Better Together: Circulating Tumor Cell Clustering in Metastatic Cancer

Overview

Journal Trends Cancer

Publisher Cell Press

Specialty Oncology

Date 2021 Sep 5

PMID 34481763

Citations 78

Authors

Emma Schuster

Rokana Taftaf

Carolina Reduzzi

Mary K Albert

Isabel Romero-Calvo

Huiping Liu

Affiliations

Soon will be listed here.

Abstract

Circulating tumor cells (CTCs) are vital components of liquid biopsies for diagnosis of residual cancer, monitoring of therapy response, and prognosis of recurrence. Scientific dogma focuses on metastasis mediated by single CTCs, but advancement of CTC detection technologies has elucidated multicellular CTC clusters, which are associated with unfavorable clinical outcomes and a 20- to 100-fold greater metastatic potential than single CTCs. While the mechanistic understanding of CTC cluster formation is still in its infancy, multiple cell adhesion molecules and tight junction proteins have been identified that underlie the outperforming attributes of homotypic and heterotypic CTC clusters, such as cell survival, cancer stemness, and immune evasion. Future directions include high-resolution characterization of CTCs at multiomic levels for diagnostic/prognostic evaluations and targeted therapies.

Citing Articles

NINJ1 in Cell Death and Ferroptosis: Implications for Tumor Invasion and Metastasis.

Chen S, Shyu I, Chi J Cancers (Basel). 2025; 17(5).

PMID: 40075648 PMC: 11898531. DOI: 10.3390/cancers17050800.

Microfluidic isolation and release of live disseminated breast tumor cells in bone marrow.

Le M, Chen D, Smith K, Tran D, Fan Z PLoS One. 2025; 20(3):e0319392.

PMID: 40073025 PMC: 11902295. DOI: 10.1371/journal.pone.0319392.

Label-Free and Rapid Microfluidic Design Rules for Circulating Tumor Cell Enrichment and Isolation: A Review and Simulation Analysis.

Mansor M, Yang C, Chong K, Jamrus M, Liu K, Yu M ACS Omega. 2025; 10(7):6306-6322.

PMID: 40028152 PMC: 11866005. DOI: 10.1021/acsomega.4c08606.

Unsupervised Detection of Rare Events in Liquid Biopsy Assays.

Murgoitio-Esandi J, Tessone D, Naghdloo A, Shishido S, Zhang B, Xu H bioRxiv. 2025; .

PMID: 39975209 PMC: 11838382. DOI: 10.1101/2025.01.29.635501.

Molecular principles underlying aggressive cancers.

Nussinov R, Yavuz B, Jang H Signal Transduct Target Ther. 2025; 10(1):42.

PMID: 39956859 PMC: 11830828. DOI: 10.1038/s41392-025-02129-7.

References

Szczerba B, Castro-Giner F, Vetter M, Krol I, Gkountela S, Landin J . Neutrophils escort circulating tumour cells to enable cell cycle progression. Nature. 2019; 566(7745):553-557. DOI: 10.1038/s41586-019-0915-y. View

Mu P, Zhang Z, Benelli M, Karthaus W, Hoover E, Chen C . SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer. Science. 2017; 355(6320):84-88. PMC: 5247742. DOI: 10.1126/science.aah4307. View

Donato C, Kunz L, Castro-Giner F, Paasinen-Sohns A, Strittmatter K, Szczerba B . Hypoxia Triggers the Intravasation of Clustered Circulating Tumor Cells. Cell Rep. 2020; 32(10):108105. PMC: 7487783. DOI: 10.1016/j.celrep.2020.108105. View

Kallergi G, Aggouraki D, Zacharopoulou N, Stournaras C, Georgoulias V, Martin S . Evaluation of α-tubulin, detyrosinated α-tubulin, and vimentin in CTCs: identification of the interaction between CTCs and blood cells through cytoskeletal elements. Breast Cancer Res. 2018; 20(1):67. PMC: 6034292. DOI: 10.1186/s13058-018-0993-z. View

Pantel K, Alix-Panabieres C . Liquid biopsy and minimal residual disease - latest advances and implications for cure. Nat Rev Clin Oncol. 2019; 16(7):409-424. DOI: 10.1038/s41571-019-0187-3. View

Putz E, Mayfosh A, Kos K, Barkauskas D, Nakamura K, Town L . NK cell heparanase controls tumor invasion and immune surveillance. J Clin Invest. 2017; 127(7):2777-2788. PMC: 5490772. DOI: 10.1172/JCI92958. View

