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

WEST LAFAYETTE, Ind. — What makes pancreatic most cancers so lethal is its covert and fast unfold. