2. Academic Validation
  3. NRCAM variant defined by microexon skipping is a targetable cell surface proteoform in high-grade gliomas

NRCAM variant defined by microexon skipping is a targetable cell surface proteoform in high-grade gliomas

  • bioRxiv. 2025 Aug 4:2025.01.09.631916. doi: 10.1101/2025.01.09.631916.
Priyanka Sehgal,  Ammar S Naqvi,  Makenna Higgins,  Jiageng Liu,  Kyra Harvey,  Julien Jarroux,  Taewoo Kim,  Berk Mankaliye,  Pamela Mishra,  Grace Watterson,  Justyn Fine,  Jacinta Davis,  Katharina E Hayer,  Annette Castro,  Adanna Mogbo,  Charles Drummer,  Daniel Martinez,  Mateusz P Koptyra,  Zhiwei Ang,  Kai Wang,  Alvin Farrel,  Mathieu Quesnel-Vallieres,  Yoseph Barash,  Jamie B Spangler,  Jo Lynne Rokita,  Adam C Resnick,  Hagen U Tilgner,  Thomas De Raedt,  Daniel J Powell,  Andrei Thomas-Tikhonenko
PMID: 39868324 DOI: 10.1101/2025.01.09.631916
Abstract

To overcome the paucity of known tumor-specific surface antigens in pediatric high-grade glioma (pHGG), we contrasted splicing patterns in pHGGs and normal brain samples. Among alternative splicing events affecting extracellular protein domains, the most pervasive alteration was the skipping of ≤30 nucleotide-long exons. Several of these skipped microexons mapped to L1-IgCAM family members, such as NRCAM . Bulk and single-nuclei short- and long-read RNA-seq revealed uniform skipping of NRCAM microexons 5 and 19 in virtually every pHGG sample. Importantly, the Δex5Δex19 (but not the full-length) NRCAM proteoform was essential for pHGG cell migration and invasion in vitro and tumor growth in vivo. We developed a monoclonal antibody selective for Δex5Δex19 NRCAM and demonstrated that "painting" of pHGG cells with this antibody enables killing by T cells armed with an FcRI-based universal immune receptor. Thus, pHGG-specific NRCAM and possibly Other L1-IgCAM proteoforms are promising and highly selective targets for adoptive immunotherapies.

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