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

2019-02-15

Merino, Delphine

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

Journal Article

0000-0002-8075-6275

0000-0003-3836-3299

0000-0003-3229-3760

0000-0001-6187-819X

0000-0002-3684-4331

0000-0001-8366-9882

0000-0002-7579-0006

0000-0002-7872-6931

0000-0003-4911-5653

0000-0001-7082-6076

0000-0003-0517-8804

0000-0002-0951-7116

0000-0001-9221-2892

0000-0002-1102-8506

0000-0001-9386-2416

0000-0001-9173-6977

0000-0003-0299-3301

10.1038/s41467-019-08595-2

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.

link

Nature Communications 2019; 10(1): 766

Nature Communications