Wnt signaling and Loxl2 promote aggressive osteosarcoma.

Cell Research
Kazuhiko MatsuokaErwin F Wagner

Abstract

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 s...Continue Reading

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Citations

May 29, 2021·Laboratory Investigation; a Journal of Technical Methods and Pathology·Xin WangLi-Jie Qin
Jun 6, 2021·Journal of Cellular and Molecular Medicine·Chongchong WangLi Cheng

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Methods Mentioned

BETA
PCR
ChIP
immunoprecipitation
xenografts
RNA-seq
acylation
X-ray
FCS
transfection

Clinical Trials Mentioned

NCT02278133
NCT02649530

Software Mentioned

Definiens Tissue Studio ®
ZEN
TARGET
ImageJ
3D Slicer
GE MicroView
Slicer
3D

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