Cited by 261Cancer Cells and MetastasisCell Adhesion Molecules ResearchMechanisms of cancer metastasis

ICAM1 initiates CTC cluster formation and trans-endothelial migration in lung metastasis of breast cancer

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Taftaf, Rokana, Liu, Xia, Singh, Salendra, Jia, Yuzhi, Dashzeveg, Nurmaa K., Hoffmann, Andrew D., El-Shennawy, Lamiaa, Ramos, Erika K. +14 more·2021·Nature Communications

Abstract

Circulating tumor cell (CTC) clusters mediate metastasis at a higher efficiency and are associated with lower overall survival in breast cancer compared to single cells. Combining single-cell RNA sequencing and protein analyses, here we report the profiles of primary tumor cells and lung metastases of triple-negative breast cancer (TNBC). ICAM1 expression increases by 200-fold in the lung metastases of three TNBC patient-derived xenografts (PDXs). Depletion of ICAM1 abrogates lung colonization of TNBC cells by inhibiting homotypic tumor cell-tumor cell cluster formation. Machine learning-based algorithms and mutagenesis analyses identify ICAM1 regions responsible for homophilic ICAM1-ICAM1 interactions, thereby directing homotypic tumor cell clustering, as well as heterotypic tumor-endothelial adhesion for trans-endothelial migration. Moreover, ICAM1 promotes metastasis by activating cellular pathways related to cell cycle and stemness. Finally, blocking ICAM1 interactions significantly inhibits CTC cluster formation, tumor cell transendothelial migration, and lung metastasis. Therefore, ICAM1 can serve as a novel therapeutic target for metastasis initiation of TNBC.

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Authors
Taftaf, R., Liu, X., Singh, S., Jia, Y., Dashzeveg, N. K., Hoffmann, A. D., El-Shennawy, L., Ramos, E. K., Adorno-Cruz, V., Schuster, E. J., Scholten, D., Patel, D., Zhang, Y., Davis, A. A., Reduzzi, C., Cao, Y., D’Amico, P., Shen, Y., Cristofanilli, M., Muller, W. A., Varadan, V., & Liu, H.
Affiliations
  • Northwestern University (US)
  • Case Comprehensive Cancer Center (US)
  • Texas A&M University System (US)
Corresponding author
Liu, Huiping
Venue
Nature Communications
Published
2021-08-11
Volume
12
Issue
1
Pages
4867-4867
ISSN
2041-1723 (ISSN-L)
OpenAlex
W3189505974
Cited by
261
References
75
Citations by year
2026: 42 · 2025: 54 · 2024: 57 · 2023: 67 · 2022: 38 · 2021: 3
FWCI
15.10
Type
journal article
Language
en
Open access
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • U.S. Department of Health & Human Services | National Institutes of Health (CA080621-15, R35GM124952)
  • Susan G. Komen (CCR18548501)
  • U.S. Department of Health & Human Services | NIH | National Cancer Institute (R01CA245699)
  • U.S. Department of Health & Human Services | NIH | NCI | Division of Cancer Epidemiology and Genetics, National Cancer Institute (R00CA160638)
Topics
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
  • Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
Keywords
ICAM-1, circulating tumor cell clusters, triple-negative breast cancer, lung metastasis, transendothelial migration, homotypic cell adhesion, metastasis initiation, therapeutic target, cell cycle, stemness, patient-derived xenografts
MeSH terms
Animals, Cell Aggregation, Cell Cycle, Cell Transformation, Neoplastic, Humans, Lung Neoplasms, Neoplastic Cells, Circulating, Biomarkers, Tumor, Signal Transduction, Intercellular Adhesion Molecule-1, Mice, Protein Interaction Domains and Motifs, Transendothelial and Transepithelial Migration, Triple Negative Breast Neoplasms

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