A research partnership between Michigan Medicine and Gift of Life Michigan has revealed a new pathway to understanding the progression of pancreatic cancer.
In a study involving 30 pancreata from donors with no known gastrointestinal disease, researchers found precancerous lesions called pancreatic intraepithelial neoplasia (PanIN) in the majority of the organs. They also discovered that the lesions bore a similar gene expression signature to that of pancreatic cancer. These findings upend conventional wisdom that all PanIN are necessarily precursors to pancreatic cancer; given that the incidence of pancreatic cancer is relatively low, it’s not likely that all (or any) of the lesions are indicators of future cancer.
According to Timothy Frankel, M.D., an Associate Professor of Surgery at Michigan Medicine and one of the lead investigators on the paper, the findings will change the way researchers and clinicians think about PanIN lesions — less as indicators of certain future cancer and more as wildcards influenced by the microenvironment surrounding them.
“They’re likely not harbingers of cancer as we thought in the past…Although we see that they are very similar transcriptionally to cancer which suggests that they actually are likely related. What is it that separates the ones that progress to cancer from those that don’t? This work has now opened the door for a decade’s worth of research,” Frankel said.
A research challenge, a serendipitous partnership
Pancreatic cancer research has been hindered by the inability to study the healthy pancreas. There is no indication to biopsy a healthy pancreas, and doing so is risky; the organ is delicate and if ruptured will leak digestive enzymes, causing it to “autodigest,” essentially destroying itself.
As such, establishing a baseline for what a healthy pancreas looks like in the past has involved autopsy studies of normal pancreata or studies of tissue adjacent to tumors. Autopsy studies are limited by the pancreas’ tendency to degrade quickly once cut off from oxygen and blood supply. “Adjacent-normal” tissue is a product of an inflammatory environment, and it turns out is not exactly normal, as it is heavily influenced by surrounding pathology. As such, it often presents with extensive inflammation and other alterations.
Frankel wondered whether colleagues in transplant surgery had insight into acquiring healthy organs for study and Chris Sonnenday, M.D., a transplant surgeon at Michigan Medicine, connected him with the Gift of Life Michigan team at exactly the right time.
The Gift of Life Michigan Donor Care Center, located six miles from Michigan Medicine’s University Hospital, had been in search of pancreatic research partners since the Centers for Medicare & Medicaid Services (CMS) had emphasized the importance of such research for organ procurement organizations. Nick Olden, research coordinator for Gift of Life, said that organs for which there were no patient recipients were a priority for research matches.
“We want to give every organ and every tissue the chance to be placed with a study and pancreas is a really good example where we just didn't have any projects to support that program,” Olden said.
Marina Pasca Di Magliano, Ph.D., Maude T. Lane Professor of Surgical Immunology at Michigan Medicine and a co-lead investigator on the paper, knew the project would be a big logistical lift.
“We had to set up a whole system to get and process the organs because it’s a lot of tissue and it’s very time sensitive. We met with people in the lab and said ‘Anyone who wants in is in this project, but what that means is you have to drop everything you’re doing. If we get a phone call, you have to drop everything.’”
A lot of people signed up, and a lot of people dropped everything when the calls came.
The process the team developed to recover pancreata ensured the organs would be good quality and have blood flow until the last possible moment, nearly eliminating any “warm ischemic” time that contributes to organ degradation. (Earlier attempts to recover organs from donors who’d suffered cardiac death resulted in degraded organs, so the team focused on brain-dead donors to recover organs in a more controlled manner.)
Within just a few months of first making contact, the team had recovered, transported and studied its first pancreas, a process that takes roughly 90 minutes from recovery to receiving.