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Nat Commun. 2019 Feb 15;10(1):766. doi: 10.1038/s41467-019-08595-2.

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

Merino D1,2,3,4, Weber TS5,6, Serrano A7,5,8, Vaillant F7,5, Liu K7,5, Pal B7,5, Di Stefano L9, Schreuder J5,6,10, Lin D5,6,10, Chen Y5,9, Asselin-Labat ML7,5, Schumacher TN11, Cameron D9, Smyth GK9,12, Papenfuss AT5,9,12,13,14, Lindeman GJ7,15,16,17, Visvader JE18,19, Naik SH20,21,22.

Author information

1
ACRF Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia. delphine.merino@onjcri.org.au.
2
Department of Medical Biology, The University of Melbourne, Melbourne, VIC, 3010, Australia. delphine.merino@onjcri.org.au.
3
Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, 3084, Australia. delphine.merino@onjcri.org.au.
4
School of Cancer Medicine, La Trobe University, Bundoora, VIC, 3086, Australia. delphine.merino@onjcri.org.au.
5
Department of Medical Biology, The University of Melbourne, Melbourne, VIC, 3010, Australia.
6
Molecular Medicine Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.
7
ACRF Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.
8
Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, 3084, Australia.
9
Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.
10
Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.
11
Division of Molecular Oncology & Immunology, Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands.
12
School of Mathematics and Statistics, The University of Melbourne, Melbourne, VIC, 3010, Australia.
13
Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia.
14
Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, 3010, Australia.
15
Department of Medical Oncology, The Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia.
16
Department of Medicine, The University of Melbourne, Melbourne, VIC, 3010, Australia.
17
Parkville Familial Cancer Centre, The Royal Melbourne Hospital and Peter MacCallum Cancer Centre, Parkville, VIC, 3050, Australia.
18
ACRF Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia. visvader@wehi.edu.au.
19
Department of Medical Biology, The University of Melbourne, Melbourne, VIC, 3010, Australia. visvader@wehi.edu.au.
20
Department of Medical Biology, The University of Melbourne, Melbourne, VIC, 3010, Australia. naik.s@wehi.edu.au.
21
Molecular Medicine Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia. naik.s@wehi.edu.au.
22
Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia. naik.s@wehi.edu.au.

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.

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