Flick, Matthew J.

Pharmacological plasminogen reduction enhanced liver regeneration experimentally and clinically. siRNA-induced plasminogen deficiency promoted hepatocyte proliferation after partial hepatectomy in mice, contrasting genetic deficiency models. In the HeLiX trial, tranexamic acid reduced post-hepatectomy liver failure odds, suggesting a novel therapeutic strategy.

Abstract Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults, with a dismal 5-year survival rate of ~6.5%. Vasogenic cerebral edema is a severe complication that occurs in the majority of GBM patients, leading to a significant increase in intracranial pressure, neurological deficits, and increased mortality rates. GBM-associated edema is almost exclusively managed by the corticosteroid dexamethasone, the use of which is associated with immunosuppression and interference with radiation therapy. While there is considerable research on edema formation, little is known about how edema resolution occurs in GBM, particularly in response to dexamethasone or other anti-edema therapies. This gap in understanding highlights the need for new approaches to treat edema effectively. The water channel aquaporin-4 (AQP4), a key player in the brain’s water homeostasis, is upregulated in GBM compared to the normal brain. To investigate the role of AQP4 in GBM-associated edema, we used the RCAS/tv-a system to generate de novo GBM with different driver mutations in Aqp4 knockout (KO) and wild-type (WT) mice. Our results indicated that Aqp4 KO tumor-bearing mice had shortened survival and increased edema content. Additionally, Aqp4 loss decreased astrocyte coverage specifically in the tumor core but not the tumor periphery. Our single cell RNA-seq data suggested that Aqp4 loss led to an astrocytic shift towards a less reactive, progenitor-like state, while also decreasing the myeloid and CD8+ T cell population in the tumor microenvironment. Interestingly, tumor-bearing mice treated with anti-VEGFA antibody, which has anti-edema properties, showed increased expression of Aqp4 and reduced vessel leakage. This suggests that AQP4 plays a critical role in mediating the effects of anti-VEGFA therapy. Overall, this study highlights the important role of AQP4 in the resolution of edema, while also revealing its additional effects on astrocyte activation and the immune microenvironment in GBM.

Abstract High-grade gliomas (HGG) have significant spatial heterogeneity, complicating therapeutic approaches. While multiparametric MRI (mpMRI) enables noninvasive assessment of this heterogeneity, most predictive models lack biological interpretability when used to classify or predict outcomes. Here, we developed an unsupervised framework that identifies novel mpMRI feature patterns through dimensional reduction, linking them to clinically relevant molecular signatures. We analyzed 18 advanced mpMRI features from 73 stereotactic biopsies across 20 HGG patients. Imaging data were normalized, followed by dimensional reduction using an iterative UMAP across varying parameters. Density-based clustering was used to generate stable image-derived clusters through consensus co-clustering. RNA-seq data from matched biopsies were analyzed using DESeq2 and GSEA to identify differentially expressed genes and enriched pathways. We then constructed a network linking specific imaging features to these transcriptional signatures. Validation was performed in an independent cohort, allowing us to extend clusters across full brain mpMRI. Unsupervised clustering of mpMRI features produced nine stable image-based clusters. These clusters were not fully explained by contrast enhancement, metabolic class, or tumor purity, shown by intraclass correlation (ICC) analyses, suggesting they capture novel biological variation. Transcriptomic analysis showed each cluster was associated with distinct gene expression patterns and enriched biological pathways, including neuronal differentiation, immune chemotaxis, and chromatin remodeling. Key imaging features (sRCBV, MTT, K2)—combined in cluster-specific patterns—enabled construction of an interpretable imaging–transcriptomic network. This was validated in an independent cohort. We then applied to full brain mpMRI, mapping spatially distinct regions to biological trends and patient outcomes. Addressing a research gap in imaging HGG, we present an interpretable network that connects specific patterns of mpMRI to clinically meaningful molecular signatures. This approach advances our understanding of tumor heterogeneity and supports future translational work in precision patient care.

Abstract Glioma stem cells (GSCs) are key drivers of glioblastoma (GBM) progression, therapy resistance, and recurrence, making them critical therapeutic targets. While the lineage-defining transcription factor OLIG2 is critical for GSC maintenance, the molecular co-regulators and downstream pathways it engages remain poorly defined. Here, we identify a previously unrecognized, functionally significant interaction between OLIG2 and STAT5B, uncovering a novel regulatory axis in GSCs. Using proximity ligation assay (PLA), we demonstrate that OLIG2 interacts with STAT5 in human and mouse GSC models, particularly in EGFRvIII-mutant cells. We find that OLIG2 preferentially partners with STAT5B and not STAT5A. Knockdown studies in GSCs reveal that OLIG2 and STAT5B co-regulate critical oncogenes BIRC5 and NUSAP1, both of which are required for sphere formation and migration capacity of EGFRvIII positive GSCs. In orthotopic xenograft models, knockdown of either STAT5B or OLIG2 significantly prolongs survival reduces expression of stemness and invasion markers, SOX2, VIMENTIN, and NUSAP1. In contrast, STAT5A knockdown fails to recapitulate these phenotypes, underscoring the role of OLIG2-STAT5B signaling in GSCs. These findings reveal a novel OLIG2-STAT5B transcriptional circuit that plays a role in GSC stemness maintenance, invasion, and tumor growth, particularly in EGFRvIII-driven gliomas. Targeting this axis may offer a new avenue for GBM treatment.