The identification of a TNBC liver metastasis gene signature by sequential CTC‐xenograft modeling

Autor: Wei Yin, Debasish Boral, Monika Vishnoi, Dario Marchetti, Antonio Scamardo, David S. Hong, Nikki Haowen Liu
Jazyk: angličtina
Rok vydání: 2019
Předmět:
0301 basic medicine
Cancer Research
Triple Negative Breast Neoplasms
bone marrow‐resident tumor cells
Metastasis
Transcriptome
Mice
0302 clinical medicine
Circulating tumor cell
CTC‐derived xenografts
Mice
Inbred NOD
Neoplasm Metastasis
Triple-negative breast cancer
Research Articles
medicine.diagnostic_test
Liver Neoplasms
General Medicine
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Neoplastic Cells
Circulating
Metastasis Gene
3. Good health
Neoplasm Proteins
Gene Expression Regulation
Neoplastic
Oncology
030220 oncology & carcinogenesis
Molecular Medicine
Heterografts
Female
Research Article
Biology
circulating tumor cells
lcsh:RC254-282
Flow cytometry
03 medical and health sciences
Breast cancer
Cell Line
Tumor
Genetics
medicine
Biomarkers
Tumor
Animals
Humans
Genomics/transcriptomic analyses of CDX‐derived CTC populations
Liquid biopsy
medicine.disease
liver metastasis
030104 developmental biology
triple‐negative breast cancer
Cancer research
Neoplasm Transplantation
Zdroj: Molecular Oncology
Molecular Oncology, Vol 13, Iss 9, Pp 1913-1926 (2019)
ISSN: 1878-0261
1574-7891
Popis: Triple‐negative breast cancer (TNBC) liver metastasis is associated with poor prognosis and low patient survival. It occurs when tumor cells disseminate from primary tumors, circulate in blood/lymph [circulating tumor cells (CTCs)], and acquire distinct characteristics during disease progression toward the metastatic phenotype. The purpose of this study was to decipher the genomic/transcriptomic properties of TNBC liver metastasis and its recurrence for potential therapeutic targeting. We employed a negative depletion strategy to isolate and interrogate CTCs from the blood of patients with TNBC, and to establish sequential generations of CTC‐derived xenografts (CDXs) through injection of patient CTCs in immunodeficient mice. The isolation and validation of CDX‐derived cell populations [analyses of CTCs were paired with bone marrow‐resident cells (BMRTCs) and liver tissue cells obtained from the same animal] were performed by multiparametric flow cytometry, immune phenotyping, and genomic sequencing of putative CTCs. Comprehensive characterization of gene expression arrays from sequentially generated CDX‐derived cell populations, online gene expression arrays, and TCGA databases were employed to discover a CTC‐driven, liver metastasis‐associated TNBC signature. We discovered a distinct transcriptomic signature of TNBC patient‐isolated CTCs from primary TNBCs, which was consistent throughout sequential CDX modeling. We established a novel TNBC liver metastasis‐specific CDX model that selectively recapitulates CTC biology for four sequential generations of mice. The evaluation of online databases and CDX‐derived populations revealed 597 genes specific to the TNBC liver metastasis signatures. Further investigation of the TNBC liver metastasis signature predicted 16 hub genes, 6 biomarkers with clinically available drugs, and 22 survival genes. The sequential interrogation of CDX‐CTCs is an innovative liquid biopsy‐based approach for the discovery of organ metastasis‐specific signatures of CTCs. This represents the first step for mechanistic and analytical validation in their application as prognostic indicators and therapeutic targets. Targeting CTC drug candidate biomarkers along with combination therapy can improve the clinical outcome of TNBC patients in general and recurrence of liver metastasis in particular.
Databáze: OpenAIRE
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