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Multiplatform molecular profiling uncovers two subgroups of malignant peripheral nerve sheath tumors with distinct therapeutic vulnerabilities

Author

Listed:
  • Suganth Suppiah

    (Princess Margaret Cancer Centre
    University of Toronto)

  • Sheila Mansouri

    (Princess Margaret Cancer Centre)

  • Yasin Mamatjan

    (Princess Margaret Cancer Centre
    Thompson Rivers University)

  • Jeffrey C. Liu

    (Princess Margaret Cancer Centre
    University of Toronto)

  • Minu M. Bhunia

    (University of Minnesota)

  • Vikas Patil

    (Princess Margaret Cancer Centre)

  • Prisni Rath

    (Ontario Institute for Cancer Research)

  • Bharati Mehani

    (National Cancer Institute)

  • Pardeep Heir

    (Princess Margaret Cancer Centre)

  • Severa Bunda

    (Princess Margaret Cancer Centre)

  • German L. Velez-Reyes

    (University of Minnesota)

  • Olivia Singh

    (Princess Margaret Cancer Centre)

  • Nazanin Ijad

    (Princess Margaret Cancer Centre)

  • Neda Pirouzmand

    (Princess Margaret Cancer Centre)

  • Tatyana Dalcourt

    (Princess Margaret Cancer Centre)

  • Ying Meng

    (University of Toronto)

  • Shirin Karimi

    (Princess Margaret Cancer Centre)

  • Qingxia Wei

    (Princess Margaret Cancer Centre)

  • Farshad Nassiri

    (Princess Margaret Cancer Centre
    University of Toronto)

  • Trevor J. Pugh

    (Ontario Institute for Cancer Research
    University of Toronto
    University Health Network)

  • Gary D. Bader

    (University of Toronto
    University Health Network
    University of Toronto
    University of Toronto)

  • Kenneth D. Aldape

    (National Cancer Institute)

  • David A. Largaespada

    (University of Minnesota
    University of Minnesota)

  • Gelareh Zadeh

    (Princess Margaret Cancer Centre
    University of Toronto)

Abstract

Malignant peripheral nerve sheath tumor (MPNST) is a highly aggressive sarcoma, and a lethal neurofibromatosis type 1-related malignancy, with little progress made on treatment strategies. Here, we apply a multiplatform integrated molecular analysis on 108 tumors spanning the spectrum of peripheral nerve sheath tumors to identify candidate drivers of MPNST that can serve as therapeutic targets. Unsupervised analyses of methylome and transcriptome profiles identify two distinct subgroups of MPNSTs with unique targetable oncogenic programs. We establish two subgroups of MPNSTs: SHH pathway activation in MPNST-G1 and WNT/ß-catenin/CCND1 pathway activation in MPNST-G2. Single nuclei RNA sequencing characterizes the complex cellular architecture and demonstrate that malignant cells from MPNST-G1 and MPNST-G2 have neural crest-like and Schwann cell precursor-like cell characteristics, respectively. Further, in pre-clinical models of MPNST we confirm that inhibiting SHH pathway in MPNST-G1 prevent growth and malignant progression, providing the rational for investigating these treatments in clinical trials.

Suggested Citation

  • Suganth Suppiah & Sheila Mansouri & Yasin Mamatjan & Jeffrey C. Liu & Minu M. Bhunia & Vikas Patil & Prisni Rath & Bharati Mehani & Pardeep Heir & Severa Bunda & German L. Velez-Reyes & Olivia Singh &, 2023. "Multiplatform molecular profiling uncovers two subgroups of malignant peripheral nerve sheath tumors with distinct therapeutic vulnerabilities," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38432-6
    DOI: 10.1038/s41467-023-38432-6
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