Expression Profiles of Five Common Cancer Membrane Protein Antigens Collected for the Development of Cocktail CAR-T Cell Therapies Applicable to Most Solid Cancer PatientsNakatsura, Takenouchi, Kataoka
et alInt J Mol Sci (2025) 26 (5)
Abstract: Although CD19 CAR-T has been highly effective against B-cell blood cancers, there are few reports of successful treatments for solid cancers, probably because there are few protein antigens specifically expressed on the surface of the cancer cell membrane. The key to developing a groundbreaking CAR-T cell therapy effective against solid cancers is to "overcome the heterogeneity of cancer antigens". For this purpose, it is necessary to target multiple cancer antigens simultaneously. In this study, we performed immunohistochemical analysis of various solid cancer specimens using antibodies against ROBO1, EphB4, CLDN1, and LAT1 in addition to GPC3, which we have previously studied. These antigens were frequently expressed in various solid cancers but shown to be rarely expressed, with some exceptions, in non-cancerous normal organs adjacent to the cancer. Although ROBO1 and GPC3 are often expressed in cytoplasm, there are also cases in which they are expressed on the cell membrane depending on the type of cancer. On the other hand, it has been revealed that three antigens-EphB4, CLDN1, and LAT1-are frequently expressed only on the cell membrane of cancer cells in various solid cancers, suggesting that they may be ideal targets for CAR-T cell therapy.
MYC regulation of the miR-92-Robo1 axis in Slit-mediated commissural axon guidanceMajumder, Khot, Suriyaarachchi
et alMol Biol Cell (2025) 36 (4), ar50
Abstract: In the developing spinal cord, translational repression of Robo1 expression by microRNA-92 (miR-92) in precrossing commissural axons (CAs) inhibits Slit/Robo1-mediated repulsion facilitating commissural axon projection and midline crossing; however, the regulatory mechanisms governing miR-92 expression in the developing commissural neurons are currently lacking. Here, we propose that the transcription factor MYC regulates miR-92 expression in the developing spinal cord (of either sex) to control Robo1 levels in precrossing CAs, modulating Slit/Robo1-mediated repulsion and midline crossing. MYC, miR-92, and Robo1 are differentially expressed in the developing chicken spinal cord. MYC binds to the promoter region upstream of the gga-miR-92 gene in vitro. MYC knockdown dramatically decreases miR-92 expression and increases chicken Robo1 (cRobo1) levels. In contrast, overexpression of MYC significantly induces miR-92 expression and reduces cRobo1 levels. MYC knockdown or overexpression results in significant inhibition or induction of miR-92 activity in the developing chicken spinal cord, respectively. Disruption of the MYC-dependent regulation of the miR-92-cRobo1 axis affects Slit2-mediated CA growth cone collapse in vitro and impairs CA projection and midline crossing in vivo. These results elucidate the role of the MYC-miR-92-cRobo1 axis in Slit2/Robo1-mediated CA repulsion and midline crossing.
Identification of 68 HLA-A24 and -A2-restricted cytotoxic T lymphocyte-inducing peptides derived from 10 common cancer-specific antigens frequently expressed in various solid cancersKinoshita, Takenouchi, Tsukamoto
et alNeoplasia (2025) 61, 101135
Abstract: Targeting cancer antigens expressed in cancer cells is necessary to develop cancer-specific immunotherapy. We have performed immunohistochemical analysis of various solid cancer specimens, adding ROBO1, AFP, TGFBI, EphB4, CLDN1, and LAT1 to the previously studied glypican-3 (GPC3), HSP105α, FOXM1, and SPARC, and found that these 10 common cancer antigens are sufficient to cover most solid cancers. These antigens were frequently expressed in various solid cancers but shown to be rarely ex-pressed, with some exceptions, in non-cancerous normal organs adjacent to the cancer. In this study, we predicted 72 and 73 peptides that bind to HLA-A24 and -A2 in silico from the full-length amino acid sequences of these 10 common cancer antigens and immunized each HLA transgenic mouse with a cocktail of synthesized peptides together with the poly I:CLC three times weekly to analyze the antigen-specific immune response. As a result, 68 peptide sequences (30 and 38, respectively) were identified that had higher cytotoxic T lymphocyte (CTL) induction ability than GPC3 298-306 and GPC3 144-152 used in the clinical trials. Furthermore, experiments with cocktail peptide vaccines using mouse models expressing subcutaneous tumors of each antigen showed promising results in terms of safety and efficacy. These peptides identified in this study, derived from 10 common cancer antigens covering all solid cancers, are expected to be clinically applicable as cocktail peptide vaccines.Copyright © 2025. Published by Elsevier Inc.
The microcephaly-associated transcriptional regulator AUTS2 cooperates with Polycomb complex PRC2 to produce upper-layer neurons in miceShimaoka, Hori, Miyashita
et alEMBO J (2025) 44 (5), 1354-1378
Abstract: AUTS2 syndrome is characterized by intellectual disability and microcephaly, and is often associated with autism spectrum disorder, but the underlying mechanisms, particularly concerning microcephaly, remain incompletely understood. Here, we analyze mice mutated for the transcriptional regulator AUTS2, which recapitulate microcephaly. Their brains exhibit reduced division of intermediate progenitor cells (IPCs), leading to fewer neurons and decreased thickness in the upper-layer cortex. Increased expression of the AUTS2 transcriptional target Robo1 in the mutant animals suppresses IPC division, and transcriptomic and chromatin profiling shows that AUTS2 primarily represses transcription of genes like Robo1 in IPCs. Regions around the transcriptional start sites of AUTS2 target genes are enriched for the repressive histone modification H3K27me3, which is reduced in Auts2 mutants. Furthermore, we find that AUTS2 interacts with Polycomb complex PRC2, with which it cooperates to promote IPC division. These findings shed light on the microcephaly phenotype observed in the AUTS2 syndrome.© 2025. The Author(s).
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