In the fight against cancer, scientists have long grappled with the ambiguous nature of stem cells. Glioblastoma tumours, the most aggressive form of brain cancer in adults, consist of these cells, which have the notable ability to self-renew. This makes these tumours notoriously hard to treat with targeted radiation therapy and difficult to permanently remove through surgery.
A McGill-led research group working at the Lady Davis Institute of the Jewish General Hospital has now put the invincibility of tumour stem cells into question. In a recent paper, the group details a new technique of sensitizing stem cells to radiation therapy, thereby increasing the therapy’s efficacy. A single mitochondrial gene called oncostatin M (OSM) was found to influence the energy levels of stem cells. Using the DNA editing tool CRISPR-Cas9, researchers were able to delete the gene and cause cancerous cells to become less resistant to ionizing radiation, the type used in cancer treatments.
Dr. Arezu Jahani-Asl, assistant professor in the Department of Oncology at McGill, has been overseeing this project since 2015.
“What makes [stem cells] unique is their capacity to undergo self-renewal and spur the growth of new tumours, but at the same time, they can evade ionizing radiation and chemotherapy,” Jahani-Asl said in an interview with The McGill Tribune. “They can regenerate a new tumour if there are only a few of these cells left after surgery.”
Considering the tenacity of these cancer cells, researchers consider the identification of the OSM gene’s role in regulating cell proliferation a promising breakthrough.
Through various molecular techniques, the team tracked the OSM gene product and its interactions within the cell. First, they established OSM’s location in the mitochondria, the part of the cell responsible for producing energy. Its location pointed to OSM’s involvement with the mitochondria’s electron transport chain, a series of protein complexes that produce ATP, the cell’s energy currency.
Researchers noticed that high expression of OSM strengthens cancer cells by promoting ATP production, providing cells with additional energy.
Armed with the knowledge that OSM affects a tumour’s energy stores, the researchers subsequently removed the gene using CRISPR-Cas9.
“When we deleted the gene, there was less oxygen consumption rate, which is a means to measure energy production,” Jahani-Asl said. “There was a decrease of activity in Complexes I, II, III and IV of the [electron transport] chain.”
Without OSM, the researchers noted that radical oxygen species, chemically reactive molecules that can cause cellular damage, accumulated in the mitochondria. This build-up triggered cell death in mice more often than when exposed to radiation alone. An increased sensitivity of these cancer cells to radiation therapy could feasibly prolong the life expectancy of glioblastoma patients undergoing treatment.
Despite the study’s use of mouse models in testing OSM suppression, the scientists also found support for their results in public health data.
“Based on public datasets, the higher the expression of OSM, the more resistant [cells] are to ionizing radiation,” Jahani-Asl said. “It is very similar to what we saw in wet experimentation with mice.”
Consistency between public health data and the results of the study suggests that gene deletion techniques may be viable for brain cancer patients. In addition, effective gene editing tools such as CRISPR are becoming more widely used in preclinical research. It will take further inquiry and experimentation, however, before human trials become possible.
For now, the lab is exploring a number of options in their continuing study of the OSM gene, including therapy antibodies and molecular profiling.
“At this point, a drug screening is required to find a drug that specifically inhibits OSM function,” Dr. Ahmad Sharanek, the lead author of the study, wrote in an email to the Tribune. “Pharmacological targeting of OSM in combination with the current standard of care for glioblastoma therapy will [become] feasible at a large scale.”