Pancreatic cancer cells. Credit: Anne Weston, London Research Institute, CRUK.

Researchers from Genentech have identified an epigenetic transcription regulator that appears to influence how aggressive pancreatic cancer cells are. When the regulator, a histone methyltransferase called SUV420H2, was repressed, it was found to promote epithelial-like properties in cancer cells, reducing their motility and invasiveness and making them more susceptible to chemotherapy. The research was published in the Journal of Cell Biology earlier this week.

Most cancers develop within epithelial tissues and exhibit the properties of epithelial cells. However, over time, some cancer cells start to become more mesenchymal in nature and this makes them more mobile and invasive. It also increases their resistance to the most common chemotherapy approaches, making them much harder to treat. This is especially true in pancreatic cancer cases, which is one of the most deadly forms of the disease and which demonstrates minimal response to existing chemotherapies.

To try to combat this resistance and aggressiveness, researchers have been looking for a way to reverse to the epithelial-to-mesenchymal transition. It is hoped that by doing so, clinicians may be able to get resistant cancers to respond to chemotherapy once more. Because of its severity and its willingness to undergo the transition, pancreatic cancer has become a focal point for this research.

“Pancreatic cancer is one of the deadliest malignancies because it is usually detected late in the course of the disease and existing treatments are typically ineffective because of intrinsic and acquired drug resistance, as well as being poorly responsive to immunotherapy,” the authors of the paper wrote. “Priming pancreatic cancers with an epithelial-inducing agent might not only decrease invasion and metastasis and limit stemness but may also increase responses to existing cancer drugs.”

The research team wanted to investigate whether or not epigenetics could be responsible for the epithelial-to-mesenchymal transition by altering gene expression. To do so, they screened 300 epigenetic factors to observe the effect they had on the cellular state. Their screen revealed that when SUV420H2 was reduced, the cancer cells began to regain some epithelial characteristics once more, such as reduced motility and invasiveness. Notably, the team also found that SUV420H2 inhibition increased the cancer’s sensitivity to two of the most common chemotherapy drugs used to treat pancreatic cancer, 5-fluorouracil and gemcitabine.

These are still early results and there is currently no indication as to whether these findings could be used to help patients. However, this research is an important stage in understanding how cancers can develop and evolve over time to proliferate more effectively.

“Collectively, these results indicated that SUV420H2 is a potent epigenetic factor in controlling epithelial/mesenchymal identity status in pancreatic cancer cells, and its repression elicits a global MET from a molecular standpoint,” the authors concluded.

“It is still unclear whether promoting a MET is in itself a beneficial strategy in oncology, considering that circulating tumour cells that have gone through an EMT at the primary lesion are thought to undergo MET for at the metastatic site. Consequently, forcing a MET could conceivably facilitate metastasis outgrowth. Nonetheless, promoting the epithelial state by targeting SUV420H2 in combination with conventional chemotherapies and decreasing resistance might prove to be an effective treatment for the devastating diagnosis of pancreatic cancer.”