Neuronal cell adhesion molecule (NRCAM) variant defined by microexon skipping is an essential, antigenically distinct, and targetable surface proteoform in high-grade glioma

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 14, 2025

Abstract To overcome the paucity of known tumor-specific surface antigens in pediatric high-grade glioma (pHGG), we contrasted splicing patterns pHGGs and normal brain samples. Among alternative events affecting extracellular protein domains, most pervasive alteration was skipping ≤30 nucleotide-long microexons. Several these skipped microexons mapped to L1-IgCAM family members, such as NRCAM . Bulk single-nuclei short- long-read RNA-seq revealed uniform 5 19 virtually every pHGG sample. Importantly, Δex5Δex19 (but not full-length) proteoform essential for cell migration invasion vitro tumor growth vivo. We developed a monoclonal antibody selective demonstrated that “painting” cells with this enables killing by T armed an FcRI-based universal immune receptor. Thus, pHGG-specific possibly other proteoforms are promising highly targets adoptive immunotherapies. Statement significance Existing chimeric antigen receptors (CAR)-armed often shared CNS tumors tissues, creating potential on-target/off-tumor toxicities. Here demonstrate glial origin, adhesion molecules have alternatively spliced proteoforms, which could be targeted therapeutic antibodies.

Language: Английский

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Poison exons: tuning RNA splicing for targeted gene regulation

Trends in Pharmacological Sciences, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Language: Английский

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Peptides from abnormal RNA processing in cancer offer an immunotherapy target

Nature, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 19, 2025

Language: Английский

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The costimulatory domain influences CD19 CAR-T cell resistance development in B-cell malignancies.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 5, 2025

Abstract CD19-CAR-T-cells emerge as a major therapeutic option for relapsed/refractory B-cell-derived malignancies, however approximately half of patients eventually relapse. To identify resistance-driving factors, we repeatedly exposed B-cell lymphoma/B-cell acute lymphoblastic leukemia to 4-1BB/CD28-based in vitro . Generated models revealed costimulatory domain-dependent differences CD19 loss. While CD19-4-1BB-CAR-T-cells induced combination epitope/total protein loss, CD19-CD28-CAR-T-cells did not drive antigen-escape. Consistent with observations relapsing after CD19-4-1BB-CAR-T-cells, identified frameshift/missense mutations affecting residues critical FMC63 epitope recognition. Mathematical simulations that between CD19-4-1BB- and activity against low-antigen-expressing tumor contribute heterogeneous responses. By integrating silico data, propose biological scenario where fail eliminate low-antigen cells, fostering CAR-resistance. These findings offer mechanistic insight into the observed clinical axi-cel (CD28-based) tisa-cel (4-1BB-based)-treated lymphoma advance our understanding on CAR-T resistance. Furthermore, underscore need specific detection deliver information antigen levels accessible CD19-CAR-T-cells. Visual abstract

Language: Английский

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SRSF2 overexpression induces transcription-/replication-dependent DNA double-strand breaks and interferes with DNA repair pathways to promote lung tumor progression

NAR Cancer, Journal Year: 2025, Volume and Issue: 7(2)

Published: April 2, 2025

Abstract SRSF2 (serine/arginine-rich splicing factor 2) is a critical regulator of pre-messenger RNA splicing, which also plays noncanonical functions in transcription initiation and elongation. Although elevated levels are associated with advanced stages lung adenocarcinoma (LUAD), the mechanisms connecting to tumor progression remain unknown. We show that overexpression increases global replicative stress LUAD cells, correlates production DNA damage, notably double-strand breaks (DSBs), likely resulting from conflicts between replication. Moreover, regulates repair pathways by promoting homologous recombination inhibiting nonhomologous end joining. Mechanistically, interacts enhances MRE11 (meiotic 11) recruitment chromatin, while downregulating 53BP1 messenger protein levels. Both events contributing SRSF2-mediated process rerouting. Lastly, we expression commonly predicts poor outcome patients. Altogether, our results identify mechanism promotes cancer through fine control both DSB repair. Finally, knockdown impairs late ionizing radiation-induced DSBs, suggesting more function recombination.

Language: Английский

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Exploring RNA biology in pseudomyxoma peritonei uncovers splicing dysregulation as a novel, targetable molecular vulnerability

Cancer Gene Therapy, Journal Year: 2025, Volume and Issue: unknown

Published: April 29, 2025

Pseudomyxoma peritonei (PMP) is a rare neoplasm coursing with uncontrollable mucus accumulation, high relapse rate. RNA biology processes have emerged as new players in cancer development and progression, nevertheless their role PMP remains unknown. In this study, we aimed to examine RNA-regulatory machineries potential contribution disease progression. We analyzed 62 splicing-related genes, 27 exosome 21 nonsense-mediated decay cohort of 29 patients using microfluidic array, comparing tumor control/reference tissues, together external RNA-seq proteomic data. Our results revealed profound dysregulation key components, which correlated relevant clinical parameters enabled distinguish between control tissues. vitro splicing inhibition Pladienolide-B, well the modulation specific factors, reduced aggressiveness parameters, enhanced effect clinically used drugs, strong correlation dysregulated genes cancer-related genes. This also affected mucin secretion variants production. Collectively, our findings provide first evidence for pivotal PMP, implying that these targetable mechanisms may be functionally altered play disease. Hence, thorough understanding its could aid discovery actionable vulnerabilities

Language: Английский

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Splicing dysregulation: hallmark and therapeutic opportunity in pancreatic cancer

Trends in Molecular Medicine, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 1, 2024

Language: Английский

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