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. SIGNIFICANCE: 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.
|Number of pages
|Published - Jan 2019
Bibliographical noteFunding Information:
We appreciate the suggestions and help of Drs. Daniel Haber, Ruth Keri, Bryan P. Toole, Jeremy Rich, David Gius, Shideng Bao, George Stark, Zhenghe Wang, Stanton Gerson, Sanford Markowitz, and Mark Jackson during manuscript preparation and thank them for access to their research resources. We received technical help from Jay T. Myers, Bryson Benjamin, James Hale, and Luke Torre-Healy in addition to all members of the Liu laboratory (especially Andrew Hoffmann, Yuzhi Jia, Beijie Yu, and Nahun Ha). We appreciate the support of the Animal, Imaging, Microscopy, Proteomics, and Flow Core Facilities of Case Western Reserve University, Cleveland Clinic Foundation, and Northwestern University. This article has been partially supported by NIH/NCI grants R00CA160638 (H. Liu), CA150344 (J.S. Condeelis), CA100324 (J.S. Condeelis), and CA216248 (J.S. Condeelis); NIH/NIGMS grant R35GM124952 (Y. Shen); American Cancer Society grant ACS127951-RSG-15-025-01-CSM (H. Liu); the Susan G. Komen Foundation CCR15332826 (H. Liu) and CCR18548501 (H. Liu); the Department of Defense W81XWH-16-1-0021 (H. Liu); Ohio Cancer Research Associates (H. Liu); Case Comprehensive Cancer Center (NCIP30 CA043703 Pilot Grant); Case Western Reserve University and Northwestern University start-up grants (H. Liu); the Albert Einstein College of Medicine Gruss Lipper Biophotonics Center and its Integrated Imaging Program (J.S. Condeelis and D. Entenberg); the Lynn Sage Cancer Research Foundation (X. Liu, M. Cristofanilli, and H. Liu) and Case Western Reserve University CTSA/KL2 TR0002547 (S. Avril).
A.S. Harney is a senior research scientist at Array BioPharma. M. Cristofanilli reports receiving commercial research grants from Pfizer, Novartis, and Merus. J.S. Condeelis is a consultant/advisory board member for MetaStat Inc. and Deciphera Pharmaceuticals. No potential conflicts of interest were disclosed by the other authors.
© 2019 American Association for Cancer Research.
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