Targeting Slug to Prevent Pancreatic Cancer Metastasis

Scientists at Sanford Burnham Prebys Medical Discovery Institute have shown that pancreatic cancer metastasis can be suppressed by inhibiting a protein called Slug that regulates cell movement. The study, published today in the Journal of Experimental Medicine, also revealed two druggable targets that interact with Slug.

“Pancreatic cancer cells are notorious for their ability to escape from a tumor. Even when pancreatic cancer is caught early, tumor cells are already found circulating throughout the body,” says senior author Cosimo Commisso. “Our study suggests that we may be able to create treatments that stop pancreatic cancer cells from untethering in the first place, which could reduce metastasis and help more people survive this deadly cancer.”

Pancreatic cancer cells, like all cancer cells, grow rapidly and deplete the nutrients in their surrounding environment quickly. To meet their energy needs, tumor cells boost metabolic pathways that normal cells don’t use. The team is working to understand how pancreatic cancer cells respond to the deprivation of nutrients—glutamine in particular—with the goal of finding treatments that stop the growth of cancer cells without harming healthy cells.

The scientists used a mouse model of pancreatic cancer to show that, in response to glutamine deficiency, a protein called Slug drives metastasis by activating the epithelial–mesenchymal transition (EMT). EMT is the process cells use to free themselves from tightly packed tissue. Inhibiting Slug reduced the cancer’s ability to spread, and patients with higher levels of Slug were linked to a poor prognosis.

“The field of pancreatic cancer research is still working to understand the role of EMT in metastasis. Our study shows that glutamine deficiency indeed activates EMT, through Slug, to allow pancreatic cancer cells to escape and look for nutrient-rich grounds,” says first author Maria Victoria Recouvreux. “In addition to revealing new therapeutic avenues that may halt pancreatic cancer metastasis, these findings might also apply to other tumors that rapidly consume glutamine, including lung and colon cancers.”

Because Slug is considered “undruggable,” the scientists continued to search for druggable proteins that interact with Slug and identified two promising targets: ERK and eIF2 alpha.