Summary: A mouse study shows that deleting the OSMR gene markedly improves glioblastoma responsiveness to therapy and extends survival.
Source: McGill University
New findings point to a gene that controls energy production in glioblastoma stem cells and could lead to more effective treatments. A McGill-led study published in Nature Communications demonstrates that suppressing the OSMR gene increases the tumor-killing effects of radiation therapy in preclinical models.
Led by the laboratory of Arezu Jahani-Asl, Assistant Professor of Medicine at McGill University, the study shows that removing OSMR in mouse models significantly improved tumor response to treatment and extended overall lifespan.
Glioblastoma is the most common and aggressive malignant brain tumor in adults, largely because it resists standard therapies. Current care combines surgery with radiation therapy and chemotherapy, but tumors frequently recur due to residual cells that survive treatment.
Starving cancer stem cells
Within glioblastoma tumors exists a small population of cancer stem cells that drive therapeutic resistance and tumor regrowth. This study reveals a previously unrecognized role for OSMR in strengthening those stem cells by enhancing mitochondrial function — the processes that generate cellular energy. OSMR travels to the mitochondria and interacts with components of the cell’s energy-producing machinery, increasing energy production that supports tumor survival and resistance.
“To improve outcomes for people with glioblastoma, we must uncover vulnerabilities in cancer stem cells and find ways to overcome their resistance to therapy,” says Jahani-Asl. “By suppressing OSMR, we were able to halt key energy pathways in cancer stem cells, effectively depriving them of the fuel they need to survive.”
The data indicate that targeting OSMR together with radiation therapy may represent a promising therapeutic strategy worth testing in clinical trials. The research team plans to translate these findings toward clinical development that could improve responses to standard treatments for glioblastoma.
Funding: The study received support from CIHR and The Brain Tumor Charity.
About this brain cancer research article
Source:
McGill University
Contacts:
Shirley Cardenas – McGill University
Image Source:
The image is credited to McGill University.
Original Research: Open access
“OSMR controls glioma stem cell respiration and confers resistance of glioblastoma to ionizing radiation” by Ahmad Sharanek, Audrey Burban, Matthew Laaper, Emilie Heckel, Jean-Sebastien Joyal, Vahab D. Soleimani, and Arezu Jahani-Asl. Nature Communications.
Abstract
OSMR controls glioma stem cell respiration and confers resistance of glioblastoma to ionizing radiation
Glioblastoma contains a rare population of self-renewing brain tumor stem cells (BTSCs) that drive tumor growth and evade standard treatments such as ionizing radiation (IR) and chemotherapy. The molecular mechanisms that enable BTSCs to resist therapy have remained unclear. The cytokine receptor oncostatin M receptor (OSMR) is known to regulate BTSC proliferation and tumorigenesis. In this study, researchers identify a mitochondrial pool of OSMR that promotes resistance to IR by enhancing oxidative phosphorylation, a function separate from its role in cell proliferation.
Mechanistically, OSMR is imported into the mitochondrial matrix through interactions with presequence translocase-associated motor complex proteins, including mtHSP70 and TIM44. Once in mitochondria, OSMR associates with complex I subunits NADH ubiquinone oxidoreductase 1 and 2 (NDUFS1/2) and stimulates mitochondrial respiration. Genetic deletion of OSMR reduces spare respiratory capacity, increases production of reactive oxygen species, and sensitizes BTSCs to radiation-induced cell death. Importantly, suppressing OSMR in preclinical models enhances glioblastoma response to radiation and extends survival, supporting OSMR as a candidate therapeutic target to overcome treatment resistance.