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A Synaptogenesis-Associated Histomorphologic Signature from H&E Whole-Slide Images Predicts Glioma Prognosis and Identifies <i>EFNB2</i>-Positive Malignant Cells as a Candidate Neuro-Glioma Communication Hub.

Overview

Authors: Xiaolong Wu1,2, Dong Liu1,2, Haoming Geng1,2, Binghan Zhang1,2, Huantong Diao1,2, Yiqiang Zhou1,2, Gang Song1,2, Ye Cheng1,2, Jiantao Liang1,2
ORCID iDs: Xiaolong Wu
  1. Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
  2. China International Neuroscience Institute, Beijing 100053, China
Institutions: Capital Medical University (China); Xuan Wu Hospital of the Capital Medical University (China)
Journal: International journal of molecular sciences, volume 27, issue 10, article 4300
Dates: received 18 March 2026; accepted 29 April 2026; published online 12 May 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.3390/ijms27104300 · PMID 42196284 · PMCID PMC13207882 · OpenAlex W7160930522
Open access: gold, a free copy (OpenAlex)
Status: data only
Categories: genetics / omics (modality), human (organism), other condition (population)
Methods: Statistics, Smoothing, state filtering, decompositions, Connectivity, Machine learning
Keywords: gliomas, neuron–glioma interactions, synaptogenesis, pathology, EFNB2
MeSH: Brain Neoplasms*, Ephrin-B2*, Glioma*, Synapses*, Biomarkers, Tumor, Female, Gene Expression Regulation, Neoplastic, Humans, Male, Prognosis (* major topic)
Topic: Glioma Diagnosis and Treatment (Genetics, Medicine), according to OpenAlex
Funding: National Key R&D Program of China (2021YFC2400803); National Natural Science Foundation of China (82373403)
Citations: not cited yet (Europe PMC); 46 references in the paper

Abstract

Synaptogenesis-related neuron–glioma interactions are increasingly recognized in glioma, yet it remains unclear whether routine H&E morphology can capture these programs and improve prognostic stratification. We integrated H&E whole-slide images, transcriptomes, and clinical data from 434 TCGA gliomas. Deep learning and quantitative pathology yielded an integrated histomorphologic feature set of 2678 features. Synaptogenesis-related activity was quantified using ssGSEA for ninety-eight synaptogenesis-related genes. In the training cohort, Spearman analysis identified 149 correlated histomorphologic features, which were refined to thirty-five by elastic net regularization. Seventeen prognostic candidates were entered into the MIME1 framework, and the most parsimonious model, Enet[0.1], retained fourteen non-zero-coefficient features to define the synaptogenesis-associated histomorphologic signature and construct the pathology-derived risk score (PRS). Multi-omic analyses, Human Protein Atlas validation, and single-nucleus RNA-seq were used to investigate the hub gene and its cellular context. PRS robustly stratified survival in both training and validation cohorts and remained an independent prognostic factor after adjustment for age and 2021 WHO CNS grade. High-risk tumors showed increased stromal and immune scores and enrichment of immune, adhesion, and phagosome-related pathways. EFNB2 emerged as the hub gene and was enriched in glioblastoma, and EFNB2-positive malignant cells displayed prominent communication with neurons, including EFNB2-EPHB1 signaling. Exploratory re-analysis of the myeloid compartment further showed that glioblastoma was enriched for suppressive TAM-like states relative to astrocytoma grade 2, supporting a shift toward a more tumor-associated and potentially immunosuppressive microenvironment. Routine H&E histomorphology can capture synaptogenesis-related molecular programs in glioma. The resulting PRS provides clinically relevant prognostic stratification, while EFNB2-positive malignant cells may represent a candidate hub for neuron–tumor communication within a remodeled tumor ecosystem.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

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Data

Datasets cited

Data Availability Statement

The data presented in this study are available in the public domain. Histopathological whole-slide images were obtained from the Genomic Data Commons (GDC) portal at https://portal.gdc.cancer.gov/ (accessed on 1 November 2025). Transcriptomic and clinical data for TCGA glioma were obtained from UCSC Xena at https://xena.ucsc.edu/ (accessed on 29 December 2022). The glioblastoma single-nucleus RNA-seq dataset is available in the Gene Expression Omnibus (GEO) at https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE274987 (accessed on 4 October 2025), reference number GSE274987. The astrocytoma grade 2 single-nucleus RNA-seq dataset is available in Zenodo at https://zenodo.org/records/10435521 (accessed on 4 October 2025), reference number 10435521. Immunohistochemical data were obtained from the Human Protein Atlas at https://www.proteinatlas.org/ (accessed on 31 January 2026). Additional molecular alteration data were derived from Ceccarelli et al. [6], and the updated 2021 WHO CNS classification annotations matched to the TCGA glioma transcriptomic samples were curated from Zakharova et al. [31].

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 28 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 9 authors, 5 keywords, 10 MeSH terms, 2 funders, 46 references.

Cite

This paper

Wu, X., Liu, D., Geng, H., Zhang, B., Diao, H., Zhou, Y., Song, G., Cheng, Y., & Liang, J. (2026). A Synaptogenesis-Associated Histomorphologic Signature from H&E Whole-Slide Images Predicts Glioma Prognosis and Identifies <i>EFNB2</i>-Positive Malignant Cells as a Candidate Neuro-Glioma Communication Hub. International journal of molecular sciences, 27(10), 4300. https://doi.org/10.3390/ijms27104300

BibTeX

@article{wu2026synaptogenesis,
author = {Wu, Xiaolong and Liu, Dong and Geng, Haoming and Zhang, Binghan and Diao, Huantong and Zhou, Yiqiang and Song, Gang and Cheng, Ye and Liang, Jiantao},
title = {{A Synaptogenesis-Associated Histomorphologic Signature from H\&E Whole-Slide Images Predicts Glioma Prognosis and Identifies \<i\>EFNB2\</i\>-Positive Malignant Cells as a Candidate Neuro-Glioma Communication Hub}},
journal = {International journal of molecular sciences},
year = {2026},
month = may,
volume = {27},
number = {10},
pages = {4300},
publisher = {Multidisciplinary Digital Publishing Institute (MDPI)},
issn = {1422-0067},
doi = {10.3390/ijms27104300},
url = {https://doi.org/10.3390/ijms27104300},
pmid = {42196284},
pmcid = {PMC13207882}
}

RIS

TY - JOUR
AU - Wu, Xiaolong
AU - Liu, Dong
AU - Geng, Haoming
AU - Zhang, Binghan
AU - Diao, Huantong
AU - Zhou, Yiqiang
AU - Song, Gang
AU - Cheng, Ye
AU - Liang, Jiantao
TI - A Synaptogenesis-Associated Histomorphologic Signature from H&E Whole-Slide Images Predicts Glioma Prognosis and Identifies <i>EFNB2</i>-Positive Malignant Cells as a Candidate Neuro-Glioma Communication Hub
T2 - International journal of molecular sciences
J2 - Int J Mol Sci
PY - 2026
DA - 2026/05/12
VL - 27
IS - 10
SP - 4300
SN - 1422-0067
PB - Multidisciplinary Digital Publishing Institute (MDPI)
DO - 10.3390/ijms27104300
UR - https://doi.org/10.3390/ijms27104300
LA - en
ER -

CSL-JSON

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