By examining the changes in prostate cancer cells over time, researchers have discovered that the activation of the MYC gene – known for its role in cancer development – triggers a series of events that causes both the onset and advancement of the disease.
By examining the changes in prostate cancer cells over time, researchers at the Johns Hopkins Kimmel Cancer Center have discovered that the activation of the MYC gene – widely recognized as a cancer-causing gene – triggers a sequence of events that leads to both the onset and the advancement of the disease.
Researchers have realized that prostate cancers differ greatly between patients and may even vary within a single patient’s tumor. Nonetheless, the study released on August 28 in Nature Communications highlights the MYC gene as a consistent factor across various prostate cancers. This research shows that the initial activation of MYC draws immune cells to the tumor but later helps the tumor evade detection by these immune cells. This finding represents an initial step towards identifying potential treatment targets along this pathway.
“This is a highly influential oncogenic pathway triggered by MYC activation,” explains Srinivasan Yegnasubramanian, M.D., Ph.D., a professor of oncology, pathology, and radiation oncology and a leader of the inHealth precision medicine initiative at Johns Hopkins. “We must delve deeply into this intricate chain of events to discover more effective management strategies for the disease.”
Investigating human tumor tissues can aid scientists in understanding prostate cancer, albeit they offer only a limited view. To gain insight into the changes that occur over time in prostate cancer, researchers utilize animal models. Yegnasubramanian and his team combined both methods to closely examine the initiation and progression of prostate cancer.
The researchers utilized single-cell RNA sequencing to demonstrate that the targets of the MYC gene are excessively expressed in samples of human tumor tissue, suggesting heightened MYC activity. They observed the subsequent developments in animal models of prostate cancer following the increase in MYC activity.
They discovered that when MYC first becomes elevated in precancerous cells, signaling pathways that alert the immune system to potential threats are activated. Over time, however, these immune-attracting pathways become inactive. As the tumor advances, it ceases to signal the immune system and remains unnoticed. This finding may clarify why treatments meant to enhance the immune system’s response to cancer do not always work effectively for prostate cancers—if the immune system is initially inactive, removing barriers will not be beneficial.
“These prostate cancer cells have figured out how to deactivate the signals that would usually notify the immune system, enabling them to escape detection,” Yegnasubramanian remarks. “Now, we can begin to develop methods to re-engage the immune response and make the tumors more responsive to immunotherapy.”
There are already drugs in development targeting TREM2 macrophages—some immune cells that are influenced by excessive MYC expression in prostate cancer—that could assist the immune system in combating prostate tumors.
The study, which also employed molecular pathology techniques, revealed that elevated MYC expression and activity commence in the epithelial cells lining the prostate. Over time, these epithelial cells transform into cancer cells and send signals to neighboring cells, reducing the immune response, causing scarring, increasing the number of tumor cells, and triggering other molecular alterations. The findings enhance the evidence suggesting that MYC could be a vital target for prostate cancer treatment or prevention, according to Yegnasubramanian.
“We have observed some of these alterations in human prostate tumors for many years; however, we did not realize that the entire process could be triggered by a single initiating event: the upregulation of MYC,” he states.
Mindy Graham and Rulin Wang of Northwestern University were the principal authors of the study; they conducted the research while affiliated with Johns Hopkins. Other contributors included Jianyong Liu, Jennifer Meyers, Alyza Skaist, Yan Zhang, Kornel Schuebel, William Nelson, Shawn Lupold, Theodore DeWeese, and Angelo De Marzo from Johns Hopkins. Researchers from the University of Maryland and Baylor College of Medicine also participated in the study.
The research received funding from the National Institutes of Health, the National Cancer Institute, the Prostate Cancer Foundation, a Pilot Project grant from Allegheny Health Network and Johns Hopkins, The Patrick C. Walsh Prostate Cancer Research Fund, the Irving A. Hansen Memorial Foundation, the Commonwealth Foundation, and the Maryland Cigarette Restitution Fund Program. The authors of the study declare no conflicts of interest.
