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Regulation of neuroblastoma migration, invasion, and in vivo metastasis by genetic and pharmacological manipulation of MDA-9/Syntenin

Oncogene volume 38, pages 6781–6793 (2019)Cite this article

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Abstract

Despite multi-modality treatments, prognosis for advanced stage neuroblastoma (NB) remains challenging with residual long-term disabilities in survivors. Advanced stage NB is metastatic, which is a principal cause of cancer-related deaths. We presently document a primary role of MDA-9 in NB progression and define the molecular mechanisms by which MDA-9 promotes transformed phenotypes. NB cell lines and clinical samples display elevated MDA-9 expression and bioinformatic analysis supports an association between elevated MDA-9 and bone metastasis and poor prognosis. Genetic (shmda-9, mda-9 siRNA) or pharmacological (small molecule inhibitor of protein-protein interactions; PDZ1i) blockade of MDA-9 decreases NB migration, invasion, and metastasis. Blocking mda-9 expression or disrupting MDA-9 partner protein interactions downregulates integrin α6 and β4, diminishing Src activity and suppressing Rho-Rac-Cdc42 activity. These signaling changes inhibit cofilin and matrix metalloproteinases reducing in vitro and in vivo NB cell migration. Overexpression of integrin α6 and β4 rescues the invasion phenotype and increases Src activity, supporting integrins as essential regulators of MDA-9-mediated NB migration and invasion. We identify MDA-9 as a key contributor to NB pathogenesis and show that genetic or pharmacological inhibition suppresses NB pathogenesis by an integrin-mediated Src-disruption pathway.

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Acknowledgements

We thank Dr Xue-Ning Shen for outstanding technical assistance. We also thank Dr Martin A. Schwartz (Cardiovascular Research Center, Mellon Prostate Cancer Institute, Departments of Microbiology and Biomedical Engineering, University of Virginia, Charlottesville, VA) for providing pGEX-TRBD, Dr. Baroda S, for providing pGEX-Rac1, and pGEX-Cdc42 and we thank Dr Filippo Giancotti for pRK5 alpha6, and beta4 plasmids. Services and products in support of the research project were also provided by the VCU Massey Cancer Center Cancer Mouse Model Shared Resource.

Funding

The present study was supported in part by the National Foundation for Cancer Research (NFCR) (to PBF), NCI Cancer Center Support Grant to VCU Massey Cancer Center (MCC) P30 CA016059 (to PBF and DS), the VCU Institute of Molecular Medicine (VIMM) (PBF) and the Genetics Enhancement Fund (PBF, SKD, and LE). Support was also provided by a Sponsored Research Agreement from InVaMet Therapeutics, Inc. (IVMT) (SKD). PBF holds the Thelma Newmeyer Corman Chair in Cancer Research at the MCC.

Author contributions

Conception and design: PB, SKD, and PBF. Development of methodology: PB, SKD, and AKP. Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): PB, AKP. Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): PB, MDB, LE, SKD, PBF. Writing, review, and/or revision of the manuscript: PB, LE, DS, SKD, PBF.

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Authors and Affiliations

  1. Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA

    Praveen Bhoopathi, Anjan K. Pradhan, Luni Emdad, Devanand Sarkar, Swadesh K. Das & Paul B. Fisher

  2. VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA

    Praveen Bhoopathi, Anjan K. Pradhan, Luni Emdad, Devanand Sarkar, Swadesh K. Das & Paul B. Fisher

  3. Weill Cornell Medical College, New York, NY, USA

    Manny D. Bacolod

  4. VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA

    Luni Emdad, Devanand Sarkar, Swadesh K. Das & Paul B. Fisher

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Correspondence to Paul B. Fisher.

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PBF is a founder of InVaMet Therapeutics, Inc. (IVMT). PBF, Virginia Commonwealth University and the Sanford Burnham Prebys Medical Discovery Institute own stock in IVMT. SKD is the Principle Investigator of a SRA provided by InVaMet Therapeutics, Inc. to Virginia Commonwealth University. No other authors declare any potential conflicts with this research.

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Bhoopathi, P., Pradhan, A.K., Bacolod, M.D. et al. Regulation of neuroblastoma migration, invasion, and in vivo metastasis by genetic and pharmacological manipulation of MDA-9/Syntenin. Oncogene 38, 6781–6793 (2019). https://doi.org/10.1038/s41388-019-0920-5

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