Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer. More than 90% of PDAC patients die within five years of diagnosis. Usually, by the time the cancer is identified, it has already spread. Researchers at Cold Spring Harbor Laboratory (CSHL) sought to understand the underlying genetic mechanisms of PDAC. They explored the role of RNA splicing in pancreatic cancer and found that high levels of a splicing-regulator protein called SRSF1 causes pancreatitis and jumpstarts PDAC tumor development.
Their findings are published in Cancer Discovery in an article titled, “Splicing Factor SRSF1 Promotes Pancreatitis and KRASG12D-Mediated Pancreatic Cancer.”
“Inflammation is strongly associated with PDAC, a highly lethal malignancy,” wrote the researchers. “Dysregulated RNA splicing factors have been widely reported in tumorigenesis, but their involvement in pancreatitis and PDAC is not well understood. Here, we report that the splicing factor SRSF1 is highly expressed in pancreatitis, PDAC precursor lesions, and tumors. Increased SRSF1 is sufficient to induce pancreatitis and accelerate KRASG12D-mediated PDAC.”
“PDAC is often found too late for treatments like chemotherapy and surgery to be very effective,” CSHL professor Adrian Krainer, PhD, explained.
Krainer and CSHL postdoc Ledong Wan, PhD, partnered with CSHL professor David Tuveson, MD, PhD, to explore RNA splicing in pancreatic cancer.
“Cells have several processes to keep SRSF1 levels constant,” said Krainer. “But cancer tends to find a way to overcome these checks and balances.”
Several genes, RNAs, and proteins work together in cells to keep SRSF1 levels steady. However, when the process gets disrupted in the pancreas, it triggers pancreatitis and accelerates PDAC.
“It’s a very pronounced effect,” Krainer explained. “We could see that patients whose tumors express higher levels of SRSF1 have worse outcomes. So, we set out to explore to what extent SRSF1 contributes to PDAC.”
The team found that higher levels of SRSF1 are essential for PDAC growth in mice and organoids—small versions of tumors. When SRSF1 returned to normal levels, the organoids stopped growing. SRSF1 is important in healthy tissue, so it may not be an ideal therapeutic target on its own. However, some of the splicing changes it promotes could be targeted instead.
“We’re excited by these developments,” he said. “But PDAC is a difficult and complicated malignancy. We’re hoping to provide actionable information for future treatments. This work spearheaded by Ledong is just the tip of the iceberg.”