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

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.

• Authors: 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, Huiping Liu
• Journal: Nature communications (Nat Commun) Vol. 12 Issue 1 Pg. 4867 (08 11 2021) ISSN: 2041-1723 [Electronic] England
• PMID: 34381029 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2021. The Author(s).

Chemical References

• Biomarkers, Tumor
• ICAM1 protein, human
• Intercellular Adhesion Molecule-1

Topics

• Animals
• Biomarkers, Tumor (genetics, metabolism)
• Cell Aggregation
• Cell Cycle
• Cell Transformation, Neoplastic
• Humans
• Intercellular Adhesion Molecule-1 (genetics, metabolism)
• Lung Neoplasms (metabolism, secondary)
• Mice
• Neoplastic Cells, Circulating (metabolism, pathology)
• Protein Interaction Domains and Motifs
• Signal Transduction
• Transendothelial and Transepithelial Migration
• Triple Negative Breast Neoplasms (metabolism, pathology)