Tumor secreted ANGPTL2 facilitates recruitment of neutrophils to the lung to promote lung pre-metastatic niche formation and targeting ANGPTL2 signaling affects metastatic disease

// Manish Charan 1 , Piyush Dravid 1 , Maren Cam 1 , Bhuvana Setty 2 , 4 , Ryan D. Roberts 1 , 4 , Peter J. Houghton 3 and Hakan Cam 1 , 4 1 Center for Childhood Cancer and Blood Diseases, Nationwide Children’s Hospital, Columbus, Ohio, USA 2 Department of Hematology & Oncology, Nationwide Children’s Hospital, Columbus, Ohio, USA 3 Greehey Children’s Cancer Research Institute, Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA 4 Department of Pediatrics, The Ohio State University, Columbus, Ohio, USA Correspondence to: Hakan Cam, email: hcam@cscc.edu Keywords: pre-metastatic niche formation; osteosarcoma; ANGPTL2; tumor microenvironment; neutrophils Received: October 22, 2019     Accepted: December 28, 2019     Published: February 04, 2020 ABSTRACT The pre-metastatic niche (PMN) represents an abnormal microenvironment devoid of cancer cells, but favoring tumor growth. Little is known about the mechanisms that generate the PMN or their effects on host cells within metastasis-prone organs. Here, we investigated by using spontaneous metastatic models whether lung epithelial cells are essential for primary tumor induced neutrophil recruitment in lung and subsequently initiating PMN formation in osteosarcoma. We found that serum levels of ANGPTL2 in osteosarcoma patients are significantly higher compared to those in healthy controls and that ANGPTL2 secretion by tumor cells plays an essential role in osteosarcoma metastasis. We determined that tumor-derived ANGPTL2 stimulates lung epithelial cells, which is essential for primary tumor-induced neutrophil recruitment in lung and subsequent pre-metastatic niche formation. Lastly, we identified that a p63 isoform, ΔNp63, drives high level of ANGPTL2 secretion and pharmaceutical inhibition of ANGPTL2 signaling by a non–RGD-based integrin binding peptide (ATN-161) diminished metastatic load in lungs likely due to reduction of the lung pre-metastatic niche formation.