FOXC2 augments tumor propagation and metastasis in osteosarcoma

// Maricel C. Gozo 1, 2, * , Dongyu Jia 1, * , Paul-Joseph Aspuria 1 , Dong-Joo Cheon 1 , Naoyuki Miura 3 , Ann E. Walts 4 , Beth Y. Karlan 1, 5 , Sandra Orsulic 1, 5 1 Women’s Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA 2 Graduate Program in Biomedical Science and Translational Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA 3 Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan 4 Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA 5 Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA * These authors have contributed equally to this work Correspondence to: Sandra Orsulic, email: orsulics@cshs.org Keywords: anoikis, forkhead box C2, osteosarcoma, metastasis, invasion Received: January 19, 2016     Accepted: September 02, 2016     Published: September 13, 2016 ABSTRACT Osteosarcoma is a highly malignant tumor that contains a small subpopulation of tumor-propagating cells (also known as tumor-initiating cells) characterized by drug resistance and high metastatic potential. The molecular mechanism by which tumor-propagating cells promote tumor growth is poorly understood. Here, we report that the transcription factor forkhead box C2 (FOXC2) is frequently expressed in human osteosarcomas and is important in maintaining osteosarcoma cells in a stem-like state. In osteosarcoma cell lines, we show that anoikis conditions stimulate FOXC2 expression. Downregulation of FOXC2 decreases anchorage-independent growth and invasion in vitro and lung metastasis in vivo , while overexpression of FOXC2 increases tumor propagation in vivo . In osteosarcoma cell lines, we demonstrate that high levels of FOXC2 are associated with and required for the expression of osteosarcoma tumor-propagating cell markers. In FOXC2 knockdown cell lines, we show that CXCR4, a downstream target of FOXC2, can restore osteosarcoma cell invasiveness and metastasis to the lung.