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.
|State||Published - Dec 1 2021|
Bibliographical noteFunding Information:
We appreciate the technical help from Drs. Charles M. Perou and Alfred L. George, their lab members, and the Liu laboratory members. We are thankful for helpful brainstorming discussions with Yong Wan. We acknowledge the tremendous support from the Northwestern Core facilities, including but not limited to the CTC Core, the Center for Comparative Medicine, Flow Cytometry Core, Small Animal Imaging, Microscopy Imaging, NU Genomics and Sequencing, Bioinformatics, Mouse Histology & Phenotyping Laboratory, and Pathology Core. We are also thankful to Case Western Reserve University Cancer Center Genomics and Sequencing Core and Proteomics Core. Portions of this research were conducted with high performance research computing resources provided by Texas A&M University (https://hprc.tamu.edu). This manuscript has been partially supported by the Department of Defense grant W81XWH-16-1-0021 and W81XWH-20-1-0679 (H.L.), the NIH grants R00CA160638 and R01CA245699 (H. L.), R35GM124952 (Y.S.), and P20GM121327 (X.L.); National Science Foundation CCF-1943008 (Y.S.); Susan G. Komen Foundation CCR18548501 (X.L.) and CCR15332826 (H.L.); American Cancer Society ACS127951-RSG-15-025-01-CSM (H.L.); and North-western University Lynn Sage Foundation, H Foundation, and start-up grant (H.L.).
© 2021, The Author(s).
ASJC Scopus subject areas
- Chemistry (all)
- Biochemistry, Genetics and Molecular Biology (all)
- Physics and Astronomy (all)