Homophilic CD44 Interactions Mediate Tumor Cell Aggregation and Polyclonal Metastasis in Patient-Derived Breast Cancer Models
Abstract
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jan 01, 2019
- Source ID
- 10.1158/2159-8290.cd-18-0065
Entities
People
- Allison S. Harney
- Antonia Patsialou
- David Entenberg
- Derek W. Abbott
- Dhwani Patel
- Elizabeth Tsui
- Hannah L. Gilmore
- Huiping Liu
- John Condeelis
- Justin D. Lathia
- Lorenzo Gerratana
- Madoka Kawaguchi
- Massimo Cristofanilli
- Rokana Taftaf
- Shivani Patel
- Simo Huang
- Stefanie Avril
- Steven M. Chirieleison
- Valery Adorno-cruz
- Wenjing Chen
- Xia Liu
- Ya-fang Chang
- Yang Shen
- Youbin Zhang
- Yue Cao
Organizations
- Albert Einstein College of Medicine
- American Cancer Society
- Case Western Reserve University
- Cleveland Clinic
- National Cancer Institute
- National Institute of General Medical Sciences
- Northwestern University
- Susan G. Komen for the Cure
- Texas A&M University
- United States Army Medical Research and Development Command
- University of Chicago
- University of Udine