Gene Targeting Helps Overcome the Resistance of Brain Cancer to Therapy

Summary: Mouse study reveals the deletion of the OSMR gene significantly improves glioblastoma tumor response to therapy and extended lifespan.

Source: McGill University

New insight into a gene that controls energy production in cancer stem cells could help in the search for a more effective treatment for glioblastoma. A McGill-led study published in Nature Communication reveals that suppressing the OSMR gene can improve the effectiveness of radiation therapy.

This approach, led by the laboratory of Arezu Jahani-Asl, Assistant Professor of Medicine at McGill University, was successful in preclinical mouse models where the deletion of the OSMR gene resulted in a significant improvement of tumour response to therapy and expanded lifespan.

Glioblastoma is the most common and aggressive cancerous brain tumour in adults due to its resistance to therapy. Treatment usually involves surgery, followed by chemotherapy and radiation therapy. Despite these intensive efforts, in most cases tumour cells regrow after treatment and the cancer recurs.

Starving cancer stem cells

Glioblastoma tumours contain rare cancer stem cells responsible for therapeutic resistance and tumour regrowth. In the study, researchers uncover the unique role OSMR plays in fortifying cancer stem cells’ resistance to therapy by strengthening mitochondria, the powerhouse of cell energy production. It makes the long journey to the mitochondria and interacts with energy-producing machineries to force them to generate more energy for cancer cells.

This shows a doctor looking at brain scans
Glioblastoma is the most common and aggressive cancerous brain tumour in adults due to its resistance to therapy. Image is credited to McGill University.

“To improve patient response to glioblastoma treatment, we must find new vulnerabilities in cancer stem cells and overcome their resistance to therapy. By suppressing OSMR, we were able to halt energy production in cancer stem cells, essentially starving them to death,” says Jahani-Asl.

The study provides evidence that targeting OSMR gene, in combination with radiation therapy, can pave the way for future clinical trials that better treat glioblastoma tumours. The next step is to leverage these tools into a clinical trial, the researchers say.

Funding: The study was supported by 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-As. 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) which are endowed with properties to proliferate, spur the growth of new tumors, and at the same time, evade ionizing radiation (IR) and chemotherapy. However, the drivers of BTSC resistance to therapy remain unknown. The cytokine receptor for oncostatin M (OSMR) regulates BTSC proliferation and glioblastoma tumorigenesis. Here, we report our discovery of a mitochondrial OSMR that confers resistance to IR via regulation of oxidative phosphorylation, independent of its role in cell proliferation. Mechanistically, OSMR is targeted to the mitochondrial matrix via the presequence translocase-associated motor complex components, mtHSP70 and TIM44. OSMR interacts with NADH ubiquinone oxidoreductase 1/2 (NDUFS1/2) of complex I and promotes mitochondrial respiration. Deletion of OSMR impairs spare respiratory capacity, increases reactive oxygen species, and sensitizes BTSCs to IR-induced cell death. Importantly, suppression of OSMR improves glioblastoma response to IR and prolongs lifespan.

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