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

Rokana Taftaf, Xia Liu, Salendra Singh, Yuzhi Jia, Nurmaa K. Dashzeveg, Andrew D. Hoffmann, Lamiaa El-Shennawy, Erika K. Ramos, Valery Adorno-Cruz, Emma J. Schuster, David Scholten, Dhwani Patel, Youbin Zhang, Andrew A. Davis, Carolina Reduzzi, Yue Cao, Paolo D’Amico, Yang Shen, Massimo Cristofanilli, William A. MullerVinay Varadan, Huiping Liu*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number4867
JournalNature communications
Volume12
Issue number1
DOIs
StatePublished - Dec 2021

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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