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An oncostatin M receptor and chloride intracellular channel 1 crosstalk drives key oncogenic pathways in glioblastoma
Mansourabadi, Amir Hossein Qu, Dianbo Cianci, Francesca Snider, Jamie Randhawa, Kamaldeep Raco, Laura Kotlyar, Max Al Ayach, Mohammad Rey, Guido Sanghvi, Shridhar
Mansourabadi, Amir Hossein
Qu, Dianbo
Cianci, Francesca
Snider, Jamie
Randhawa, Kamaldeep
Raco, Laura
Kotlyar, Max
Al Ayach, Mohammad
Rey, Guido
Sanghvi, Shridhar
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s41392-026-02723-3.pdf
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Author
Mansourabadi, Amir Hossein
Qu, Dianbo
Cianci, Francesca
Snider, Jamie
Randhawa, Kamaldeep
Raco, Laura
Kotlyar, Max
Al Ayach, Mohammad
Rey, Guido
Sanghvi, Shridhar
Abovsky, Mark
Singh, Harpreet
Luchman, H Artee
Burger, Dylan
Rak, Janusz
Soleimani, Vahab D
Jurisica, Igor
Stagljar, Igor
Mazzanti, Michele
Jahani-Asl, Arezu
Qu, Dianbo
Cianci, Francesca
Snider, Jamie
Randhawa, Kamaldeep
Raco, Laura
Kotlyar, Max
Al Ayach, Mohammad
Rey, Guido
Sanghvi, Shridhar
Abovsky, Mark
Singh, Harpreet
Luchman, H Artee
Burger, Dylan
Rak, Janusz
Soleimani, Vahab D
Jurisica, Igor
Stagljar, Igor
Mazzanti, Michele
Jahani-Asl, Arezu
Supervisor
Department
Computational Biology
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Journal article
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http://creativecommons.org/licenses/by/4.0/
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English
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Abstract
Oncostatin M receptor (OSMR) plays diverse roles in several human malignancies, including brain, breast, and pancreatic cancer. In glioblastoma (GB), OSMR orchestrates a feedforward signaling mechanism with the truncated active mutant of epidermal growth factor receptor (EGFR), the EGFRvIII, and signal transducer and activator of transcription 3 (STAT3) to drive GB progression. Beyond EGFRvIII, OSMR promotes brain tumor stem cell (BTSC) respiration and therapy resistance. The molecular mechanisms underlying OSMR’s multifaceted roles remain largely unclear. Here, we systematically mapped the OSMR interactome using Mammalian Membrane Two-Hybrid High-Throughput Screening (MaMTH-HTS). We identified OSMR-specific and OSMR/EGFRvIII-specific high-confidence candidate binding proteins, highlighting OSMR context-dependent functions. Among a subset of common interactors, we uncovered chloride intracellular channel 1 (CLIC1) as a critical regulator of OSMR-STAT3 signaling and the OSMR/EGFRvIII complex. CLIC1 physically associates with OSMR and EGFRvIII and facilitates EGFRvIII packaging into extracellular vesicles (EVs). Genetic deletion of CLIC1 disrupts the OSMR/EGFRvIII interaction, impairs STAT3 activation, reduces EGFRvIII EV content, and slows GB progression. Using whole-cell patch-clamp recordings and a monoclonal antibody that selectively targets transmembrane CLIC1 (tmCLIC1omab), we establish a distinct pharmacologically and biophysically tmCLIC1-mediated current in GB indispensable for sustaining EGFRvIII/STAT3 signaling. Importantly, we show that OSMR is required for maintaining CLIC1-mediated ionic balance at the plasma membrane (PM). Our study uncovers a bidirectional crosstalk between OSMR and tmCLIC1 in GB, essential for fueling its malignant growth.
Citation
A.H. Mansourabadi, D. Qu, F. Cianci, J. Snider, K. Randhawa, L. Raco , et al., "An oncostatin M receptor and chloride intracellular channel 1 crosstalk drives key oncogenic pathways in glioblastoma," Signal Transduction and Targeted Therapy, vol. 11, no. 1, pp. 194-194, 2026, https://doi.org/10.1038/s41392-026-02723-3.
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Signal Transduction and Targeted Therapy
Conference
Keywords
31 Biological Sciences, 3101 Biochemistry and Cell Biology, Animals, Cell Line, Tumor, Chloride Channels, ErbB Receptors, Glioblastoma, Humans, Oncostatin M Receptor beta Subunit, Signal Transduction, STAT3 Transcription Factor
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Publisher
Springer Nature