TY - JOUR
T1 - High-resolution clonal mapping of multi-organ metastasis in triple negative breast cancer
AU - Echeverria, Gloria V.
AU - Powell, Emily
AU - Seth, Sahil
AU - Ge, Zhongqi
AU - Carugo, Alessandro
AU - Bristow, Christopher
AU - Peoples, Michael
AU - Robinson, Frederick
AU - Qiu, Huan
AU - Shao, Jiansu
AU - Jeter-Jones, Sabrina L.
AU - Zhang, Xiaomei
AU - Ramamoorthy, Vandhana
AU - Cai, Shirong
AU - Wu, Wenhui
AU - Draetta, Giulio
AU - Moulder, Stacy L.
AU - Symmans, William F.
AU - Chang, Jeffrey T.
AU - Heffernan, Timothy P.
AU - Piwnica-Worms, Helen
N1 - Publisher Copyright:
© 2018, The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - Most triple negative breast cancers (TNBCs) are aggressively metastatic with a high degree of intra-tumoral heterogeneity (ITH), but how ITH contributes to metastasis is unclear. Here, clonal dynamics during metastasis were studied in vivo using two patient-derived xenograft (PDX) models established from the treatment-naive primary breast tumors of TNBC patients diagnosed with synchronous metastasis. Genomic sequencing and high-complexity barcode-mediated clonal tracking reveal robust alterations in clonal architecture between primary tumors and corresponding metastases. Polyclonal seeding and maintenance of heterogeneous populations of low-abundance subclones is observed in each metastasis. However, lung, liver, and brain metastases are enriched for an identical population of high-abundance subclones, demonstrating that primary tumor clones harbor properties enabling them to seed and thrive in multiple organ sites. Further, clones that dominate multi-organ metastases share a genomic lineage. Thus, intrinsic properties of rare primary tumor subclones enable the seeding and colonization of metastases in secondary organs in these models.
AB - Most triple negative breast cancers (TNBCs) are aggressively metastatic with a high degree of intra-tumoral heterogeneity (ITH), but how ITH contributes to metastasis is unclear. Here, clonal dynamics during metastasis were studied in vivo using two patient-derived xenograft (PDX) models established from the treatment-naive primary breast tumors of TNBC patients diagnosed with synchronous metastasis. Genomic sequencing and high-complexity barcode-mediated clonal tracking reveal robust alterations in clonal architecture between primary tumors and corresponding metastases. Polyclonal seeding and maintenance of heterogeneous populations of low-abundance subclones is observed in each metastasis. However, lung, liver, and brain metastases are enriched for an identical population of high-abundance subclones, demonstrating that primary tumor clones harbor properties enabling them to seed and thrive in multiple organ sites. Further, clones that dominate multi-organ metastases share a genomic lineage. Thus, intrinsic properties of rare primary tumor subclones enable the seeding and colonization of metastases in secondary organs in these models.
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U2 - 10.1038/s41467-018-07406-4
DO - 10.1038/s41467-018-07406-4
M3 - Article
C2 - 30498242
AN - SCOPUS:85057522111
SN - 2041-1723
VL - 9
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 5079
ER -