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Ablation of neuropilin-1 improves the therapeutic response in conventional drug-resistant glioblastoma multiforme

Oncogene volume 39, pages 7114–7126 (2020)Cite this article

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Abstract

Glioblastoma multiforme (GBM) is a highly proliferative and locally invasive cancer with poor prognosis and a high recurrence rate. Although anti-VEGF (vascular endothelial growth factor) therapy offers short-term benefit to GBM patients, this approach fails as the tumor develops into a more invasive and drug-resistant phenotype and ultimately recurs. Recently, both glioma stemlike cells (GSCs) and brain tumor–initiating cells (BTICs) have been implicated in GBM recurrence and its resistance to therapy. We observed that patient-derived GBM cells expressing shRNAs of VEGF or neuropilin-1 (NRP-1) attenuate cancer stem cell markers, inhibit the tumor-initiating cell’s neurosphere-forming capacity, and migration. Furthermore, both VEGF and NRP-1 knockdown inhibit the growth of patient-derived GBM xenografts in both zebrafish and mouse models. Interestingly, NRP-1–depleted patient-derived GBM xenografts substantially prolonged survival in mice compared to that of VEGF depletion. Our results also demonstrate that NRP-1 ablation of patient-derived GBM cells improves the sensitivity of TMZ and enhances the overall survival of the respective tumor-bearing mice. This improved outcome may provide insight into the inhibition of GBM progression and effective treatment strategies by targeting NRP-1 in addition to chemotherapy and radiotherapy.

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Fig. 1: GBM1A and GBM22 Express Stem Cell Markers and GBM-associated Genes.
Fig. 2: VEGF and NRP-1 Knockdown in GBM Cells.
Fig. 3: Abrogation of VEGF or NRP-1 Inhibits GBM Cell Migration and Neurosphere Formation and Enhances Animal Survival in Mice Xenograft.
Fig. 4: NRP-1 Knockdown has a Prolonged Effect on Tumor Inhibition.
Fig. 5: Abrogation of VEGF or NRP-1 Inhibits Tumor Growth in Zebrafish.
Fig. 6: Effect of VEGF or NRP-1 Knockdown on Chemotherapy and Animal Survival in Mice Xenograft.

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Acknowledgements

The authors thank Dr Leonard Zon, Children’s Hospital, Boston, Massachusetts, for providing the Casper zebrafish strain, and Dr Ying Wang, Mayo Clinic, Jacksonville, for assistance with lentiviral preparation. The work was supported by the NIH Grant to DM R01CA 78383, RO1HL140411, R01CA150190, Florida Department of Health Cancer Research Chair Fund Florida #3 J. AQH was supported by the Mayo Clinic Professorship and a Clinician Investigator award, the Florida Department of Health Cancer Research Chair Fund, and the NIH (R43CA221490, R01CA200399, R01CA195503, and R01CA216855).

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Author notes

  1. Sujan Kumar Mondal

    Present address: Department of Pathology, University of Pittsburgh Medical Center, UPMC Hillman Center, Pittsburgh, PA, USA

  2. Fei Wang

    Present address: Department of Neurosurgery, Inner Mongolia Medical University Affiliated Hospital, 010050, Inner Mongolia, China

  3. These authors contributed equally: Ramcharan Singh Angom, Sujan Kumar Mondal, Fei Wang

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Jacksonville, FL, USA

    Ramcharan Singh Angom, Fei Wang, Vijay Sagar Madamsetty, Enfeng Wang, Shamit K. Dutta, Yash Gulani & Debabrata Mukhopadhyay

  2. Department of Neurosurgery, Mayo Clinic College of Medicine and Science, Jacksonville, FL, USA

    Sujan Kumar Mondal, Rachel Sarabia-Estrada & Alfredo Quiñones-Hinojosa

  3. Department of Radiation Oncology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA

    Jann N. Sarkaria

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Contributions

Conception: DM Study design: RSA, SKM, RSE, AQH, DM. Development of methodology: RSA, SKM, FW, DM. Acquisition of data: RSA, SKM, FW, VSM, YG, EW. Analysis and interpretation of data: RSA, SKM, FW, VSM, AQH, DM. Writing the paper: RSA, SKM. Administrative, technical, or material support; JNS and SKD. Study supervision: DM and AQH.

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Correspondence to Alfredo Quiñones-Hinojosa or Debabrata Mukhopadhyay.

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Angom, R.S., Mondal, S.K., Wang, F. et al. Ablation of neuropilin-1 improves the therapeutic response in conventional drug-resistant glioblastoma multiforme. Oncogene 39, 7114–7126 (2020). https://doi.org/10.1038/s41388-020-01462-1

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