Summary: Researchers have identified specific proteins that drive the development of cancer stem cells. They report targeting and suppressing galectin1, in addition to radiation therapy, could be an effective treatment for glioblastoma brain cancer.
Source: McGill University
McGill University researchers identify proteins that drive cancer stem cells. Targeting and supressing a particular protein called galectin1 could provide a more effective treatment for glioblastoma, in combination with radiation therapy.
Due to its resistance to therapy, glioblastoma is the most common and aggressive cancerous brain tumour in adults. It grows fast and spreads quickly. While treatments such as surgery, radiation, and chemotherapy can help ease symptoms for a few months, in most cases tumour cells regrow after treatment and the cancer recurs.
According to the researchers, no matter how low the weeds are cut, if the roots are not pulled out, the weeds will just grow back.
Getting to the root of the problem
Among all cancerous cells, some act as stem cells that reproduce themselves and sustain the cancer, much like normal stem cells typically renew and sustain our organs and tissues, say the researchers. By targeting the way the cells operate, they discovered a new way to disrupt the production of new tumours.
“What we found was really astonishing for us. After we inhibited the galectin1 protein, the brain tumours simply didn’t grow for several months,” says Arezu Jahani-Asl, an Associate Professor of Medicine at McGill University. “To improve patient response to therapy, we must exploit these newly identified vulnerabilities in cancer stem cells.”
The researchers discovered that a protein called galectin1 interacts with another protein called HOXA5 to control the genetic programs that drive cancer stem cell behaviour. By supressing galectin1 in preclinical models, they found a significant improvement in tumour response to radiation therapy, resulting in expanded lifespan.
The researchers also analyzed patient databases and found that glioblastoma patients with low expression of galectin1 and HOXA5 proteins had the best prognosis. Together, these proteins along with another called STAT3 activate mechanisms that promote a particularly aggressive type of glioblastoma.
Paving the way for new therapies
The discovery sheds light on the mechanisms that regulate cancer stem cells. The findings provide evidence that targeting galectin1 protein, in combination with radiation therapy, can pave the way for future clinical trials to treat glioblastoma tumours. The next step is to compare the effectiveness of different approaches to supressing the galectin1 and HOXA5 complex in the brain, with advances in gene therapy through CRISPR technology.
•Galectin1 forms a complex with HOXA5 and promotes glioblastoma and resistance to therapy
Brain tumor stem cells (BTSCs) and intratumoral heterogeneity represent major challenges in glioblastoma therapy. Here, we report that the LGALS1 gene, encoding the carbohydrate binding protein, galectin1, is a key regulator of BTSCs and glioblastoma resistance to therapy.
Genetic deletion of LGALS1 alters BTSC gene expression profiles and results in downregulation of gene sets associated with the mesenchymal subtype of glioblastoma.
Using a combination of pharmacological and genetic approaches, we establish that inhibition of LGALS1 signaling in BTSCs impairs self-renewal, suppresses tumorigenesis, prolongs lifespan, and improves glioblastoma response to ionizing radiation in preclinical animal models.
Mechanistically, we show that LGALS1 is a direct transcriptional target of STAT3 with its expression robustly regulated by the ligand OSM. Importantly, we establish that galectin1 forms a complex with the transcription factor HOXA5 to reprogram the BTSC transcriptional landscape.
Our data unravel an oncogenic signaling pathway by which the galectin1/HOXA5 complex maintains BTSCs and promotes glioblastoma.