Nature communications · 2023
Multiplatform molecular profiling uncovers two subgroups of malignant peripheral nerve sheath tumors with distinct therapeutic vulnerabilities.
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Suppiah Suganth, Mansouri Sheila, Mamatjan Yasin, Liu Jeffrey C, Bhunia Minu M, Patil Vikas, Rath Prisni, Mehani Bharati, Heir Pardeep, Bunda Severa, Velez-Reyes German L, Singh Olivia, Ijad Nazanin, Pirouzmand Neda, Dalcourt Tatyana, Meng Ying, Karimi Shirin, Wei Qingxia, Nassiri Farshad, Pugh Trevor J, Bader Gary D, Aldape Kenneth D, Largaespada David A, Zadeh Gelareh
Аннотация
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.