Lifestyle

Scientists reverse pancreatic cancer progression in ‘time machine’ made of human cells

WEST LAFAYETTE, Ind. — What makes pancreatic cancer so deadly is its rapid and secretive spread. Now, a “time machine” built by Purdue University engineers has shown a way to reverse cancer before it spreads throughout the pancreas.

“These findings open up the possibility of designing a new gene therapy or drug because we can now deliver a drug,” said Bumsoo Han, professor of mechanical engineering and program leader of the Purdue Cancer Research Center. change the cancer cells back to their normal state. Han has a courtesy appointment in biomedical engineering.

The time machine Han’s lab built is a lifelike reproduction of a pancreatic structure called the acinus, which produces and secretes digestive enzymes into the small intestine. Pancreatic cancer tends to develop from chronic inflammation that occurs when a mutation causes these digestive enzymes to digest the pancreas on its own.

If there was a way to go back in time to reprogram the cancerous acinar cells to produce those enzymes, it would be possible to completely reset the pancreas.

For the past decade, Stephen Konieczny, professor emeritus in Purdue University’s Department of Biological Sciences, has been working on a potential reset node: a gene called PTF1a.

“The PTF1a gene is extremely important for the normal development of the pancreas. If you lack the PTF1a gene, you won’t develop a pancreas,” says Konieczny. “So our whole idea was, if we turned the PTF1a gene back on in pancreatic cancer cells, what would happen? Will we revert the cancer phenotype? Indeed, that is exactly what happens.”

Konieczny collaborated with Han’s lab to take these findings in molecular biology research to the next level by testing them in a realistic model of the acinus, the time machine. The published research is published on the cover of the October 7 issue of the Royal Chemical Society’s Lab on a Chip journal.

han-slides
In the glass background of this microscope slide, the researchers reconstructed two anatomical structures involved in the spread of pancreatic cancer. (Purdue University/John Underwood Photo) Download images

Researchers often investigate possible pancreatic cancer treatments in animal models, but it can take several months for pancreatic cancer to develop in animals. Having a way to study cancer treatment and development concepts in a reality-like microenvironment saves time and gives researchers more control over the model.

The model that Purdue University researchers developed overcame a major challenge in accurately capturing the anatomical complexity of the acinus, a circular cavity lined with cells.

“From a technical perspective, creating this kind of three-dimensional cavity is not easy. So figuring out how to build this cavity was an innovation in itself,” said Han.

Han’s lab has experience building a realistic model of another pancreatic structure, the duct, where cancer develops after emerging from the acinus. The researchers used this knowledge and developed a new technique to build both ducts and mammary glands in a two-step process of “making viscous fingers.”

Here’s how it works: This model, a postage stamp-sized glass platform on a microscope slide, has two interconnected chambers. Loading a collagen solution into a cavity fills the finger-like shape of the pancreatic duct, which bulges and then expands to create the cavity structure of the acinus in the second cavity.

Dropping human cancer cells into the acinar chamber makes the model even more realistic. Konieczny’s lab engineered the PTF1a gene of a pancreatic cancer cell line to turn on in the presence of doxycycline, a compound commonly used in antibiotics. After the gene was activated, the cells began to build the remains of the acinus in Han’s model, showing that they were no longer cancerous and had been reprogrammed.

“In this model, not only were the cancer cells reprogrammed, but for the first time, we were able to show the normal three-dimensional structure of the acinus, which looks very similar to the same structures that we have. found in a healthy pancreas. ,” said Konieczny.

Han’s lab is currently conducting experiments exploring a possible gene therapy based on these findings.

This research was supported in part by grants from the National Institutes of Health, the Walther Embedded Program in Physical Sciences in Cancer, and the Purdue Cancer Research Center, one of seven Laboratory Cancer Centers. National Cancer Institute baseline trials nationwide.

About Purdue University

Purdue University is a leading public research institution developing practical solutions to today’s toughest challenges. Ranked by US News & World Report for the past 4 years as one of the 10 most innovative universities in the United States, Purdue offers world-changing research and out-of-this-world exploration. Committed to hands-on and online, real-world learning, Purdue provides a transformative education for all. Committed to affordability and accessibility, Purdue froze tuition and most fees at 2012-13 levels, enabling more students than ever to graduate debt-free. See how Purdue relentlessly pursues the next giant leap at https://purdue.edu/.

Writers, Media Contact: Kayla Wiles, 765-494-2432, wiles5@purdue.edu

source: Bumsoo Han, bumsoo@purdue.edu

Stephen Konieczny, sfk@purdue.edu


ABSTRACT

Engineering of a functional pancreas with cancer cells reprogrammed by inducing PTF1a manifestation

Stephanie M. Venis, Hye-ran Moon, Yi Yang, Sagar M. Utturkar, Stephen F. Konieczny and Bumsoo Han

DOI: https://doi.org/10.1039/D1LC00350J

A pancreas is a functional unit of the exocrine pancreas that produces digestive enzymes. Its pathogenesis is important for pancreatic diseases including pancreatitis and pancreatic cancer, possibly starting with pancreatic acini. However, the study of pancreatic acini has been significantly hampered by the difficulty of culturing normal acinar cells. in vitro. In this study, one in vitro a model of the normal pancreas, named pancreatic ductus arteriosus (PAC), was developed using reprogrammed pancreatic cancer cells. The model developed is a microfluidic platform with epithelial tubules and acinar vesicle geometries that are micro-fabricated using a newly developed two-step controlled “viscous finger” technique. In this model, human pancreatic cancer cells, Panc-1, are reprogrammed to return to a normal state when induced PTF1a gene expression, cultured. Bioinformatics analyzes showed that, when inducing PTF1a expression, Panc-1 cells switch to a more normal and differentiated acinar phenotype. The model’s microscopic and exocrine functions were characterized to confirm normal acinus phenotypes. The model developed provides a new and reliable test to study the initiation and progression of pancreatic cancer.



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