Characterization of circulating breast cancer cells with tumorigenic and metastatic capacity

Abstract

Functional studies giving insight into the biology of circulating tumor cells (CTCs) remain scarce due to the low frequency of CTCs and lack of appropriate models. Here, we describe the characterization of a novel CTC‐derived breast cancer cell line, designated CTC‐ITB‐01, established from a patient with metastatic estrogen receptor‐positive (ER+) breast cancer, resistant to endocrine therapy. CTC‐ITB‐01 remained ER+ in culture, and copy number alteration (CNA) profiling showed high concordance between CTC‐ITB‐01 and CTCs originally present in the patient with cancer at the time point of blood draw. RNA‐sequencing data indicate that CTC‐ITB‐01 has a predominantly epithelial expression signature. Primary tumor and metastasis formation in an intraductal PDX mouse model mirrored the clinical progression of ER+ breast cancer. Downstream ER signaling was constitutively active in CTC‐ITB‐01 independent of ligand availability, and the CDK4/6 inhibitor Palbociclib strongly inhibited CTC‐ITB‐01 growth. Thus, we established a functional model that opens a new avenue to study CTC biology.

High Sensitivity of Circulating Tumor Cells Derived from a Colorectal Cancer Patient for Dual Inhibition with AKT and mTOR Inhibitors

“…Drug sensitivity screening using CTCs has been conducted in the past [ 27 , 28 , 55 ]. In 2014, Yu et al were the first to establish drug sensitivity testing on six stable CTC lines in vitro as well as in a xenograft mouse model in vivo [ 27 ].…”

“…However, further characterization of CTCs is still limited by the low number of CTCs [ 26 ]. The recent establishment of cell lines from CTCs of cancer patients has therefore opened a new avenue for functional analyses of CTCs [ 4 , 27 , 28 ]. The CTC-MCC-41 colon CTC line that we analyzed in this study was the first long-term stable CTC line established from a patient with colon cancer.…”

Epithelial Cell Adhesion Molecule: An Anchor to Isolate Clinically Relevant Circulating Tumor Cells

“…Moreover, using a xenograft assay, Bacelli et al demonstrated that CTCs with a tumor-initiating phenotype (CD45 − , EpCAM + , CD44 + , CD47 + , MET + ) can produce metastases [ 109 ]. Similarly, Koch et al established an EpCAM + CTC line derived from breast cancer [ 112 ] and Faugeroux et al generated CTC-derived explant models by using EpCAM + CTCs isolated from blood samples of patients with castration-resistant prostate cancer ( Figure 2 ) [ 113 ].…”

“…In vitro and in vivo models are essential to identify and characterize metastasis-competent CTCs. The successful expansion of this more aggressive subset of CTCs after negative selection showed a clear EpCAM-positive phenotype in different studies from independent research groups [ 105 , 106 , 107 , 108 , 109 , 112 , 113 ].…”

Predicting therapy response by analysis of metastasis founder cells: emerging perspectives for personalized tumor therapy

“…Within the last decades a range of methods have been developed to specifically isolate CTCs [53] and to cultivate these rare cells by optimized in vitro culture conditions such as spheroid and organoid cultures, or by in vivo transplantation into immunodeficient mice [54][55][56][57][58]. To date, the generation of CTC-derived models has been reported for melanoma, breast, colorectal, lung, gastroesophageal, pancreatic, and prostate cancer patients (Table 1) [54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69]. CTC models from metastatic melanoma patients that recapitulate the patient's disease and responses to therapies have been developed, highlighting the power of such models as potential 'avatars' for testing personalized treatments in the future [60].…”