Biology subjects

Tiek, D.

Publications and source records attributed to Tiek, D..

4 recordsLinked to original sources

bioRxiv2026

iPSC-Derived Microglia-like Cells Exhibit Protocol-Dependent Transcriptomic Features and Robust Phagocytosis of Glioma Cells

Microglia are the brain-resident macrophages and key regulators of the brain tumor microenvironment. Although induced pluripotent stem cell-derived microglia (iMG) provide a valuable model for studying human microglial, systematic comparisons of differentiation protocols are limited, and their utility for modeling microglia-tumor cell interactions remains underexplored. Here, we analyzed 54 public RNA-seq datasets representing 22 iMG differentiation protocols, including embryoid body (EB)-based, two-dimensional (2D), transcription factor-induced, and coculture-based approaches. Most iMG closely resembled primary human microglia, although substantial protocol-dependent differences were observed. iMG generated using EB-based protocols showed higher TMEM119 expression, whereas those generated using 2D-based protocols showed higher P2RY12 expression. A widely adopted EB-based protocol showed the highest phagocytosis gene signature. Using this protocol, we generated iMG that efficiently phagocytosed patient-derived glioma stem-like cells and upregulated inflammatory and immunoregulatory genes following phagocytosis. These findings provide a transcriptomic benchmark for current iMG models and support their use in investigating microglia-glioma interactions. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=105 SRC="FIGDIR/small/739939v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@893ebforg.highwire.dtl.DTLVardef@769c08org.highwire.dtl.DTLVardef@fe06ccorg.highwire.dtl.DTLVardef@1705d70_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2025

A Single-Cell Atlas of RNA Alternative Splicing in the Glioma-Immune Ecosystem

Single-cell analysis has refined our understanding of cellular heterogeneity in glioma, yet RNA alternative splicing (AS)--a critical layer of transcriptome regulation--remains underexplored at single-cell resolution. Here, we present a pan-glioma single-cell AS analysis in both tumor and immune cells through integrating seven SMART-seq2 datasets of human gliomas. Our analysis reveals lineage-specific AS across glioma cellular states, with the most divergent AS landscapes between mesenchymal- and neuronal-like glioma cells, exemplified by AS in TCF12 and PTBP2. Comparison between core and peripheral glioma cells highlights AS-redox co-regulation of cytoskeleton organization. Further analysis of glioma-infiltrating immune cells reveals potential isoform-level regulation of protein glycosylation in regulatory T cells and a link between MS4A7 AS in macrophages and clinical response to anti-PD-1 therapy. This study emphasizes the role of AS in glioma cellular heterogeneity, highlighting the importance of an isoform-centric approach to better understand the complex biological processes driving tumorigenesis.

genomics↗

bioRxiv2025

Targeting CHEK2-YBX1&YBX3 regulatory hub to potentiate immune checkpoint blockade response in gliomas

Although GBMs immunosuppressive environment is well known, the tumors resistance to CD8+ T cell killing is not fully understood. Our previous study identified Checkpoint Kinase 2 (Chek2) as the key driver of CD8+ T cell resistance in mouse glioma through an in vivo CRISPR screen and demonstrated that Chk2 inhibition, combined with PD-1/PD-L1 blockade, significantly enhanced CD8+ T cell-mediated tumor killing and improved survival in preclinical model. Here, we aimed to elucidate the immunosuppressive function of Chek2. Immunoprecipitation (IP) followed by mass spectrometry (MS) and phosphoproteomics identified an association between Chek2 with the DNA/RNA-binding proteins YBX1 and YBX3 that are implicated in transcriptional repression of pro-inflammatory genes. Single-gene knock-out and overexpression studies of CHEK2, YBX1, and YBX3 in multiple glioma cell lines revealed that these proteins positively regulate each others expression. RNA sequencing coupled with chromatin immunoprecipitation-sequencing (ChIP-seq) analysis demonstrated common inflammatory genes repressed by CHK2-YBX1&YBX3 hub. Targeting one of the hub proteins, YBX1, with the YBX1 inhibitor SU056 led to degradation of CHK2-YBX1&YBX3 hub. Targeting of this hub by SU056 led to enhanced antigen presentation and antigen specific CD8+ T cell proliferation. Further, combination of SU056 with ICB significantly improved survival in multiple glioma models. Collectively, these findings reveal an immunosuppressive mechanism mediated by the CHK2-YBX1&YBX3 hub proteins. Therefore, CHK2-YBX1&YBX3 hub targeting in combination with immune checkpoint blockade therapies in gliomas is warranted.

cancer biology↗

bioRxiv2022

SGC-CLK-1 (CAF-170) a chemical probe for the Cdc2-Like kinases CLK1, CLK2, and CLK4

Small molecule modulators are important tools to study both basic biology and the complex signaling of protein kinases. The cdc2-like kinases (CLK) are a family of four kinases that have garnered recent interest for their involvement in a diverse set of diseases such as neurodegeneration, autoimmunity, and many cancers. Targeted medicinal chemistry around a CLK inhibitor hit identified through screening of a kinase inhibitor set against a large panel of kinases allowed us to identify a potent and selective inhibitor of CLK1, 2 and 4. Here, we present the synthesis, selectivity, and potential binding site of this compound - SGC-CLK-1. We further show CLK2 has the highest binding affinity, and high CLK2 expression correlates with a lower IC50 in a screen of multiple cancer cell lines. Finally, we show that SGC-CLK-1 not only reduces serine arginine rich (SR) protein phosphorylation, but also alters SR protein and CLK2 subcellular localization in a reversible way. Therefore, we anticipate that this compound will be a valuable tool for increasing our understanding of CLKs and their targets, SR proteins, at the level of phosphorylation and subcellular localization.

cancer biology↗