Characterization of circulating breast cancer cells with tumorigenic and metastatic capacity

• Published in: EMBO molecular medicine Vol. 12; no. 9; pp. e11908 - n/a
• Main Authors: Koch, Claudia, Kuske, Andra, Joosse, Simon A, Yigit, Gökhan, Sflomos, George, Thaler, Sonja, Smit, Daniel J, Werner, Stefan, Borgmann, Kerstin, Gärtner, Sebastian, Mossahebi Mohammadi, Parinaz, Battista, Laura, Cayrefourcq, Laure, Altmüller, Janine, Salinas‐Riester, Gabriela, Raithatha, Kaamini, Zibat, Arne, Goy, Yvonne, Ott, Leonie, Bartkowiak, Kai, Tan, Tuan Zea, Zhou, Qing, Speicher, Michael R, Müller, Volkmar, Gorges, Tobias M, Jücker, Manfred, Thiery, Jean‐Paul, Brisken, Cathrin, Riethdorf, Sabine, Alix‐Panabières, Catherine, Pantel, Klaus
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07.09.2020; John Wiley & Sons, Inc; EMBO Press; Wiley Open Access; John Wiley and Sons Inc; Springer Nature
• Subjects: Analysis; Animal models; Animals; Biology; Biomarkers, Tumor; Biopsy; Breast cancer; Breast Neoplasms; Cancer; Carcinogenesis; Cell culture; circulating tumor cells; Copy number; Cyclin-dependent kinase 4; DNA Copy Number Variations; EMBO03; EMBO34; Endocrine therapy; Estrogen receptors; Female; functional studies; Human health and pathology; Humans; Life Sciences; liquid biopsy; Metastases; Metastasis; Mice; Neoplasm Metastasis; Neoplastic Cells, Circulating; Patients; Ribonucleic acid; RNA; Tumor cells; Tumors; Vagina; breast cancer; functional studies; circulating tumor cells; metastasis; liquid biopsy; Liquid biopsy; Breast cancer; Metastasis; Circulating tumor cells; Functional studies
• ISSN: 1757-4676; 1757-4684; 1757-4684
• DOI: 10.15252/emmm.201911908

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. Synopsis Blood‐born dissemination and subsequent outgrowth of tumor cells ‐ a process called metastasis ‐ is the leading cause of cancer‐related death. Cell lines derived from circulating tumor cells (CTCs) in blood of cancer patients provide excellent models to study the largely unknown biology of CTCs. The cell line established from CTCs of an estrogen receptor (ER)‐positive breast cancer patient mirrored the in situ CTCs and provided therefore a realistic model to investigate CTC biology. Xenograft experiments demonstrated a pattern of metastasis similar to ER‐positive breast cancer patients involving bone, liver and lung as secondary organs. Growth pattern and protein analyses revealed subtle signs of epithelial‐mesenchymal transition (EMT) with CTCs falling on the more epithelial end of the EMT spectrum. CTCs carried mutations in druggable genes relevant to cancer therapy (e.g., PIK3CA mutations). In vitro drug screening experiments indicated a cytostatic activity of the CDK4/6 inhibitor Palbociclib on CTCs. Graphical Abstract Blood‐born dissemination and subsequent outgrowth of tumor cells ‐ a process called metastasis ‐ is the leading cause of cancer‐related death. Cell lines derived from circulating tumor cells (CTCs) in blood of cancer patients provide excellent models to study the largely unknown biology of CTCs.