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; Gelareh Zadeh

doi:10.1038/s41467-023-38432-6

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

Nat Commun. 2023 May 10;14(1):2696. doi: 10.1038/s41467-023-38432-6.

Authors

Suganth Suppiah^{1

2}, Sheila Mansouri^#¹, Yasin Mamatjan^#^{1

3}, Jeffrey C Liu^#^{1

4}, Minu M Bhunia⁵, Vikas Patil¹, Prisni Rath⁶, Bharati Mehani⁷, Pardeep Heir¹, Severa Bunda¹, German L Velez-Reyes⁵, Olivia Singh¹, Nazanin Ijad¹, Neda Pirouzmand¹, Tatyana Dalcourt¹, Ying Meng², Shirin Karimi¹, Qingxia Wei¹, Farshad Nassiri^{1

2}, Trevor J Pugh^{6

8

9}, Gary D Bader^{8

9

10

11}, Kenneth D Aldape⁷, David A Largaespada^{5

12}, Gelareh Zadeh^{13

14}

Affiliations

¹ MacFeeters-Hamilton Centre for Neuro-Oncology Research, Princess Margaret Cancer Centre, Toronto, ON, Canada.
² Division of Neurosurgery, Department of Neurosurgery, University of Toronto, Toronto, ON, Canada.
³ Faculty of Science, Thompson Rivers University, Kamloops, BC, Canada.
⁴ The Donnelly Centre, University of Toronto, Toronto, ON, Canada.
⁵ Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
⁶ Ontario Institute for Cancer Research, Toronto, ON, Canada.
⁷ Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
⁸ Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
⁹ Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
¹⁰ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
¹¹ Department of Computer Science, University of Toronto, Toronto, ON, Canada.
¹² Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.
¹³ MacFeeters-Hamilton Centre for Neuro-Oncology Research, Princess Margaret Cancer Centre, Toronto, ON, Canada. Gelareh.zadeh@uhn.ca.
¹⁴ Division of Neurosurgery, Department of Neurosurgery, University of Toronto, Toronto, ON, Canada. Gelareh.zadeh@uhn.ca.

^# Contributed equally.

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.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.
Research Support, Non-U.S. Gov't

MeSH terms

Humans
Nerve Sheath Neoplasms* / genetics
Nerve Sheath Neoplasms* / metabolism
Nerve Sheath Neoplasms* / pathology
Neurofibromatosis 1* / genetics
Neurofibrosarcoma* / genetics
Neurofibrosarcoma* / metabolism
Schwann Cells / metabolism
Wnt Signaling Pathway / genetics

Grants and funding

UH3 CA244687/CA/NCI NIH HHS/United States