Xu L, Mao X, Guo T, Chan P, Shaw G, Hines J . The Novel Association of Circulating Tumor Cells and Circulating Megakaryocytes with Prostate Cancer Prognosis. Clin Cancer Res. 2017; 23(17):5112-5122. DOI: 10.1158/1078-0432.CCR-16-3081. View

Hurtado P, Martinez-Pena I, Pineiro R . Dangerous Liaisons: Circulating Tumor Cells (CTCs) and Cancer-Associated Fibroblasts (CAFs). Cancers (Basel). 2020; 12(10). PMC: 7599894. DOI: 10.3390/cancers12102861. View

Lecharpentier A, Vielh P, Perez-Moreno P, Planchard D, Soria J, Farace F . Detection of circulating tumour cells with a hybrid (epithelial/mesenchymal) phenotype in patients with metastatic non-small cell lung cancer. Br J Cancer. 2011; 105(9):1338-41. PMC: 3241564. DOI: 10.1038/bjc.2011.405. View

10.

Bulfoni M, Gerratana L, Del Ben F, Marzinotto S, Sorrentino M, Turetta M . In patients with metastatic breast cancer the identification of circulating tumor cells in epithelial-to-mesenchymal transition is associated with a poor prognosis. Breast Cancer Res. 2016; 18(1):30. PMC: 4784394. DOI: 10.1186/s13058-016-0687-3. View

11.

Aceto N, Bardia A, Miyamoto D, Donaldson M, Wittner B, Spencer J . Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. Cell. 2014; 158(5):1110-1122. PMC: 4149753. DOI: 10.1016/j.cell.2014.07.013. View

12.

Sarioglu A, Aceto N, Kojic N, Donaldson M, Zeinali M, Hamza B . A microfluidic device for label-free, physical capture of circulating tumor cell clusters. Nat Methods. 2015; 12(7):685-91. PMC: 4490017. DOI: 10.1038/nmeth.3404. View

13.

Paoletti C, Miao J, Dolce E, Darga E, Repollet M, Doyle G . Circulating Tumor Cell Clusters in Patients with Metastatic Breast Cancer: a SWOG S0500 Translational Medicine Study. Clin Cancer Res. 2019; 25(20):6089-6097. PMC: 6801082. DOI: 10.1158/1078-0432.CCR-19-0208. View

14.

Larsson A, Jansson S, Bendahl P, Jorgensen C, Loman N, Graffman C . Longitudinal enumeration and cluster evaluation of circulating tumor cells improve prognostication for patients with newly diagnosed metastatic breast cancer in a prospective observational trial. Breast Cancer Res. 2018; 20(1):48. PMC: 5994056. DOI: 10.1186/s13058-018-0976-0. View

15.

Cristofanilli M, Budd G, Ellis M, Stopeck A, Matera J, Miller M . Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med. 2004; 351(8):781-91. DOI: 10.1056/NEJMoa040766. View

16.

Krol I, Schwab F, Carbone R, Ritter M, Picocci S, De Marni M . Detection of clustered circulating tumour cells in early breast cancer. Br J Cancer. 2021; 125(1):23-27. PMC: 8257701. DOI: 10.1038/s41416-021-01327-8. View

17.

Ocana O, Corcoles R, Fabra A, Moreno-Bueno G, Acloque H, Vega S . Metastatic colonization requires the repression of the epithelial-mesenchymal transition inducer Prrx1. Cancer Cell. 2012; 22(6):709-24. DOI: 10.1016/j.ccr.2012.10.012. View

18.

Cheng S, Xie M, Chen Y, Xiong J, Liu Y, Chen Z . Three-Dimensional Scaffold Chip with Thermosensitive Coating for Capture and Reversible Release of Individual and Cluster of Circulating Tumor Cells. Anal Chem. 2017; 89(15):7924-7932. DOI: 10.1021/acs.analchem.7b00905. View

19.

Toss A, Mu Z, Fernandez S, Cristofanilli M . CTC enumeration and characterization: moving toward personalized medicine. Ann Transl Med. 2014; 2(11):108. PMC: 4245508. DOI: 10.3978/j.issn.2305-5839.2014.09.06. View

20.

Brabletz T . EMT and MET in metastasis: where are the cancer stem cells?. Cancer Cell. 2012; 22(6):699-701. DOI: 10.1016/j.ccr.2012.11.009. View