Every other week Ruchi Shah, a sophomore biology major, will take a look at Stony Brook-related research and science news.
Dr. Sumita Bhaduri-McIntosh, an assistant professor in the Departments of Pediatrics and Molecular Genetics and Microbiology at Stony Brook University School of Medicine, has uncovered a previously unidentified mechanism through which a prominent protein in cells, STAT3, affects cancerous tumor formation.
Bhaduri-McIntosh’s research lab focuses on the Epstein-Barr virus (EBV), the first virus associated with human cancer 50 years ago. It is associated with B cell lymphomas and epithelial cell cancers. Although about 95 percent of the human population is infected with this virus, most individuals lead healthy lives because the immune system prevents EBV from taking control and causing cancer.
Normally, the body wards off cancer or uncontrolled cell growth through the DNA Damage Response (DDR). This innate barrier to tumor formation, found in every cell, serves as a policeman in the cell community.
As cells replicate, there are often errors that occur such as damage or defects to the DNA sequence. The job of DDR is to signal to other community members to slow or halt replication until repair is done. The DDR prevents genetic defects from accumulating so cancer will not occur.
According to Bhaduri-McIntosh, “DDR must be suppressed or bypassed in order for any cancer to develop.” This idea in the field of cancer biology is supported by at least two lines of evidence.
The first showed that if an oncogene, cancer-causing gene, was activated in healthy cells, the cells usually died or aged. However, when the protective DDR mechanism was simultaneously suppressed or the policeman taken away, the cells began growing and became cancerous.
The second found that while precancerous cells showed the presence of DDR signaling, cancer cells had a significant decrease in DDR signaling.
Bhaduri-McIntosh wanted to understand how DDR suppression was happening for oncogenes to successfully drive cell growth and proliferation. After examining publicly available sequencing data of genomes from sporadic human cancers, Bhaduri-McIntosh recognized that most of the signaling pathways that were activated and associated with growth in these cancers, converge on a protein called STAT3.
Bhaduri-McIntosh asked if STAT3, which is also known to be activated in many human cancers, is exploited by cancer-causing triggers such as EBV to suppress the DDR, thereby driving cell proliferation.
Through a series of experiments, Bhaduri-McIntosh found that EBV infection results in the activation and increase of STAT3 in cells, which in turn led to the alteration of other proteins in a DDR signaling pathway.
In other words, the results identified how the virus uses the cellular protein STAT3 to evade the policeman such that the policeman fails to interact with community members to keep the cell in order.
Overall, the results of Bhaduri-McIntosh’s study show that STAT3 interrupts ATR-Chk1, signaling to allow oncovirus-mediated cell proliferation, which means that STAT3 can “abnormally evade recognition of DNA errors and damage leading to bypass of a critical cell-cycle checkpoint and uncontrolled cell proliferation.”
The significant role that STAT3 and other proteins in the signaling pathway play in cancer formation make them ideal targets for future therapeutics. Bhaduri-McIntosh also plans to further explore the pathway and identify if the mechanism is present in other cancers to increase understanding of this disease.
