By Riya Gandhi ‘22

Researchers in the Department of Neurological Surgery at the University of California have made a progressive discovery regarding tumor cell immortality, especially in brain-related cancers such as glioblastoma, which recently claimed the life of Senator John McCain. Their work involved TERT promoter mutations, which are responsible for activating telomerase and thereby enabling cell immortality. Approximately 90 percent of human tumors reactivate telomerase reverse transcriptase; this is what allows cancer cells to avoid cell death – which is tied to telomere shortening – and thereby gain immortality. Therefore, this discovery is an enormous victory for cancer researchers around the globe.

First, the researchers had to determine which gene, GABPβ1S, GABPβ1L, or GABPβ2, regulated the mutant TERT promoter. In order to do this, they performed gene knockdown experiments in vitro using siRNA, which led to the knockdown of β1 and β2 in three TERT promoter mutant glioma cell lines. Ultimately, researchers discovered that the knockdown of β1 reduced TERT expression more so than that of β2. By using a tetramer-forming isoform of GABP known as GABPβ1L to silence TERT, telomere loss and cell death occurred, but only in the TERT promoter mutant cells. Thus researchers concluded that mitotic cell death and TERT promoter mutations are directly correlated. Next, they used gene editing to investigate the elimination of GAPBβ1L from glioblastoma cells in laboratory cultures and doing so exponentially slowed down cell growth. Finally, to test and verify findings, researchers grafted glioblastoma cells from patients into mice. By analyzing xenografts of GABPβ1L-reduced, TERT promoter glioblastoma cells, researchers found that cells that had been genetically altered to not have GABPβ1L were less lethal and grew at significantly slower rates. The cells that had been left unedited, on the other hand, grew aggressively.

Understanding how the TERT mutation works may lead to the discovery of means by which the immortality of tumor cells in brain cancer and thereby tumor growth could be reduced. In the future, scientists may be able to engineer a method by which to suppress TERT expression in its entirety to terminate tumor growth.

References

1. A. Mancini, Disruption of the β1L isoform of GABP reverses glioblastoma replicative immortality in a TERT promoter mutation-dependent manner. Cancer Cell 34, 513-528 (2018). doi: https://doi.org/10.1016/j.ccell.2018.08.003.  
2. Image retrieved from: https://www.pexels.com/photo/man-old-depressed-headache-23180/