115: A Transcriptomic, Proteomic, and Functional Genetic Atlas Dissects Neurofibromin Function in the Peripheral Nervous System

Episode 115: A Transcriptomic, Proteomic, and Functional Genetic Atlas Dissects Neurofibromin Function in the Peripheral Nervous System

In this episode of PaperCast Base by Base, we explore how an integrated multi‑omics and CRISPR interference atlas maps the function of the NF1 tumor suppressor neurofibromin in peripheral nerve cells and reveals context‑specific therapeutic sensitivities relevant to neurofibromatosis type 1 and related tumors.

Study Highlights:
Using CRISPR interference in immortalized peripheral nerve cells, the authors systematically repressed NF1 and key upstream Ras regulators and profiled transcriptomes, phosphoproteomes, and drug responses to delineate neurofibromin’s roles. NF1 repression increased Ras‑GTP, promoted proliferation and dedifferentiation, and reduced sensitivity to the MEK inhibitor selumetinib due to feedback rewiring of the Ras/RAF/MEK/ERK pathway. PTPN11 repression produced the inverse gene‑expression program and sensitized cells to selumetinib, whereas SOS1 inhibition showed limited efficacy because of compensation by SOS2. Proximity proteomics revealed that KRAS, but not HRAS or NRAS, associates with neurofibromin, and pan‑KRAS inhibition blocked ERK and CDK1/2 activation in NF1‑mutant cells, nominating KRAS as a direct therapeutic dependency in the peripheral nervous system context.

Conclusion:
By unifying CRISPRi perturbations with transcriptomic, phosphoproteomic, proximity‑labeling, and pharmacologic readouts, this atlas clarifies NF1‑driven pathway wiring and prioritizes KRAS inhibition as a rational complement to MEK therapy in NF1‑mutant peripheral nerve tumors.

Reference:
Vasudevan HN, Arang N, Sacconi Nunez M, Mohabeer S, Chien J, Wright A, Sale MJ, Krogan NJ, Forget A, McCormick F, et al. A transcriptomic, proteomic, and functional genetic atlas dissects neurofibromin function in the peripheral nervous system. Proceedings of the National Academy of Sciences. 2025;122:e2506823122. https://doi.org/10.1073/pnas.2506823122

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

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Keywords: NF1; neurofibromin; KRAS; CRISPR interference; phosphoproteomics

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