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 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.

Comprehensive epigenetic analyses reveal master regulators driving lung metastasis of breast cancer

“…Despite the improvement made by chemotherapy, radiotherapy and targeted therapy in recent years, the treatment outcome remain unsatisfactory for breast cancer with distant metastasis. Notably, triple negative breast cancer (TNBC), characterized by high malignant degree, high incidence of metastasis and poor prognosis, has no effective treatment currently because of an absence of therapeutic targets . Therefore, understanding the transcription regulatory programs of TNBC distant metastasis holds important implications for the identification of novel therapy and prognosis targets.…”

Morphologic and Genomic Heterogeneity in the Evolution and Progression of Breast Cancer

“…The genomic analysis of matched primary and metastatic samples has revealed fascinating insight regarding the evolution of metastatic disease [73,75,[82][83][84]86,90,[98][99][100]. Such efforts reveal, for example, that driver mutations that are enriched in metastasis are indeed rarely found in the matched primary tumour, indicating they arose either in a small subclone not sampled when the primary tumour was sequenced, or they occurred during the metastatic process after cells had disseminated from the breast (i.e., treatment induced mutations) [39,73,79,80,82,101].…”

DNA barcode-guided lentiviral CRISPRa tool to trace and isolate individual clonal lineages in heterogeneous cancer cell populations

“…Cancer consists of multiple genetically related, distinct subclones 1 that evolve in parallel and display heterogeneity at genomic 2,3 , epigenetic [4][5][6][7] , or phenotypic level [8][9][10] . As malignancy progresses, particular subclonal populations of cancer cells develop differing aggressive phenotypes, such as faster proliferation, metastatic potential 11,12 , or drug resistance 13,14 . To understand which molecular features promote an aggressive phenotype in particular subclones, and hence, further the tumor progression, elucidating the biology of individual cell lineages would be particularly insightful.…”

“…DNA barcoding (tagging of individual cells with unique DNA sequences) enables highthroughput tracking of individual clonal lineages by next-generation sequencing (NGS). The barcoding approach accurately and quantitatively determines the lineages that get enriched or depleted following tumor initiation 15,16 , drug resistance 13,[17][18][19] , metastatic spread 11,12,20 , or another type of phenotype selection. Moreover, current developments allow for the use of DNA barcoding to link multiple phenotypes to a lineage 21 , or even to couple lineage tracing with single-cell transcriptomics 22 .…”