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.
Highlights
Breast cancer mortality is caused by metastasis; a complex process involving dissemination, deposition, and growth of tumor cells at distant sites[6,7]
Open questions included: what fraction of clones can disseminate; how reflective are these of the primary tumor; which clones contribute to metastatic disease in different organs; and what is the consequence of therapy to clonal diversity? To this end we utilized breast patient-derived xenografts (PDXs), which largely retain the original patient tumor heterogeneity and exhibit reproducible kinetics during secondary xenografting[13,14,15,20,21]
All three tumors were transplanted and gave rise to primary tumors and metastases (Supplementary Table 1 and Supplementary Figure 1A and B) and were intermediate in their growth kinetics amongst our PDX bank and comparable to those reported by others[23]
Summary
Breast cancer mortality is caused by metastasis; a complex process involving dissemination, deposition, and growth of tumor cells at distant sites[6,7]. To this end we utilized breast PDXs, which largely retain the original patient tumor heterogeneity and exhibit reproducible kinetics during secondary xenografting[13,14,15,20,21]. Open questions included: what fraction of clones can disseminate; how reflective are these of the primary tumor; which clones contribute to metastatic disease in different organs; and what is the consequence of therapy to clonal diversity? These models enable studies on the behavior of human ‘drug-naïve’ tumors in a physiological and therapeutic context, in contrast to specimen analysis at autopsy, and are considered ‘pseudo-primary’ tumor models. Our findings provide insights into the spatio-temporal diversity of clones in metastatic disease, and in response to therapy, with implications for the diagnosis, monitoring, and treatment of patients
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