Barcoding reveals complex clonal behavior in patient-derived xenografts of metastatic triple negative breast cancer

D. Merino, T. S. Weber, A. Serrano, F. Vaillant, K. Liu, B. Pal, L. Di Stefano, J. Schreuder, D. Lin, Y. Chen, M. L. Asselin-Labat, T. N. Schumacher, D. Cameron, G. K. Smyth, A. T. Papenfuss, G. J. Lindeman, J. E. Visvader, S. H. Naik

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

Primary triple negative breast cancers (TNBC) are prone to dissemination but sub-clonal relationships between tumors and resulting metastases are poorly understood. Here we use cellular barcoding of two treatment-naïve TNBC patient-derived xenografts (PDXs) to track the spatio-temporal fate of thousands of barcoded clones in primary tumors, and their metastases. Tumor resection had a major impact on reducing clonal diversity in secondary sites, indicating that most disseminated tumor cells lacked the capacity to ‘seed’, hence originated from ‘shedders’ that did not persist. The few clones that continued to grow after resection i.e. ‘seeders’, did not correlate in frequency with their parental clones in primary tumors. Cisplatin treatment of one BRCA1-mutated PDX model to non-palpable levels had a surprisingly minor impact on clonal diversity in the relapsed tumor yet purged 50% of distal clones. Therefore, clonal features of shedding, seeding and drug resistance are important factors to consider for the design of therapeutic strategies.

Original languageEnglish (US)
Article number766
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Merino, D., Weber, T. S., Serrano, A., Vaillant, F., Liu, K., Pal, B., Di Stefano, L., Schreuder, J., Lin, D., Chen, Y., Asselin-Labat, M. L., Schumacher, T. N., Cameron, D., Smyth, G. K., Papenfuss, A. T., Lindeman, G. J., Visvader, J. E., & Naik, S. H. (2019). Barcoding reveals complex clonal behavior in patient-derived xenografts of metastatic triple negative breast cancer. Nature communications, 10(1), [766]. https://doi.org/10.1038/s41467-019-08595-2