Glioblastoma is the most malignant primary brain tumor for which the prognosis remains dismal even with aggressive surgical, medical, and radiation therapies. Glioblastoma stem cells (GSCs) promote therapeutic resistance and cellular heterogeneity due to their self-renewal properties and capacity for plasticity. To understand the molecular processes essential for maintaining GSCs, we performed an integrative analysis comparing active enhancer landscapes, transcriptional profiles, and functional genomics profiles of GSCs and non-neoplastic neural stem cells (NSCs). We identified sorting nexin 10 (SNX10), an endosomal protein sorting factor, as selectively expressed in GSCs compared to NSCs and essential for GSC survival. Targeting SNX10 impaired GSC viability and proliferation, induced apoptosis, and reduced self-renewal capacity. Mechanistically, GSCs utilized endosomal protein sorting to promote platelet-derived growth factor receptor β (PDGFRβ) proliferative and stem cell signaling pathways through post-transcriptional regulation of the PDGFR tyrosine kinase. Targeting SNX10 expression extended survival of orthotopic xenograft-bearing mice, and high SNX10 expression correlated with poor glioblastoma patient prognosis, suggesting its potential clinical importance. Thus, our study reveals an essential connection between endosomal protein sorting and oncogenic receptor tyrosine kinase signaling and suggests that targeting endosomal sorting may represent a promising therapeutic approach for glioblastoma treatment.
The diacylglycerol kinases (DGKs) are a family of enzymes responsible for the conversion of diacylglycerol (DAG) to phosphatidic acid (PA). In addition to their primary function in lipid metabolism, DGKs have recently been identified as potential therapeutic targets in multiple cancers, including glioblastoma (GBM) and melanoma. Aside from its tumorigenic properties, DGKα is also a known promoter of T-cell anergy, supporting a role as a recently-recognized T cell checkpoint. In fact, the only significant phenotype previously observed in Dgka knockout (KO) mice is the enhancement of T-cell activity. Herein we reveal a novel, macrophage-specific, immune-regulatory function of DGKα. In bone marrow-derived macrophages (BMDMs) cultured from wild-type (WT) and KO mice, we observed increased responsiveness of KO macrophages to diverse stimuli that yield different phenotypes, including LPS, IL-4, and the chemoattractant MCP-1. Knockdown (KD) of Dgka in a murine macrophage cell line resulted in similar increased responsiveness. Demonstrating in vivo relevance, we observed significantly smaller wounds in Dgka-/- mice with full-thickness cutaneous burns, a complex wound healing process in which macrophages play a key role. The burned area also demonstrated increased numbers of macrophages. In a cortical stab wound model, Dgka-/- brains show increased Iba1+ cell numbers at the needle track versus that in WT brains. Taken together, these findings identify a novel immune-regulatory checkpoint function of DGKα in macrophages with potential implications for wound healing, cancer therapy, and other settings.
BACKGROUND Patients with brain metastases from gastroesophageal primary cancers have poor prognoses, and current management remains unclear. The authors present the largest single-institution experience of utilizing stereotactic radiosurgery (SRS) to treat patients with brain metastases from primary gastroesophageal cancers. METHODS A retrospective review of 71 patients (64 male, 90.14%) treated with Gamma Knife SRS from 2000 to 2022 for gastroesophageal primary cancers was conducted. Overall, 243 brain metastases were treated, and the median number of metastases per patient was 2 (range:1-21). The primary sites were esophagus (59 patients, 83.10%), gastric (7 patients, 9.86%), and gastroesophageal junction (5 patients, 7.04%). The median age at SRS was 66 years (range: 26-85), and the median KPS was 80 (range: 50-100). The median cumulative tumor volume was 6.7 cc (range: 0.27-104.76), and the median margin dose was 18 Gy (range: 11-20). RESULTS The median overall survival after SRS was 7 months (range: 1-64). At the last follow-up, 54 (76.06%) patients were deceased, and 8 (14.81%) patients died due to intracranial metastases. Four patients (5.63%) experienced local tumor progression at a median time of 8 months (range: 2-13) after SRS. On univariate analysis, > 2 brain metastases at SRS presentation (p=0.02, HR: 10.76, 95% CI: 1.48-78.40) was found to be the only significant predictor of local tumor progression. Ten patients (14.08%) experienced new tumor development at a median time of 4 months (range: 0-14) after SRS. On multivariate analysis, both the absence of concurrent systemic therapy (p=0.01, HR: 6.58, 95% CI: 1.55-27.0) and ≤ 2 tumors at SRS presentation (p<0.01, HR: 1.21, CI: 1.08-1.36) were found to be significant predictors of distant tumor control. The incidence of transient adverse radiation effects was 8.45%. CONCLUSIONS SRS can safely and effectively be used to treat primary gastroesophageal cancer brain metastases while allowing patients to focus on primary disease management.
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