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

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, Nazanin Ijad, Neda Pirouzmand, Tatyana Dalcourt, Ying Meng, Shirin Karimi, Qingxia Wei, Farshad Nassiri, Trevor J. Pugh, Gary D. Bader, Kenneth D. Aldape, David A. Largaespada and Gelareh Zadeh ()
Additional contact information
Suganth Suppiah: Princess Margaret Cancer Centre
Sheila Mansouri: Princess Margaret Cancer Centre
Yasin Mamatjan: Princess Margaret Cancer Centre
Jeffrey C. Liu: Princess Margaret Cancer Centre
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
Trevor J. Pugh: Ontario Institute for Cancer Research
Gary D. Bader: University of Toronto
Kenneth D. Aldape: National Cancer Institute
David A. Largaespada: University of Minnesota
Gelareh Zadeh: Princess Margaret Cancer Centre

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-38432-6

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