Direct neuronal fate can be achieved by blocking TAZ/HDAC complexes, uncovering a novel mode of cellular differentiation that can be utilized as a non-cytotoxic therapeutic strategy for malignant gliomas.
Abstract
Brain tumors such as glioblastomas contain hierarchically organized, tumor-propagating glioma stem-like cells (GSCs). A non-cytotoxic strategy to limit the growth of these cells involves promoting terminal differentiation and mitotic exit; however, these approaches have remained largely unsuccessful. In this study, we combined in silico, in vitro, and in vivo methods to determine the influence of transcriptional coactivator with PDZ-binding motif (TAZ), an oncogenic transcription coactivator, in regulating cellular hierarchies in GSCs. We found that TAZ inhibits the neuronal lineage pathway in gliomas and GSCs, and that TAZ expression inversely correlates the master transcription factors (TFs) that drive neuronal fate. Overexpression of TAZ in GSCs disrupted neuronal differentiation by restructuring the enhancer landscape and downregulating essential master TFs associated with neurogenesis, such as OLIG2 and ASCL1. These effects were mediated by histone deacetylases 1 HDAC1). Knockdown of TAZ and its paralog YAP caused aberrant neuronal differentiation of GSCs. Thus, directed neuronal fate can be achieved by blocking TAZ/HDAC complexes, uncovering a novel mode of cellular differentiation that can be utilized as a non-cytotoxic therapeutic strategy for malignant gliomas.
Glioma stem-like cells (GSCs) exploit developmental signaling programs that contribute to glioblastoma heterogeneity and therapy resistance. Here, we define a role for the arginine methyltransferase coactivator-associated arginine methyltransferase 1 (CARM1) in regulating GSC lineage state and survival signaling. CARM1 depletion slows GSC growth, increases apoptosis, alters histone post-translational modifications, and shifts transcriptomic and proteomic profiles toward a radial glial-like state. Loss of CARM1 increases NGFR/NTRK signaling and sensitizes GSCs to NTRK and AKT inhibition. Mechanistically, NFIA is a CARM1 substrate, and mutation of NFIA arginine 389 increases NGFR expression, supporting a role for CARM1-dependent NFIA methylation in NGFR repression. In orthotopic xenografts, CARM1 depletion reduces tumor burden and prolongs survival. These findings identify CARM1 as a regulator of GSC developmental programs and NGFR/NTRK-dependent survival.
Dejauwne L Young, Stephanie Stransky, Maria G Molero et al.· Cell Reports· 0 citations
It is demonstrated that TUG1, which is highly expressed in tumors, regulates early embryonic development in mice and is transformed from a cancer-specific effector to a critical regulator of the ZGA, raising the possibility that related regulatory principles may operate in other biological contexts.
Jian-Wu Wang, Guang Yang, Qingbo Yang et al.· Cellular and Molecular Life...· 0 citations
Abstract This study aims to elucidate the role of suppressor of cytokine signaling 3 (SOCS3) in glioma stem cells (GSCs) via single‐cell RNA sequencing (scRNA‐seq), focusing on its regulation of STAT3‐mediated self‐renewal, apoptosis resistance, and tumor microenvironment (TME) remodeling. ScRNA‐seq data from 19 high‐grade glioma patients were analyzed using Seurat, Harmony, and SingleR for clustering, annotation, and SOCS3 stratification (SOCS3‐High: n = 4; SOCS3‐Low: n = 15). Differential gene analysis, pathway enrichment, and CellChat were employed for TME characterization. In vitro, SOCS3‐overexpressing/silenced GSC11 models were tested via MTT, TUNEL, neurosphere assays, and STAT3 pathway modulation (IL‐6). In vivo, intracranial xenografts in nude mice evaluated tumor growth and survival. SOCS3 was downregulated in GSCs and neurons. SOCS3‐Low GSCs exhibited 777 differentially expressed genes enriched in T‐cell receptor, p53, and JAK‐STAT axis, suppressed T‐cell/microglia infiltration, and promoted oligodendrocyte precursor cell/astrocyte survival. SOCS3 overexpression reduced GSC proliferation, induced apoptosis, inhibited neurosphere formation, and suppressed STAT3 phosphorylation and stemness markers (OCT4/SOX2/NANOG). IL‐6 reactivated STAT3, reversing SOCS3‐mediated tumor suppression. In vivo, SOCS3 overexpression attenuated tumor growth and prolonged survival, counteracted by IL‐6. Low SOCS3 expression contributes to glioma progression by promoting STAT3 activation and an immunosuppressive TME. Targeting the SOCS3‐STAT3 axis may offer therapeutic potential.
