Wnt signaling and Loxl2 promote aggressive osteosarcoma  

作　　者：Kazuhiko Matsuoka Latifa Bakiri Lena I.Wolff Markus Linder Amanda Mikels-Vigdal Ana Patiño-García Fernando Lecanda Christine Hartmann Maria Sibilia Erwin F.Wagner 

机构地区：[1]Laboratory Genes and Disease,Department of Dermatology,Medical University of Vienna(MUV),Vienna,1090,Austria [2]Laboratory Genes and Disease,Department of Laboratory Medicine,Medical University of Vienna(MUV),Vienna,1090,Austria [3]Genes,Development and Disease Group,Spanish National Cancer Research Centre(CNIO),Madrid,28029,Spain [4]Department of Bone and Skeletal Research,Medical Faculty,Institute of Musculoskeletal Medicine,University of Münster,Münster,48149,Germany [5]Department of Medicine I,Comprehensive Cancer Center,Institute of Cancer Research,Medical University of Vienna(MUV),Vienna,1090,Austria [6]Gilead Sciences Inc.,Foster City,CA,94404,USA [7]Navarra Institute for Health Research(IdISNA)and Program in Solid Tumors,Center for Applied Medical Research(CIMA),University of Navarra,Pamplona,31008,Spain [8]Department of Pediatrics,University Clinic of Navarra,Pamplona,31008,Spain [9]Centro de Investigación Biomédica en Red de Cáncer(CIBERONC),Pamplona,31008,Spain

出　　处：《Cell Research》2020年第10期885-901,共17页细胞研究（英文版）

基　　金：We thank Drs.Mirna Perez-Moreno,Monica Musteanu and Mariano Barbacid for sharing reagents,protocols and helpful suggestions,Massimo Squatrito for invaluable help with human data analyses and Jean-Pierre David,who unfortunately passed away recently,and Agamemnon Grigoriadis for critical reading of the manuscript.We are grateful to members of the Wagner laboratory for discussions,V.Bermeo for technical help;S.Leceta,G.Medrano and P.García for assisting with mouse experiments,the staff at the Imaging Unit at CNIO for help with Micro-CT and G.Timelthaler at the MUV/Institute of Cancer Research Core facilities for help with TMA digital acquisition and analysis.K.M.was the recipient of grants from the Uehara Memorial Foundation and the AECC.The Wagner laboratory is supported by the ERC(ERC‐AdG 2016 CSI‐Fun)and the Medical University of Vienna(MUV).

摘　　要：Osteosarcoma(OS)is the most frequent primary malignant bone tumor in urgent need of better therapies.Using genetically modified mouse models(GEMMs),we demonstrate that Wnt signaling promotes c-Fos-induced OS formation via the actions of the collagen-modifying enzyme Loxl2.c-Fos/AP-1 directly regulates the expression of the Wnt ligands Wnt7b and Wnt9a in OS cells through promoter binding,and Wnt7b and Wnt9a in turn promote Loxl2 expression in murine and human OS cells through the transcription factors Zeb1 and Zeb2.Concordantly,inhibition of Wnt ligand secretion by inactivating the Wnt-less(Wls)gene in osteoblasts in c-Fos GEMMs either early or in a therapeutic setting reduces Loxl2 expression and progression of OS.Wls-deficient osteosarcomas proliferate less,are less mineralized and are enriched in fibroblastic cells surrounded by collagen fibers.Importantly,Loxl2 inhibition using either the pan-Lox inhibitor BAPN or a specific inducible shRNA reduces OS cell proliferation in vitro and decreases tumor growth and lung colonization in murine and human orthotopic OS transplantation models.Finally,OS development is delayed in c-Fos GEMMs treated with BAPN or with specific Loxl2 blocking antibodies.Congruently,a strong correlation between c-FOS,LOXL2 and WNT7B/WNT9A expression is observed in human OS samples,and c-FOS/LOXL2 co-expression correlates with OS aggressiveness and decreased patient survival.Therefore,therapeutic targeting of Wnt and/or Loxl2 should be considered to potentiate the inadequate current treatments for pediatric,recurrent,and metastatic OS.

关 键 词：OSTEOSARCOMA WNT AGGRESSIVE 

分 类 号：R738.1[医药卫生—肿瘤]