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High-resolution clonal mapping of multi-organ metastasis in triple negative breast cancer

ABSTRACT: Most triple negative breast cancers (TNBCs) are aggressively metastatic with a high degree of intratumoral heterogeneity. We employed patient-derived xenograft models established from the breast tumors of patients with treatment-naïve metastatic TNBC to study clonal dynamics during metastasis. Genomic sequencing coupled with high-complexity barcode-mediated clonal tracking revealed robust alterations in clonal architecture between primary tumors and corresponding metastases that were deterministic rather than stochastic. The presence of numerous rare subclones in each metastatic lesion demonstrated that polyclonal seeding occurred and that heterogeneous populations of low-abundance clones were maintained in metastases. An identical population of subclones was enriched in lung, liver, and brain metastases, demonstrating that primary tumor clones harbor properties enabling them to seed and thrive in multiple organ sites. Further, clones that dominated multi-organ metastases shared a genomic lineage. Thus, intrinsic properties of rare primary tumor subclones enable the seeding and colonization of metastases in multiple organ sites.

ORGANISM(S): Homo sapiens

PROVIDER: GSE120753 | GEO | 2018/12/11

REPOSITORIES: GEO

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Project description:Following the removal of implanted mammary tumors, nude mice develop multiple-organ metastases at late stage. The metastases may originate from the primary tumors before the resection surgery, or alternatively, from some established metastases. By multiple approaches, we have proved that bone environment could invigorate cancer cells for further dissemination. this study aims to examine if metastatic dissemination from bone to other sites occurs in natural setting of metastatic spread. We herein apply the rapidly evolving barcode system using homing guide RNA/Cas9 to trace the metastases formation in mouse. hgRNA/Cas9 is a self-targeting Crispr system which allows the mutation occurs in the DNA sequence of guide RNA. Tumor cells wer labelled with doxycycline inducible evolving barcoding system. Upon doxycycline treatment the DNA sequence of hgRNA accumulate mutations with time. The diversity of barcodes in each lesion can infer the timeing of seeding while the mutation patterns of barcodes suggest the phylogenetic correlation of metastases. Several findings were made on this study. First, at the terminal stage, multi-organ metastases are not genetically grouped according to sites of metastases. Nonnegative Matrix Factorization (NMF) analysis of mutant barcodes suggested the early disseminated metastases, which have highest level of Shannon entropy, were featured with a common cluster of mutant barcodes irrespective of their locations. Second, most metastases are potentially multiclonal as indicated by multiple clusters of independent mutant barcodes. Third, when we use Shannon entropy as an index of metastasis age , putative parent-child relationship between metastases with unique mutant barcodes clearly exemplified secondary metastatic seeding from bone to other organs. Finally, we did not observe a clear correlation between tumor burden and Shannon entropy across different metastases, suggesting that putative parental metastases might remain small after seeding further metastases.

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High-resolution clonal mapping of multi-organ metastasis in triple negative breast cancer

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