Biology subjects

Zamler, D. B.

Publications and source records attributed to Zamler, D. B..

3 recordsLinked to original sources

bioRxiv2020

Oncostreams: Self-organization and dynamics determine spatial heterogeneity and malignant behavior in gliomas

Intra-tumoral heterogeneity and diffuse infiltration are hallmarks of glioblastoma that challenge treatment efficacy. However, the mechanisms that set up both tumor heterogeneity and invasion remain poorly understood. Herein, we present a comprehensive spatiotemporal study that aligns distinctive intra-tumoral histopathological structures, oncostreams, with dynamic properties and a unique, actionable, spatial transcriptomic signature. Oncostreams are dynamic multicellular fascicles of spindle-like and aligned cells with mesenchymal properties, detected using ex vivo explants and in vivo intravital imaging. Their density correlates with tumor aggressiveness in genetically engineered mouse glioma models, and high-grade human gliomas. Oncostreams facilitate the intra-tumoral distribution of tumoral and non-tumoral cells, and the invasion of the normal brain. These fascicles are defined by a specific molecular signature that regulates their organization and function. Oncostreams structure and function depend on overexpression of COL1A1. COL1A1 is a central gene in the dynamic organization of glioma mesenchymal transformation, and a powerful regulator of glioma malignant behavior. Inhibition of COL1A1 eliminated oncostreams, reprogramed the malignant histopathological phenotype, reduced expression of the mesenchymal associated genes, induced changes in the tumor microenvironment and prolonged animal survival. Oncostreams represent a novel pathological marker of potential value for diagnosis, prognosis, and treatment.

cancer biology↗

bioRxiv2020

Immune landscape of a genetically-engineered murine model of glioma relative to human glioma by single-cell sequencing

BackgroundThis study focuses on the evaluation of intratumoral immune infiltrates of the Qk/trp53/Pten (QPP) triple-knockout mouse model of glioblastoma with the purpose of establishing its relevance compared to the human disease. This included an analysis at the single cell level, of immune cells composition in both spontaneous and implanted mouse tumors and of samples obtained from human tumor resections. MethodsWe analyzed a cohort of fifteen spontaneous QPP mice, nine implanted QPP mice and 10 glioma patients by standard immune profiling methods such as IHC. Of those, we analyzed three spontaneous QPP mice, three implanted QPP mice, and 10 glioma patients by single cell RNA sequencing. ResultsIn the QPP samples we identified a predominantly myeloid cell population of monocytes, macrophages, and microglia, with minor populations of T, B, and NK cells. When comparing spontaneous and implanted mouse samples, we found that there were more neutrophil, T and NKT cells in the implanted model. In human samples, most of the lymphoid and myeloid compartments were immunosuppressive. While the complexity of the myeloid cell populations is preserved between the QPP model and the human disease, we observed significantly more immune-stimulatory populations in the implanted mouse model. ConclusionsWe found that, despite differences at the subpopulation level, the immunosuppressive nature of the immune system in glioma, is recapitulated in our mouse model. Although we observed differences in the proportions of immune infiltrates derived from the spontaneous and implanted mouse models and in LGG compared to GBM, the major constituents are present in all cases and these differences may be caused by various etiological or pathogenic influences on tumor-immune interactions. Key PointsO_LINew GBM mouse model for immunotherapy C_LIO_LISingle cell profiling of the immune systems in human and mouse GBM C_LI

cancer biology↗

bioRxiv2019

THE PROTO-ONCOGENE FYN INHIBITS THE ANTI-GLIOBLASTOMA IMMUNE RESPONSE

BackgroundHigh grade gliomas are aggressive and immunosuppressive brain tumors. Molecular mechanisms that regulate the inhibitory immune tumor microenvironment (TME) and glioma progression remain poorly understood. FYN tyrosine kinase is a downstream target of the oncogenic receptor tyrosine kinases pathway and is overexpressed in human gliomas. FYNs role in vivo in glioma growth remains unknown. We investigated whether FYN regulates glioma initiation, growth and invasion. MethodsWe evaluated the role of FYN using genetically engineered mouse glioma models (GEMM). We also generated FYN knockdown stem cells to induce gliomas in immune-competent and immune-deficient mice (NSG, CD8-/-, CD4-/-). We analyzed molecular mechanism by RNA-Seq and bioinformatics analysis. Flow cytometry was used to characterize immune cellular infiltrates in the FYN knockdown glioma TME. ResultsWe demonstrate that FYN knockdown in diverse immune-competent GEMMs of glioma reduced tumor progression and significantly increased survival. Gene ontologies (GOs) analysis of differentially expressed genes in wild type vs. FYN knockdown gliomas showed enrichment of GOs related to immune reactivity. However, in NSG, CD8-/- and CD4-/- immune-deficient mice, FYN knockdown gliomas failed to show differences in survival. These data suggest that the expression of FYN in glioma cells reduces anti-glioma immune activation. Examination of glioma immune infiltrates by flow-cytometry displayed reduction in the amount and activity of immune suppressive myeloid derived cells (MDSCs) in the FYN glioma TME. ConclusionsGliomas employ FYN mediated mechanisms to enhance immune-suppression and promote tumor progression. We propose that FYN inhibition within glioma cells could improve the efficacy of anti-glioma immunotherapies. Key pointsInhibition of FYN tyrosine kinase in genetically engineered mouse glioma models delays tumor initiation and progression. The oncogenic effects of FYN in vivo are mediated by downregulation of anti-glioma immunity. Importance of the StudyFYN is an effector of receptor tyrosine kinases (RTK) signaling in glioma. However, its role in vivo remains unknown. Our study demonstrates that FYN tyrosine kinase is a novel regulator of the anti-glioma immune response. We show that FYN inactivation suppresses glioma growth, increases survival, and enhances anti-tumor immune reactivity. Our findings suggest that suppressing the expression of FYN in glioma cells could provide a novel therapeutic target.

cancer biology↗