Identification of CD146 as a marker enriched for tumor-propagating capacity reveals targetable pathways in primary human sarcoma
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Qingxia Wei2,*, Yuning J. Tang1,2,9,*, Veronique Voisin3, Shingo Sato2, Makoto Hirata2, Heather Whetstone2, Ilkyu Han2, Laurie Ailles4,5, Gary D. Bader3,6, Jay Wunder7,8, Benjamin A. Alman1,2,9
1Department of Orthopaedic Surgery, Duke University, Durham, NC, USA
2Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada
3The Donnelly Centre, University of Toronto, Toronto, ON, Canada
4Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
5Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
6Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
7Samuel Lunenfeld Research Institute, Division of Orthopaedic Surgery, Department of Surgery, Mount Sinai Hospital, Toronto, ON, Canada
8University Musculoskeletal Oncology Unit, Division of Orthopaedic Surgery, Department of Surgery, Mount Sinai Hospital, Toronto, ON, Canada
9Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
*These authors have contributed equally to this work
Benjamin A. Alman, e-mail: [email protected]
Keywords: human sarcoma, tumor propagating cells, CD146, cell signaling, self-renewal
Received: July 06, 2015 Accepted: August 28, 2015 Published: October 26, 2015
Tumor-propagating cells (TPCs) are believed to drive cancer initiation, progression and recurrence. These cells are characterized by enhanced tumorigenicity and self-renewal. The ability to identify such cells in primary human sarcomas relies on the dye exclusion ability of tumor side population (SP) cells. Here, we performed a high-throughput cell surface antigen screen and found that CD146 is enriched in the SP population. In vivo serial transplantation assays showed that CD146+ cells are highly tumorigenic, capable of self-renewal and thus enriches for the TPC population. In addition, depletion of SP cells from the CD146+ population show that CD146+ cells and SP cells are a distinct and overlapping TPC populations. Gene expression profiling of CD146+ and SP cells revealed multiple pathways commonly upregulated in both of these populations. Inhibition of one of these upregulated pathways, Notch signaling, significantly reduced tumor growth and self-renewal. Our data demonstrate that CD146 is an effective cell surface marker for enriching TPCs in primary human sarcomas. Targeting differentially activated pathways in TPCs may provide new therapeutic strategies for treating sarcoma.
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