Jing-Tao Wang, Gaolei Hou, Zhaofei Song et al.· Journal of cell communicatio...· 0 citations
Glioblastoma (GBM) is characterized by marked heterogeneity, glioma stem-like cells (GSCs), and resistance to therapy. Because GSCs share features with neural progenitor cells (NPCs), we investigated whether neurodevelopmental programs contribute to their response to irradiation. Transcriptional profiling of four patient-derived GSC lines revealed cell line-specific responses, with radiosensitivity correlating with the magnitude of p53 activation and basal expression of its negative regulator, MDM2. Despite this heterogeneity, radiation consistently activated p53-dependent pathways and suppressed cell-cycle programs. Among these, genes associated with primary hereditary microcephaly (MCPH) that regulate NPC proliferation were coordinately repressed. Single-cell RNA sequencing localized this response to G2/M-cycling cells. FOXM1 was similarly reduced following irradiation, emerged as a candidate regulator of a subset of MCPH genes, and correlated with their expression in GBM tumors. Pharmacological inhibition of FOXM1 reduced expression of selected MCPH genes and enhanced radiosensitivity in U251 cells. Together, these findings identify coordinated suppression of a FOXM1-associated MCPH program as part of the GBM radiation response, while suggesting that the radiosensitizing effects of pharmacological FOXM1inhibition extend beyond this transcriptional axis.
L. Van Eupen, E. Etlioglu, K. Tabury et al.· bioRxiv· 0 citations
These findings suggest a highly conserved role for HDAC9 and class IIA HDACs in vertebrate pancreatic tumorigenesis and may lead to new strategies for reactivating (normal acinar/epithelial) differentiation programs to intercept and treat PDAC.
Somer Matar, Sandra Blázquez-Araguás, Andrea Diéguez-Docampo et al.· Cellular and Molecular Gastr...· 0 citations
Although immunotherapy has transformed the treatment landscape for many types of cancer, its therapeutic efficacy in glioblastoma (GBM) is limited by insufficient antigen presentation and the immunogenic cell exclusion in the tumor microenvironment. Here, we develop a candidate-based CRISPR activation (CRISPRa) functional screen to identify regulators of conventional dendritic cell (cDC)-fate specification. We determine that the transcription factors Zfp366/Znf366, Pu.1, Irf8, and Batf3 (ZPIB) are sufficient to convert GBM cells into cDC-like cells. ZPIB-mediated reprogramming results in global transcriptional and epigenetic remodeling in glioma cells. Single-cell RNA sequencing (scRNA-seq) profiling also reveals efficient and dynamic reprogramming of GBM cells to cDCs in vivo. Moreover, reprogrammed tumor cells remodel the microenvironment and elicit systemic tumor-eradicating and durable antitumor immunity in multiple mouse GBM models. Antitumor immunity elicited by ZPIB-DCs is synergistic with immune checkpoint inhibitors. Finally, we evaluate the clinical applicability of this approach by generating ZPIB-DCs from GBM patients within a humanized model. Our study represents a cellular reprogramming therapeutic strategy with broad implications for clinical immunotherapy.
Xiao Liu, Mao-Rong Zhu, Cheng Zou et al.· Cell Reports Medicine· 0 citations
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