Researchers Find Key Mechanism Behind How Cancer Spreads
Quite a bit is known about how primary cancer cells grow, but our understanding of how they spread—metastasize—is less known. Researchers last year identified a gene, mEAK-7, that now appears to play a significant role in how lung cancer metastasizes.
The research was led by Paul Krebsbach, dean of UCLA’s School of Dentistry and a professor of periodontics. The research was published in the journal iScience.
They began by comparing mEAK-7 expression levels in normal cells to cancer cells using tissue samples from cancer patients and cancer genetics data from several databases.
“By focusing on non-small cell lung cancer, we found that mEAK-7, which is important for cell proliferation and migration, was highly expressed in metastatic non-small cell lung cancer,” stated Joe Nguyen, first author and postdoctoral scholar at the National Cancer Institute (NCI).
He added, “We also discovered that mEAK-7 was expressed in primary cancer cells but not expressed in non-cancerous cells, which shows that the protein could be a key culprit in cancer metastasis.”
In addition, they found that mEAK-7 combined with a molecule that helps regulate DNA repair and controls or enhances cancer cell growth called DNA-PKcs, caused the creation of an alternative mTOR signaling pathway. This is used by cancer cells to grow and spread. In healthy cells, two pathways are controlled by the mTOR gene, which regulates normal cell growth, proliferation and survival.
“This third complex or pathway is very important for cancer stem cells, which begin the process of colony formation and cell proliferation, and lead to metastasis that is the leading cause of death in most cancers,” Krebsbach stated. “We determined that there are high mEAK-7 protein levels in the tumors and lymph nodes of metastatic cancer patients. Development of mEAK-7 inhibitors may benefit patients with metastatic cancers that demonstrate aberrant mTOR signaling associated with high levels of mEAK-7.”
The third mTOR complex was made up of mTOR, mEAK-7 and DNA-PKcs. The researchers believe that understanding metastatic cancer’s molecular interactions is vital to developing treatments for cancers that have move into later metastasis stages.
“Currently, treatments for solid tumors include surgery and radiation therapies,” stated Jin Koo Kim, co-author and a UCLA Dentistry project scientist. “However, many patients relapse, as the target tumors develop resistance to radiation and other treatments. This study found that this resistance is correlated to higher mEAK-7 expression in cancer cells.”
Abnormal mTOR or rapamycin signaling is associated with many forms of human cancer. mEAK-7 was found to be an activator of mTOR signaling. mEAK-7 has a preferential expression pattern in human cancer cells.
The researchers acknowledge that the research is limited because they don’t have animal models that could duplicate human disease. Most of their work has been on identifying novel binding partners and the mechanisms they use to interact. Future research will be needed to study the role of mEAK-7 in vivo. They also are concerned that off-target effects and DNA-PKcs knockout cells lines may not duplicate all the physiology involved. This, they say, suggests that “genetic approaches in vivo are required to understand the role of DNA-PKcs binding to mTOR to form mTORC3.”