NRCAM variant defined by microexon skipping is a targetable cell surface proteoform in high-grade gliomas PMID: 40782352

ADC Targets in Oncology

2026-04-10

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

Cell Rep. 2025 Aug 26;44(8):116099. doi: 10.1016/j.celrep.2025.116099.

Priyanka Sehgal ¹ , Ammar S Naqvi ² , Makenna Higgins ¹ , Jiageng Liu ³ , Kyra Harvey ⁴ , Julien Jarroux ⁵ , Taewoo Kim ⁵ , Berk Mankaliye ⁵ , Pamela Mishra ⁶ , Grace Watterson ⁷ , Justyn Fine ⁸ , Jacinta Davis ¹ , Katharina E Hayer ⁶ , Annette Castro ¹ , Adanna Mogbo ⁹ , Charles Drummer 4th ¹ , Daniel Martinez ¹⁰ , Mateusz P Koptyra ² , Zhiwei Ang ¹ , Kai Wang ¹¹ , Alvin Farrel ¹² , Mathieu Quesnel-Vallieres ¹³ , Yoseph Barash ¹³ , Jamie B Spangler ¹⁴ , Jo Lynne Rokita ² , Adam C Resnick ² , Hagen U Tilgner ¹⁵ , Thomas De Raedt ⁴ , Daniel J Powell Jr ¹⁶ , Andrei Thomas-Tikhonenko ¹⁷

Affiliations

1. Division of Cancer Pathobiology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
2. Center for Data-Driven Discovery in Biomedicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
3. Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA.
4. Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
5. Center for Neurogenetics, Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA.
6. Division of Cancer Pathobiology, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Biomedical & Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
7. Cell and Molecular Biology Graduate Group, University of Pennsylvania, Philadelphia, PA, USA.
8. Program in Molecular Biophysics, Johns Hopkins University, Baltimore, MD, USA.
9. Vagelos Life Sciences Management Program, University of Pennsylvania, Philadelphia, PA, USA.
10. Pathology Core, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
11. Department of Pathology & Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA; Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
12. Department of Biomedical & Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
13. Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA.
14. Program in Molecular Biophysics, Johns Hopkins University, Baltimore, MD, USA; Department of Chemical & Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA.
15. Center for Neurogenetics, Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA; Helen and Robert Appel Alzheimer's Disease Research Institute, Weill Cornell Medicine, New York, NY, USA.
16. Department of Pathology & Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
17. Division of Cancer Pathobiology, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Cell and Molecular Biology Graduate Group, University of Pennsylvania, Philadelphia, PA, USA; Department of Pathology & Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: [email protected].

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-nt-long exons. Several of these skipped microexons mapped to L1-immunoglobulin cell adhesion molecule (IgCAM) family members, such as neuronal CAM (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" 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.

Keywords

CP: Cancer; CP: Immunology; alternative splicing; antibodies; cell adhesion molecules; glioblastoma; glioma; immunotherapy; mRNA processing; microexons.