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Updated: Jan 6, 2026
A Preclinical Mouse Model of Osteosarcoma to Define the Extracellular Vesicle-mediated Communication Between Tumor and Mesenchymal Stem Cells
Published on: May 6, 2018
SEMA4C is a novel target to limit osteosarcoma growth, progression, and metastasis
Branden A Smeester1,2,3, Nicholas J Slipek1,2,3, Emily J Pomeroy1,2,3
1Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.
Abstract:
Semaphorins, specifically type IV, are important regulators of axonal guidance and have been increasingly implicated in poor prognoses in a number of different solid cancers. In conjunction with their cognate PLXNB family receptors, type IV members have been increasingly shown to mediate oncogenic functions necessary for tumor development and malignant spread. In this study, we investigated the role of semaphorin 4C (SEMA4C) in osteosarcoma growth, progression, and metastasis. We investigated the expression and localization of SEMA4C in primary osteosarcoma patient tissues and its tumorigenic functions in these malignancies. We demonstrate that overexpression of SEMA4C promotes properties of cellular transformation, while RNAi knockdown of SEMA4C promotes adhesion and reduces cellular proliferation, colony formation, migration, wound healing, tumor growth, and lung metastasis. These phenotypic changes were accompanied by reductions in activated AKT signaling, G1 cell cycle delay, and decreases in expression of mesenchymal marker genes SNAI1, SNAI2, and TWIST1. Lastly, monoclonal antibody blockade of SEMA4C in vitro mirrored that of the genetic studies. Together, our results indicate a multi-dimensional oncogenic role for SEMA4C in metastatic osteosarcoma and more importantly that SEMA4C has actionable clinical potential.
Insights
Semaphorin 4C (SEMA4C) drives osteosarcoma growth and metastasis. Blocking SEMA4C inhibits tumor progression and offers potential therapeutic strategies for this bone cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Type IV semaphorins regulate axonal guidance and are linked to poor prognosis in solid cancers.
- Semaphorins and their receptors (PLXNB family) mediate oncogenic functions in tumor development and spread.
Purpose of the Study:
- Investigate the role of semaphorin 4C (SEMA4C) in osteosarcoma growth, progression, and metastasis.
- Determine the expression and localization of SEMA4C in osteosarcoma tissues.
- Evaluate the therapeutic potential of targeting SEMA4C.
Main Methods:
- Analysis of SEMA4C expression and localization in primary osteosarcoma tissues.
- In vitro and in vivo studies using RNA interference (RNAi) knockdown of SEMA4C.
- Assessment of cellular transformation, proliferation, adhesion, migration, colony formation, and metastasis.
- Monoclonal antibody blockade of SEMA4C.
Main Results:
- SEMA4C overexpression promoted cellular transformation.
- RNAi knockdown of SEMA4C reduced proliferation, migration, tumor growth, and lung metastasis.
- SEMA4C inhibition led to reduced AKT signaling, G1 cell cycle arrest, and decreased expression of mesenchymal markers (SNAI1, SNAI2, TWIST1).
- Monoclonal antibody blockade of SEMA4C replicated genetic inhibition effects.
Conclusions:
- SEMA4C plays a multifaceted oncogenic role in metastatic osteosarcoma.
- Targeting SEMA4C demonstrates actionable clinical potential for osteosarcoma treatment.
