Stagljar Lab collaboration identifies CLIC1: a potential therapeutic target for glioblastoma
Researchers at the Donnelly Centre are part of a global collaboration that discovered a new therapeutic target for glioblastoma.
“Glioblastoma is the deadliest form of brain cancer and one of the deadliest cancers in general,” says Igor Stagljar, Donnelly PI and co-corresponding author on the paper. “It's devastating because it mostly hits people who are between 50 and 65 years old—they are in the best intellectual phase of their life.”
As a grade 4 brain cancer, glioblastoma is particularly difficult due to the tumour’s genetically diverse profile and aggressive nature. There are two major drivers of glioblastoma: a mutation called EGFRvIII and a receptor named Oncostatin M Receptor (OSMR). With a poor prognosis of an average 12-month life expectancy, there is a high demand to understand how these drivers “talk” to one another to fuel tumour growth.
“We discovered a new therapeutic target for glioblastoma,” Stagljar says. “This paper is a blueprint for anybody in this field who might initiate further research.”
The study used the Stagljar Lab-designed Mammalian Membrane Two-Hybrid (or MaMTH, pronounced like “mammoth”) technology to reveal the interactions between protein molecules on the cell membrane. Observing these protein-protein interactions (PPIs) can help researchers determine potential drug targets—such is the case with directed therapies like the breast cancer drug Herceptin, which block the signalling of the HER2 protein and stops HER2-positive cancer cell growth. Finding an equivalent target in glioblastoma would help develop similar antagonists, which would drastically shift the natural progression of the cancer.
Collaborating with experts Arezu Jahani-Asl and Michele Mazzanti, Stagljar set out to map the interactome (a complete profile of all PPIs) of the OSMR receptor.
“We can run MaMTH on any human membrane protein,” Stagljar explains, “in this large screen, we looked at all human proteins associated with OSMR in the presence or absence of EGFRvIII.”
The team mapped the interactome with MaMTH—essentially creating a social network map for OSMR and EGFRvIII. Imagine visualizing the conversations that take place at a large get-together: Certain individuals are the life of the party; they talk to many different people, are a common mutual friend, and act like a hub of contact for the partygoers. Stagljar’s lab took a magnifying glass to this “party” and identified a major player: chloride intracellular channel 1, or CLIC1.
“CLIC1's classified as an ion channel—and that's one of its functions—but it actually does a bunch of complex physiological things,” says Jamie Snider, the Stagljar Lab research associate who performed the MaMTH screenings. “We found that it interacts physically with both OSMR and the EGFR mutant—it helps drive that signaling and promotes uncontrolled growth in glioblastoma.”
In the high-stress, acidic environment of glioblastoma, CLIC1 inserts itself into the cell’s plasma membrane. CLIC1 becomes the proverbial middleman between OSMR and EGFRvIII, acting as a structural bridge and electrical regulator.
“We identified another villain in glioblastoma,” Stagljar says. “This bidirectional crosstalk keeps the cancer's signaling active; When we used CRISPR technology to delete the CLIC1 protein, the glioblastoma cells lost their ability to spread.”
“We better understand the biology of the signaling involved in glioblastoma,” says Snider. “These projects identify the targets needed to develop cancer treatments that work.”
To target CLIC1, the research team developed what Stagljar refers to as a “guided missile”: a monoclonal antibody that selectively attacks the version of CLIC1 found on cancer cell membranes. While the study is currently in the preclinical stage, Stagljar expects to see attempted developments of CLIC1-targeted therapies, similar to how anti-HER2 agents were developed for breast cancer.
For his own lab, however, Stagljar is setting his sights on the bigger picture.
“We plan to extend MaMTH technology to screen all human cancer-causing receptors,” Stagljar says. “MaMTH is very sensitive, fast, and high-throughput. It will identify novel targets, similar to CLIC1, to develop new therapies and interventions.”
The full Signal Transduction and Targeted Therapy paper, “An OSMR-CLIC1 cross talk drives key oncogenic pathways in glioblastoma” is now publicly available:
Read now
About the Donnelly Centre
The Donnelly Centre for Cellular and Biomolecular Research is a research hub at the University of Toronto’s Temerty Faculty of Medicine, where scientists from diverse fields work together to advance medicine and health. Founded in 2005, the Donnelly Centre is a global leader in research on systems biology, regenerative medicine and disease modelling.
For more information about the Donnelly Centre, follow us on X, LinkedIn and Bluesky.
Media Contact
Kira Belaoussoff
Communications Coordinator at the Donnelly Centre
donnelly.communications@utoronto.ca
416-946-8253
