In a recent study entitled “YAP1 Regulates OCT4 Activity and SOX2 Expression to Facilitate self-renewal and Vascular Mimicry of Stem-like Cells” researchers show how YAP1 protein promotes lung cancer stem cell renewal and tumor angiogenesis. The study was published in the journal Stem Cells.
Non-small cell lung cancer (NSCLC) patients have very low survival rates, with NSCLC accounting for most common type of lung cancer-related mortality (85% of lung cancer patients die from NSCLC). A specific type of cells within tumors, cancer stem‐like cells (CSCs), is considered a key factor in cancer progression due to tumor-initiating capacities, coupled with a high drug resistance. Thus CSCs are thought to repopulate tumor with cancer cells upon triggers from the tumor microenvironment. Previous work showed that the oncogenic YAP1 protein promotes lung cancer cells growth, however, the mechanisms behind this phenotype remained unknown.
Here, researchers from the Moffitt Cancer Center discovered that YAP1 protein is highly expressed in lung cancer stem cells. By binding to another protein, Oct4, the research team found that YAP1 induces the expression of SOX2 and this interaction promotes stem cells to continuously renovate themselves (a self-renewal process), while supporting tumors’ ability to form new blood vessels (a process known as angiogenesis), thus allowing tumors to expand, invade and ultimately disseminate to distant body parts. Notably, the authors compared YAP1‐Oct4 interaction levels between lung tumor tissue and adjacent healthy tissue and found higher levels in lung tumors. Furthermore, the team evaluated NSCLC patients’ outcomes, observing that those expressing higher levels of YAP1 in their tumors exhibited poorer outcomes.
The team went on to show that by blocking YAP1 they were able to inhibit stem cells’ renewal and tumors angiogenesis, therefore preventing tumor growth and dissemination. These results suggest that targeting YAP1 ‐ Oct4 interaction therapeutically might result in improved outcomes for NSCLC patients.
Srikumar P. Chellappan, Ph.D., chair of the Department of Tumor Biology at Moffitt and study lead author commented in a press release, “These results raise the possibility that inhibitors of YAP1 function or agents that can disrupt the binding of YAP1 to OCT4 could have anti-cancer effects. The identification of novel and effective inhibitors of YAP1 activity can be expected to have significant benefits as anticancer agents.”