seed and thrive in multiple organ sites. Further, clones that dominated multi-organ metastases shared a genomic lineage. Thus, intrinsic properties of rare primary tumor subclones enable the seeding and colonization of metastases in multiple organ sites. A tumor from a breast cancer patient was engrafted into the mammary fat pad of NOD-SCID/gamma mice as a PDX model. At passage 3, the tumors were allowed to grow and metastasize to the lung. Samples were collected from the primary mammary gland as well as the lung metastases. The transcription profiles were generated, and the changes in the profiles from primary to metastatic tumors were compared. *** Raw data are not available due to patient privacy concerns. ***