American Association for Cancer Research
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Supplementary Figures S1-S9 from Homophilic CD44 Interactions Mediate Tumor Cell Aggregation and Polyclonal Metastasis in Patient-Derived Breast Cancer Models

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journal contribution
posted on 2023-04-03, 21:43 authored by Xia Liu, Rokana Taftaf, Madoka Kawaguchi, Ya-Fang Chang, Wenjing Chen, David Entenberg, Youbin Zhang, Lorenzo Gerratana, Simo Huang, Dhwani B. Patel, Elizabeth Tsui, Valery Adorno-Cruz, Steven M. Chirieleison, Yue Cao, Allison S. Harney, Shivani Patel, Antonia Patsialou, Yang Shen, Stefanie Avril, Hannah L. Gilmore, Justin D. Lathia, Derek W. Abbott, Massimo Cristofanilli, John S. Condeelis, Huiping Liu

Supplementary Figures S1-S9




American Cancer Society

Susan G. Komen Foundation

Department of Defense

Ohio Cancer Research Associates

Case Comprehensive Cancer Center

Case Western Reserve University and Northwestern University

Case Western Reserve University



Circulating tumor cells (CTC) seed cancer metastases; however, the underlying cellular and molecular mechanisms remain unclear. CTC clusters were less frequently detected but more metastatic than single CTCs of patients with triple-negative breast cancer and representative patient-derived xenograft models. Using intravital multiphoton microscopic imaging, we found that clustered tumor cells in migration and circulation resulted from aggregation of individual tumor cells rather than collective migration and cohesive shedding. Aggregated tumor cells exhibited enriched expression of the breast cancer stem cell marker CD44 and promoted tumorigenesis and polyclonal metastasis. Depletion of CD44 effectively prevented tumor cell aggregation and decreased PAK2 levels. The intercellular CD44–CD44 homophilic interactions directed multicellular aggregation, requiring its N-terminal domain, and initiated CD44–PAK2 interactions for further activation of FAK signaling. Our studies highlight that CD44+ CTC clusters, whose presence is correlated with a poor prognosis of patients with breast cancer, can serve as novel therapeutic targets of polyclonal metastasis. CTCs not only serve as important biomarkers for liquid biopsies, but also mediate devastating metastases. CD44 homophilic interactions and subsequent CD44–PAK2 interactions mediate tumor cluster aggregation. This will lead to innovative biomarker applications to predict prognosis, facilitate development of new targeting strategies to block polyclonal metastasis, and improve clinical outcomes.See related commentary by Rodrigues and Vanharanta, p. 22.This article is highlighted in the In This Issue feature, p. 1

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