Multiplatform molecular profiling uncovers two subgroups of malignant peripheral nerve sheath tumors with distinct therapeutic vulnerabilities
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- May 10, 2023
- Source ID
- 10.1038/s41467-023-38432-6
Entities
People
- Bharati Mehani
- David A. Largaespada
- Farshad Nassiri
- Gary D. Bader
- Gelareh Zadeh
- German L. Velez-reyes
- Jeffrey C. Liu
- Kenneth Aldape
- Minu Bhunia
- Nazanin Ijad
- Neda Pirouzmand
- Olivia Singh
- Pardeep Heir
- Prisni Rath
- Qingxia Wei
- Severa Bunda
- Sheila Mansouri
- Shirin Karimi
- Suganth Suppiah
- Tatyana Dalcourt
- Trevor J Pugh
- Vikas Patil
- Yasin Mamatjan
- Ying Meng
Organizations
- United States Department of Defense