Spatial Gene-Expression Profiling Unveils Immuno-oncogenic Programs of NF1-Associated Peripheral Nerve Sheath Tumor...

Area of Science:

• Oncology
• Genetics
• Immunology

Background:

• Plexiform neurofibromas (PNF) are benign tumors in neurofibromatosis type 1 (NF1).
• A subset of PNFs progress to malignant peripheral nerve sheath tumors (MPNST), a major cause of mortality in NF1.
• Malignant transformation is often preceded by atypical neurofibroma (ANF) lesions, but early transcriptional changes are poorly understood.

Purpose of the Study:

• To define gene-expression profiles across the neurofibroma-to-MPNST spectrum in NF1.
• To identify early molecular features associated with PNF evolution and malignant transformation.

Main Methods:

• Analysis of gene-expression profiles in PNST from NF1 patients and mouse models.
• Investigated transcriptional changes in neurofibromas, atypical neurofibromas, and MPNSTs.
• Targeted key mediators like CENPF and BIRC5 in MPNST cell lines and precursors.

Main Results:

• Atypical neurofibromas show enhanced antigen presentation and immune response signatures, which decrease during malignant progression.
• MPNSTs exhibit dysregulated survival and mitotic fidelity pathways.
• Targeting CENPF and BIRC5 inhibited MPNST growth and viability.
• Neurofibromas near MPNSTs displayed altered oncogenic and immune surveillance programs, suggesting early molecular events precede visible malignancy.

Conclusions:

• Identified molecular signatures in PNST that may predict malignant transformation risk.
• These signatures could serve as diagnostic tools to augment histopathology.
• Facilitates risk-adapted care for NF1 patients with PNF.