January 17, 2013

Study helps define pancreatic cancer’s cellular origins

Vanderbilt and University of California investigators have discovered the “cell of origin” for pancreatic ductal adenocarcinoma, a finding that could lead to early detection methods and new treatments.

Christopher Wright, D.Phil, Fong Cheng Pan and colleagues are studying the ‘cell of origin’ for the most common form of pancreatic cancer. (photo by Joe Howell)

Pancreatic cancer — usually diagnosed at an advanced stage — is particularly deadly, with fewer than 5 percent of patients surviving five years after diagnosis. Developing early detection methods and new treatments requires understanding how the cancer begins and progresses.

Vanderbilt developmental biologist Christopher Wright, D.Phil., and colleagues at the University of California have now discovered the “cell of origin” for pancreatic ductal adenocarcinoma, the most common form of pancreatic cancer. They report in the journal Cancer Cell that digestive enzyme-secreting cells of the pancreas (acinar cells) — not ductal epithelial cells as previously believed — give rise to pancreatic tumors.

“[rquote]It was a complete surprise and reconfiguration of how we think about pancreatic cancer[/rquote],” said Wright, the Louise B. McGavock Professor of Cell and Developmental Biology.

The findings will make it possible to explore the earliest changes that give rise to pancreatic cancer, Wright said.

“We can now look at the genomic level programs that are altered in the cell of origin at the very inception of cancer,” he said. “And we can watch as things go wrong and the acinar cell becomes more and more destabilized and eventually metastatic.”

The researchers knew from previous studies that activation of the signaling molecule Kras — the genetic mutation most commonly found in human cancer — in the mouse pancreas produced lesions that are pathologically identical to human pancreatic cancer.

They coupled Kras activation with genetic tools that Wright and his colleagues, including critical collaborative work with Mark Magnuson, M.D., have developed over the past ten years to label and trace specific pancreatic cell populations (such as acinar cells and ductal cells). The investigators found that activating Kras in acinar cells – but not in ductal cells – resulted in pancreatic tumors.

They showed that the acinar cells switch from an enzyme-secreting cell type to a duct-like cell type, “which is so destabilized that it goes crazy and moves off into a dysplastic, cancerous state,” Wright said.

The switch in cell type depended on expression of the gene Sox9, which may represent a target for preventing early tumor-initiating events.

The studies not only define the cell of origin for pancreatic cancer, but they also introduce a mouse model with focal, adult-stage pancreatic cancer that is the best current mimic of human pancreatic adenocarcinoma.

“This is exactly the kind of mammalian model we need as a platform for pancreatic cancer drug discovery,” Wright added.

Wright and his University of California colleagues are part of the Beta Cell Biology Consortium (BCBC), an interdisciplinary team science initiative to advance understanding of pancreatic islet (which includes the insulin-secreting beta cells) development and function. The fundamental studies of the BCBC aimed at developing innovative therapies for diabetes have now “erupted” into a whole new set of tools and activities that can be rapidly applied to pancreatic cancer, Wright said.

“These developmental biology and cell biological tools that we are generating at Vanderbilt – and our ability to dissect and define genetic programs in the developmental process – place us in a powerful position at the forefront of cancer research,” he said.

Wright’s colleagues on the Cancer Cell paper include Matthias Hebrok, Ph.D., director of the UC San Francisco Diabetes Center, and Maike Sander, M.D., director of the UC San Diego Pediatric Diabetes Research Center. The research was supported by grants from the National Institutes of Health (DK078803, DK089570, CA112537). Magnuson is the Louise B. McGavock Professor of Molecular Physiology and Biophysics at Vanderbilt.