Molecular characterization of breast cancer CTCs associated with brain metastasis

Boral, Debasish; Vishnoi, Monika; Liu, Haowen N.; Yin, Wei; Sprouse, Marc L.; Scamardo, Antonio; Hong, David S.; Tan, Tuan Zea; Thiery, Jean Paul; Chang, Jenny C.; Marchetti, Dario

doi:10.1038/s41467-017-00196-1

Cited by 172 publications

(214 citation statements)

References 64 publications

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“…EpCAM-negative breast cancer CTCs containing stem-cell properties (CD44 +/CD24−) have been isolated by multiparametric flow cytometry from blood of breast cancer patients. These cells possessed high competence to generate breast cancer brain metastasis in xenografts [138,139]. Incidentally, breast cancer is the second most common cancer to metastasize to the brain and the prognosis of patient diagnosed with brain metastasis remains poor [140].…”

Section: Methods To Isolate and Identify Ctcmentioning

confidence: 99%

Liquid biopsy - emergence of a new era in personalized cancer care

2018

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The most successful treatment for cancer involves identifying druggable, biological markers for targeted therapy. In the clinical setting, surgical removal of tumors is the only procedure for identifying such targetable molecules. Shed from tumor cells, these markers are also present in circulating blood, albeit in very negligible amounts. Liquid biopsy is a procedure performed on a blood sample to look for such circulating cancer markers cells or pieces of nucleic acid from the tumor. The procedure shows promise in revolutionizing personalized cancer treatments. Here we briefly review the technique, characterization, and its utilization in clinics.

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Section: Methods To Isolate and Identify Ctcmentioning

confidence: 99%

Liquid biopsy - emergence of a new era in personalized cancer care

2018

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“…Both in vitro and in vivo BC studies have been performed using GIP which demonstrated both anti-growth and anti-metastatic activities. For example, in a microarray study, GIP was found to down-regulate the mRNA (1.5 to 8 fold) of many proteins detected in the "CTC signature" of the BC-derived circulating cells described by Boral et al [10] . Such proteins included CD44, CD40, TNF, NFkB, IL-1 receptor, Serpin I-1, and p53 AIP1 among others.…”

Section: Afp-derived Peptides Ctcs and Metastasismentioning

confidence: 99%

“…In a recent study using breast cancer (BC) cells, Boral et al [10] reasoned that mRNA characterization of CTCs from BC derived cells could provide a means for early diagnosis of brain metastases; this knowledge could aid in planning therapeutic strategies and determining the effectiveness of targeting metastatic cells. Boral's studies confirmed that patients with BC produce CTCs that express high levels of biomarkers that are associated with regulation of cell growth, proliferation, and signal transduction pathways directly involved with metastasis.…”

Section: Background Studiesmentioning

confidence: 99%

“…[10] devised a computer-based genomic and mRNA workflow strategy which revealed a higher cell surface frequency and expression of metastaticassociated biomarkers in BC patient's cells versus cells from healthy blood donors [10] . Finally, these investigators utilized parametric flow cytometry and MRI-proven metastasis brain scans to analyze their BC patient's cell populations.…”

Section: Background Studiesmentioning

confidence: 99%

“…The CTC signature derived from circulating BC cells was parsed down to 126 genes involved in metastatic cell activities and signaling cascades [10] . Overall results from the 126 genes demonstrated that mRNA from 73 genes in the BC-CTC group were up-regulated while 53 genes were down-regulated.…”

Section: Components Of the Ctc Signaturementioning

confidence: 99%

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Cancer, circulating tumor cells, and metastasis: could protein-derived peptide fragments impede brain metastases?

Mizejewski¹

2018

JCMT

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The majority of cancer deaths can be attributed to cancer cell metastases that migrate to distant target organs. Brain metastases constitute one of the leading causes of morbidity and mortality among cancer patients, occurring in about 40% of patients with metastatic disease. Thus, there exists an unmet need for early detection, diagnosis, and treatment directed against early stage cancer cell metastasis. Previous studies have reported the development of methods to detect and identify early circulating tumor cells (CTCs) in the bloodstream prior to their seeding into distant organs. Using a comprehensive analysis of total CTCs mRNA content, investigators have developed a mRNA "transcriptome signature" of 126 genes involved in CTC metastatic events. The genes were parsed into various metastatic-related activities indicating that CTCs sustained a semi-dormancy state bent on: (1) stress survival; (2) metabolic maintenance; (3) DNA and translational stability; and (4) chemotactic pro-inflammatory capabilities. These activities suggested that CTCs might be susceptible to interactions with protein-derived peptide segments whose actions are involved with metastatic activities such as cell invasiveness, contact, adhesion, motility, spreading, and migration. The use of proteinderived (encrypted) peptides to impede CTC metabolic activities and disrupt signaling pathways could have therapeutic potential in patients with early metastatic disease.

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

et al. 2019

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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.

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Molecular characterization of breast cancer CTCs associated with brain metastasis

Cited by 172 publications

References 64 publications

Liquid biopsy - emergence of a new era in personalized cancer care

Liquid biopsy - emergence of a new era in personalized cancer care

Cancer, circulating tumor cells, and metastasis: could protein-derived peptide fragments impede brain metastases?

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

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