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. Muller, Vinay Varadan and Huiping Liu ()
Additional contact information
Rokana Taftaf: Department of Pharmacology, Northwestern University Feinberg School of Medicine
Xia Liu: Department of Pharmacology, Northwestern University Feinberg School of Medicine
Salendra Singh: Case Western Reserve University
Yuzhi Jia: Department of Pharmacology, Northwestern University Feinberg School of Medicine
Nurmaa K. Dashzeveg: Department of Pharmacology, Northwestern University Feinberg School of Medicine
Andrew D. Hoffmann: Department of Pharmacology, Northwestern University Feinberg School of Medicine
Lamiaa El-Shennawy: Department of Pharmacology, Northwestern University Feinberg School of Medicine
Erika K. Ramos: Department of Pharmacology, Northwestern University Feinberg School of Medicine
Valery Adorno-Cruz: Department of Pharmacology, Northwestern University Feinberg School of Medicine
Emma J. Schuster: Department of Pharmacology, Northwestern University Feinberg School of Medicine
David Scholten: Department of Pharmacology, Northwestern University Feinberg School of Medicine
Dhwani Patel: Department of Pharmacology, Northwestern University Feinberg School of Medicine
Youbin Zhang: Northwestern University Feinberg School of Medicine
Andrew A. Davis: Northwestern University Feinberg School of Medicine
Carolina Reduzzi: Northwestern University Feinberg School of Medicine
Yue Cao: TEES-AgriLife Center for Bioinformatics and Genomic Systems Engineering, Texas A&M University
Paolo D’Amico: Northwestern University Feinberg School of Medicine
Yang Shen: TEES-AgriLife Center for Bioinformatics and Genomic Systems Engineering, Texas A&M University
Massimo Cristofanilli: Northwestern University Feinberg School of Medicine
William A. Muller: Northwestern University Feinberg School of Medicine
Vinay Varadan: Case Western Reserve University
Huiping Liu: Department of Pharmacology, Northwestern University Feinberg School of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-25189-z

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