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SEMA4C is a novel target to limit osteosarcoma growth, progression, and metastasis

Oncogene volume 39, pages 1049–1062 (2020)Cite this article

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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.

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Acknowledgements

The authors would like to thank Dr. Kyle Williams for helpful discussion throughout the study, Dr. Sterbs for her intoxicating enthusiasm during the preparation of this paper, Dr. Juan Abrahante for statistical advice, and the Clinical and Translational Science Institute (CSTI) Histology and Research Laboratory team members Dr. Colleen Forester and Lori Holm for tissue preparation and histology services. Author BAS is supported by an NIH NIAMS T32 AR050938 Musculoskeletal Training Grant. Author EJP is supported by an NIH NIAID T32 AI997313 Immunology Training Grant. This work was made possible through funding from the Sobiech Osteosarcoma Fund Award, Randy Shaver Cancer and Community Fund, University of Minnesota Foundation, Rein in Sarcoma Foundation, Aflac-AACR Career Development Award, and the Children’s Cancer Research Fund to author BSM Portions of this work were conducted in the Minnesota Nano Center, which is supported by the National Science Foundation through the National Nano Coordinated Infrastructure Network (NNCI) under Award Number ECCS-1542202. SEMA4C RNA expression results in data set #2 were in whole or part based upon data generated by the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative, phs000218, managed by the NCI. The data used are available (dbGaP accession phs000218.v21.p7). Information about TARGET can be found at http://ocg.cancer.gov/programs/target.

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Authors and Affiliations

  1. Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA

    Branden A. Smeester, Nicholas J. Slipek, Emily J. Pomeroy, Joseph J. Peterson, Margaret R. Crosby, Garrett M. Draper, Kelsie L. Becklin, David A. Largaespada & Branden S. Moriarity

  2. Center for Genome Engineering, University of Minnesota, Minneapolis, MN, USA

    Branden A. Smeester, Nicholas J. Slipek, Emily J. Pomeroy, Joseph J. Peterson, Margaret R. Crosby, Garrett M. Draper, Kelsie L. Becklin, David A. Largaespada & Branden S. Moriarity

  3. Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA

    Branden A. Smeester, Nicholas J. Slipek, Emily J. Pomeroy, Ghaidan A. Shamsan, Joseph J. Peterson, Margaret R. Crosby, Garrett M. Draper, Kelsie L. Becklin, James B. McCarthy, David J. Odde, David A. Largaespada & Branden S. Moriarity

  4. Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN, USA

    Heather E. Bomberger, Ghaidan A. Shamsan, David J. Odde & David K. Wood

  5. Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK

    Eric P. Rahrmann

  6. Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA

    James B. McCarthy

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  1. Branden A. Smeester
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Contributions

Conception and design: BAS, DAL, BSM. Development and acquisition of data: BAS, NJS, EJP, HEB, GAS, MRC, JJP, GMD, KLB, EPR. Analysis and interpretation: BAS, NJS, DJO, DKW, JBM, DAL, BSM. Writing, review and revisions: BAS, NJS., EJP, HEB, GAS, MRC, JJP, GMD, KLB, EPR, JBM, DJ.O, DKW, DAL, BSM. Study oversight: BAS, DAL, BSM.

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Correspondence to Branden S. Moriarity.

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Smeester, B.A., Slipek, N.J., Pomeroy, E.J. et al. SEMA4C is a novel target to limit osteosarcoma growth, progression, and metastasis. Oncogene 39, 1049–1062 (2020). https://doi.org/10.1038/s41388-019-1041-x

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