Keeping glioblastoma grounded

Mount Sinai scientists find that deactivating the protein TEAD1 could make it possible to stop glioblastoma tumor cells from spreading

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NEW YORK—Glioblastoma is the most common type of brain tumor in adults, as well as one of the most deadly. This particular tumor type is extremely prone to traveling, and migrates rapidly from the original tumor site to spread throughout the brain. A research team from the Icahn School of Medicine at Mount Sinai, however, may have pinpointed a primary culprit for that migration, perhaps leading eventually to a target that can be therapeutically acted upon to halt tumor cell migration. Their results were published in a paper titled “Analysis of chromatin accessibility uncovers TEAD1 as a regulator of migration in human glioblastoma,” which appeared in Nature Communications.
As noted in the Nature Communications paper, “The diffusely infiltrative nature of tumor growth in GBM greatly confounds surgical therapy, as infiltrative cells inevitably extend beyond the resection margin. Moreover, glioma cells away from the tumor’s contrast-enhancing core respond poorly to chemotherapy, and have been implicated in tumor recurrence1,2,3. Given the unique microenvironment and transcriptional signatures of tumor cells at the infiltrative edge vs. those at the tumor core4,5, the two populations are likely regulated by distinct molecular pathways.”
“Our study is one of the first to take human patient glioblastoma cells directly from the tumor immediately after surgery and isolate the most aggressive tumor subclones—the glioma stem cells—to specifically characterize the machinery responsible for tumor migration,” noted Dr. Nadejda Tsankova, Associate Professor of Pathology and Neuroscience at the Icahn School of Medicine at Mount Sinai and senior author of the paper. “We found that the transcription factor TEAD1 directs the activity of genes responsible for tumor migration and, particularly, our research implicates the AQP4 gene as one of TEAD1’s direct pro-migratory partners.”
The researchers began by characterizing the epigenetics behind aggressive glioblastoma cells, and were able to pinpoint a signature with a footprint that relates specifically to the migration of tumors. Within that signature, TEAD1 was identified as having the most enriched footprint. The team then used CRISPR to delete TEAD1 from tumor cells, and in its absence, glioblastoma cells' migratory genes became inactive and they lost the ability to migrate in vitro and in vivo. Upon adding TEAD1 back into the cells, they regained most of their migratory abilities.
Looking at the epigenetic background of the tumor cells, and particularly chromatin, is important for a number of reasons. As explained by the study's authors, “Epigenetics is critical for allowing plasticity during normal stem-cell development and differentiation6,7 as well as for the maintenance of an aberrant cancer stem-cell state8,9,10. In GBM, chromatin remodeling supports the re-emergence of developmental programs in glioma stem cells (GSCs), leading to progressive tumor growth8,10,11,12,13,14,15. The regulatory promoter/enhancer regions at key developmentally driven oncogenes, such as the epidermal growth factor receptor (EGFR)16, are maintained in a poised or open chromatin state, enabling their accessibility for transcriptional dysregulation in GBM.”
After determining that TEAD1 was largely responsible for influencing the migratory abilities of glioblastoma tumor cells, the team decided to look a little closer. Dr. Jessica Tome-Garcia, senior postdoctoral fellow in the Tsankova Research Laboratory at Mount Sinai and leading experimental researcher of the Nature Communications study, examined a number of sites within the genome where TEAD1 might bind to trigger migration, and one of those sites was at the gene that encodes the AQP4 protein. This protein controls water movement, allowing cells to change their shape as they penetrate the brain. Tumor cells with no TEAD1 activity presented with the AQP4 gene turned off, but if AQP4 was introduced—either by reactivating TEAD1 or administering AQP4—migration started back up again.
“Our study data provides convincing evidence that TEAD1 signals through AQP4 to promote tumor migration—and furthermore, that if we can inhibit activity of TEAD1, we can potentially stop tumor cells from migrating away from the main tumor mass,” Tsankova explained. “This newfound information has important implications for brain tumor treatment, potentially increasing the success rate of removing the entire tumor during surgery or at least prolonging the time it takes for the tumor to come back.”
There has been some previous work into TEAD proteins in the past, though the authors note that “The oncogenic activity of TEAD proteins has been predominantly described outside of the CNS and in the context of Hippo pathway signaling, where their interaction with the transcriptional co-activators YAP/TAZ has been implicated in cell growth, invasion, EMT, and metastasis. Well-characterized TEAD targets in non-CNS tumors include CTGF, Cyr61, MYC, CCNE1, AREG, and EGFR.”
As for their next step, a Mount Sinai press release noted that Tsankova and her team are evaluating drugs—in vitro and in vivo—that inhibit TEAD1 to see if they work as well as deleting the target via CRISPR when it comes to halting migration.

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