ABSTRACT
Tumor-associated macrophages (TAMs) residing in the tumor microenvironment (TME) are characterized by their pivotal roles in tumor progression, antitumor immunity, and TME remodeling. However, a thorough comparative characterization of tumor-TAM crosstalk across IDH-defined categories of glioma remains elusive, likely contributing to mixed outcomes in clinical trials. We delineated the phenotypic heterogeneity of TAMs across IDH-stratified gliomas. Notably, two TAM subsets with a mesenchymal phenotype were enriched in IDH-WT glioblastoma (GBM) and correlated with poorer patient survival and reduced response to anti-PD-1 immune checkpoint inhibitor (ICI). We proposed SLAMF9 receptor as a potential therapeutic target. Inference of gene regulatory networks identified PPARG, ELK1, and MXI1 as master transcription factors of mesenchymal BMD-TAMs. Our analyses of reciprocal tumor-TAM interactions revealed distinct crosstalk in IDH-WT tumors, including ANXA1-FPR1/3, FN1-ITGAVB1, VEGFA-NRP1, and TNFSF12-TNFRSF12A with known contribution to immunosuppression, tumor proliferation, invasion and TAM recruitment. Spatially resolved transcriptomics further elucidated the architectural organization of highlighted communications. Furthermore, we demonstrated significant upregulation of ANXA1, FN1, NRP1, and TNFRSF12A genes in IDH-WT tumors using bulk RNA-seq and RT-qPCR. Longitudinal expression analysis of candidate genes revealed no difference between primary and recurrent tumors indicating that the interactive network of malignant states with TAMs does not drastically change upon recurrence. Collectively, our study offers insights into the unique cellular composition and communication of TAMs in glioma TME, revealing novel vulnerabilities for therapeutic interventions in IDH-WT GBM.
Subject(s)
Brain Neoplasms , Glioma , Isocitrate Dehydrogenase , Transcriptome , Tumor Microenvironment , Tumor-Associated Macrophages , Humans , Tumor Microenvironment/genetics , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Brain Neoplasms/metabolism , Isocitrate Dehydrogenase/genetics , Tumor-Associated Macrophages/metabolism , Tumor-Associated Macrophages/pathology , Glioma/genetics , Glioma/pathology , Glioma/metabolism , Single-Cell AnalysisABSTRACT
Ulcerative colitis (UC) is a chronic idiopathic inflammatory bowel disease (IBD) that progressively affects mucosa and submuccosa of the colon and rectum in a continual pattern. In comparison, Crohn disease (CD), the other type of IBD, is a chronic transmural inflammatory disorder that can involve any part of the gastrointestinal tract. MR enterography (MRE) has emerged as an important imaging modality for the diagnosis and detection of disease activity and complications in CD, with comparable results to those of endoscopy. But MRE has been underused for assessment of UC in recent years, and clinicians heavily rely on endoscopic findings for management of UC. Despite UC being considered an endoscopically assessable disease, MRE can provide useful information beyond that obtained with endoscopy about mural or extramural abnormalities, inaccessible parts of the colonic lumen, associated extraintestinal diseases, and superimposed pathologic conditions. Moreover, endoscopy might be contraindicated in some clinical settings due to the risk of colonic perforation. In addition to depicting the features of UC activity in different phases, MRE demonstrates findings of disease chronicity that cannot be achieved with endoscopy, particularly in a patient with colitis of unknown cause. The valuable diagnostic role of MRE to exclude undiagnosed CD in patients with UC who have refractory disease or those with postproctocolectomy complications is also emphasized. Radiologists can play a crucial role in the management of UC with MRE by addressing what is beyond endoscopy. ©RSNA, 2023 Test Your Knowledge questions are available in the supplemental material.
Subject(s)
Colitis, Ulcerative , Crohn Disease , Inflammatory Bowel Diseases , Humans , Colitis, Ulcerative/diagnostic imaging , Crohn Disease/diagnostic imaging , Endoscopy, Gastrointestinal , RectumABSTRACT
BACKGROUND: Ameloblastoma is a common locally invasive but slow-growing neoplasm of the jaws with an odontogenic origin. Association between BRAF V600E mutation and clinicopathologic features and behavior of ameloblastoma remains controversial. This study aimed to evaluate BRAF V600E gene mutation and expression of its related proteins with clinicopathologic parameters in conventional ameloblastoma. MATERIAL AND METHODS: 50 Formalin-fixed paraffin-embedded blocks were included in this study. Immunohistochemistry was done using rabbit monoclonal BRAF V600E mutation-specific antibody VE1. Quantitative real-time polymerase chain reaction assay was used for evaluating of BRAF V600E mutation. RESULTS: Expression of BRAF V600E antibody was Positive in 42 out of 50 cases (84%). 46 (92%) out of 50 specimens showed BRAF V600E mutation. There were 13 cases of recurrence (26%). 3 out of 4 cases with negative mutations did not show recurrence. CONCLUSIONS: We report the highest frequency (92%) of BRAF V600E mutation in ameloblastomas in the Iranian population. Although there was not a significant association between BRAF V600E-positive immunoexpression and recurrence and clinicopathologic parameters, its high frequency could emphasize its role as a therapeutic marker in the future
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