WEST LAFAYETTE, Ind. – What makes pancreatic cancer so deadly is its secret and rapid spread. Today, a “time machine” built by engineers at Purdue University has shown a way to reverse the course of cancer before it spreads to the pancreas.
“These findings open up the possibility of designing a new gene therapy or a new drug because we can now convert cancer cells back to their normal state,” said Bumsoo Han, professor of mechanical engineering at Purdue and program manager at the Purdue Center for Cancer Research. Han has a courtesy appointment in Biomedical Engineering.
The time machine Han’s lab built is a realistic reproduction of a pancreatic structure called acinus, which produces and secretes digestive enzymes in the small intestine. Pancreatic cancer tends to develop from a chronic inflammation that occurs when a mutation causes these digestive enzymes to digest the pancreas itself.
If there was a way to go back in time to reprogram the acinar cancer cells that produce these enzymes, then it would be possible to completely reset the pancreas.
For the past decade, Stephen Konieczny, professor emeritus in the Department of Biological Sciences at Purdue, has studied a potential reset button: a gene called PTF1a.
“The PTF1a gene is absolutely essential for the normal development of the pancreas. If you don’t have the PTF1a gene, you don’t develop a pancreas, ”Konieczny said. “So our whole idea was that if we reactivated the PTF1a gene in a pancreatic cancer cell, what would happen? Are we going to reverse the cancer phenotype? Indeed, that is exactly what is happening.
Konieczny collaborated with Han’s lab to take these findings to the next level in molecular biology studies by testing them in a realistic model of the acinus – the time machine. The published study is on the cover of the Oct. 7 issue of Lab on a Chip, a journal of the Royal Society of Chemistry.
Researchers typically study possible approaches to treating pancreatic cancer in animal models, but the development of pancreatic cancer in an animal can take months. Having a way to study cancer development and treatment concepts in an equally realistic microenvironment would save time and give researchers more control over the model.
The model developed by Purdue researchers overcomes a major challenge by accurately capturing the anatomical complexity of the acinus, a circular cavity lined with cells.
“From a technical point of view, creating this type of three-dimensional cavity is not trivial. So finding a way to build this cavity is an innovation in itself, ”Han said.
Han’s lab had previously built a realistic model of another pancreatic structure, the duct, where cancer grows after emerging from the acinus. The researchers took this knowledge and developed a new technique that builds both the canal and the acinus in a two-step “viscous fingering” process.
Here’s how it works: The model, a postage stamp-sized glass platform on top of a microscope slide, has two interconnected chambers. Loading a collagen solution into one chamber fills the finger-like shape of a pancreatic duct, which swells and then expands to create the structure of the acinus cavity in the second chamber.
Dropping human cancer cells into the acinar chamber made the model even more realistic. Konieczny’s lab designed the PTF1a gene from a pancreatic cancer cell line to activate in the presence of doxycycline, a compound commonly used in antibiotics. Once the gene was activated, the cells began to build the rest of the acinus in Han’s model, indicating that they were no longer cancerous and had been reprogrammed.
“In this model, not only are cancer cells reprogrammed, but for the first time, we are able to show the normal three-dimensional architecture of the acinus, which looks a lot like the same structures we see in a healthy pancreas. “Konieczny said.
Han’s lab is currently conducting experiments exploring possible gene therapy based on these findings.
This study was partially funded by grants from the National Institutes of Health, the Walther Embedding Program in Physical Sciences in Oncology, and the Purdue Center for Cancer Research, which is one of the National Cancer Institute Basic’s seven cancer centers. Country laboratory.
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Editor, Media Contact: Kayla Wiles, 765-494-2432, [email protected]
Sources: Bumsoo Han, [email protected]
Stephen Konieczny, [email protected]
Engineering of a functional pancreatic acinus with reprogrammed cancer cells by PTF1a expression
Stephanie M. Venis, Hye-ran Moon, Yi Yang, Sagar M. Utturkar, Stephen F. Konieczny and Bumsoo Han
A pancreatic acinus is a functional unit of the exocrine pancreas that produces digestive enzymes. Its pathobiology is crucial for pancreatic diseases, including pancreatitis and pancreatic cancer, which can start from pancreatic acini. However, research on pancreatic acini has been significantly hampered due to the difficulty of growing normal acinar cells. in vitro. In this study, a in vitro The model of normal acinus, called the pancreatic acinus on a chip (PAC), is developed using reprogrammed pancreatic cancer cells. The developed model is a microfluidic platform with epithelial canal and acinar sac geometry microfabricated by a novel two-step controlled “viscous fingering” technique. In this model, human pancreatic cancer cells, Panc-1, reprogrammed to return to normal upon induction of PTF1a gene expression, are grown. Bioinformatic analyzes suggest that, upon induction PTF1a expression, Panc-1 cells change to a more normal and differentiated acinar phenotype. The model’s microanatomy and exocrine functions are characterized to confirm normal acinar phenotypes. The model developed provides a new reliable test bed to study the initiation and progression of pancreatic cancers.