Editors' ChoiceCancer

The attack of the “seeding” clones

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Science Translational Medicine  13 Mar 2019:
Vol. 11, Issue 483, eaax0872
DOI: 10.1126/scitranslmed.aax0872

Abstract

Tumor clone tracking in breast cancer xenografts identifies a small subset of circulating tumor cells as “seeders” associated with metastasis.

Understanding how cancer cells metastasize is a major scientific challenge for clinical oncology. In the past, tumor heterogeneity at different molecular levels and cancer evolution over time complicated clonal studies trying to identify which cells escape the primary tumor, disseminate, and cause metastasis.

To address this question, Merino and colleagues used a sophisticated barcoding system to precisely track clones and their spatiotemporal diversity throughout triple negative breast cancer (TNBC) progression. They used cells isolated from TNBC patient–derived xenografts (PDXs) that underwent cellular barcoding and were then transplanted into mammary fat pads of immunocompromised mice. With this system, the authors could follow the clonal evolution at the primary site, at early and late metastases to the lungs after resection, and even at the relapse stage. Analyzing the clones’ composition and abundance in each lesion, they could define several attributes: growing in primary tumors; “shedding” into circulation, “seeding” distal organs, and contribution to relapse after chemotherapy.

Although TNBC PDXs presented different biological characteristics, this work describes important findings. Primary tumors retained their barcoded clones during growth. Moreover, the spatial clonal distribution and mosaicism observed in the analyzed tumors provide evidence that routinely obtained biopsies may undervalue heterogeneity. The authors found that circulating tumor cells are representative of primary tumor biomass and mostly present with shedding but not seeding characteristics, suggesting that they are poor predictors of metastasis. In fact, only very few clones (<10%) had multiorgan seeding capacity, which was not correlated with their proportion in the primary tumor. Cisplatin treatment of a BRCA1-mutated TNBC PDX resulted in tumor remission, but most barcoded clones (~80%) survived, hence preserving heterogeneity and allowing relapse.

This study makes essential biological observations by analyzing barcoded clones’ evolution to understand how metastases arise but because the study used immunocompromised mice, these observations must be validated in patients. In addition, further analyses will be needed to distinguish between shedders and seeders to design effective and durable treatments for TNBC and other cancers.

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