PATHOLOGY

Gene Plays Jekyll and Hyde in Brain Cancer

STAT3 Found to Suppress or Activate Glioblastoma, Depending on Related-gene Mutations

Perhaps the only positive spin one can put on the brain cancer glioblastoma is that it is relatively uncommon. Other than that, the news is bad. It is nearly always fatal; it tends to strike people in the prime of their lives; and the limited treatment options have changed little over decades. It is no wonder then that many researchers are determined to find new ways to treat this poorly understood cancer.

Courtesy Núria de la Iglesia	Courtesy Genevieve Konopka	Graham Ramsay
From left, Núria de la Iglesia, Genevieve Konopka, and Azad Bonni have found that the same gene in the same cancer can act as either an oncogene or a tumor suppressor.

One approach focuses on the gene STAT3. In several types of glioblastoma STAT3 takes the role of an oncogene. So blocking it would deal a major blow. But a new study led by a team from HMS has found that STAT3 is not always the villain, since in other glioblastomas, it becomes a tumor suppressor. Apparently the same gene in the same cancer may play a completely different role from one person to the next, depending on the genetic nuances of the individual.

“This discovery lays the foundation for a more tailored therapeutic intervention,” said Azad Bonni, an HMS associate professor of pathology and senior author on the study, which appears in the Feb. 15 Genes and Development and was published online Feb. 7. “And that’s really important. You can’t just go blindly treating people by inhibiting STAT3.”

Disease Determinants
Nearly all brain cancers occur in astrocytes or in the neural stem cells that generate them. Bonni, a neurologist and neuroscientist by training, decided to investigate the genetic etiology of glioblastoma by studying whether STAT3 and certain other genes that control the generation of astrocytes during normal development also play a role in these tumors.

Bonni and two lead authors, postdoc Núria de la Iglesia and former graduate student Genevieve Konopka, in collaboration with investigators in the laboratory of Ronald DePinho, HMS professor of medicine (genetics) at the Dana–Farber Cancer Institute, began by genetically manipulating mouse astrocytes, then placing them into a second group of immunocompromised mice. The findings surprised them.

Taking advantage of previously published data, the researchers looked closely at how two genes, EGFR and PTEN—whose mutated forms are associated with glioblastoma—affect the function of STAT3 in astrocytes. Bonni’s group found that when EGFR is mutated, STAT3 is an oncogene; with a PTEN mutation, STAT3 is a tumor suppressor.

“EGFR, in its normal state, is a transmembrane receptor, usually performing its functions at the cell surface,” said Bonni. “However, when it’s mutated, we find it in the cell’s nucleus interacting with STAT3—and turning it into an oncogene. STAT3 itself is not mutated or damaged. It’s the process of regulating STAT3 that gets damaged.”

With PTEN, it is a completely different story. PTEN is itself a tumor suppressor gene. When PTEN becomes disabled in astrocytes, these potential tumors still have STAT3 standing in their way. This is because STAT3 normally acts as a tumor suppressor in astrocytes. As more PTEN becomes disabled, however, a cascade of molecular events is set in motion with the express purpose of inhibiting STAT3 function and thereby turning the tide in the cells toward tumor formation.

The researchers confirmed these findings in human glioblastoma tumors, as well.

Personal Oncology
“The belief that STAT3 can only be an oncogene has been a pretty entrenched dogma in the field,” said Bonni, “so we performed many, many experiments to make sure this was correct. It took some very persistent investigators in my lab to get the job done. As a result, we’re convinced of our data.”

Courtesy Azad Bonni

The two faces of Stat3. The oncogene (top): when EGFR—a cell-surface receptor—mutates in glioblastoma, the Stat3 protein becomes oncogenic, promoting tumor growth. The image on the top left shows EGFR-mutated cancerous tissue in which Stat3 is active and therefore advancing tumor development. The image, top right, shows the same tissue without Stat3 activity; the result is a healthier sample.

The tumor suppressor (bottom): in other subtypes of glioblastoma, Stat3 functions as a tumor suppressor gene. In these tissue samples, the cancer has lost the tumor-suppressor PTEN, leaving that function almost entirely up to Stat3. In the bottom left image, an active Stat3 holds the cancer at bay. But when Stat3 is lost, bottom right, the tumor grows.

Though glioblastoma tends to be uncommon, STAT3 has also been implicated in prostate and breast cancers, so these results may translate to other types of tumor, as well.

In addition, the findings contribute to the growing rationale for “personalized medicine,” showing that many types of cancer contain subgroups that require different treatments.

—David Cameron

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