Volume 30, No 10, Oct 2020

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 30 Issue 10, October 2020: 885-901   |  Open Access

ORIGINAL ARTICLES

Wnt signaling and Loxl2 promote aggressive osteosarcoma

Kazuhiko Matsuoka^1,3 , Latifa Bakiri^2,3 , Lena I. Wolff⁴ , Markus Linder⁵ , Amanda Mikels-Vigdal⁶ , Ana Patiño-García^7,8 , Fernando Lecanda^7,9 , Christine Hartmann⁴ , Maria Sibilia⁵ , Erwin F. Wagner^1,2,*

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

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.

https://doi.org/10.1038/s41422-020-0370-1

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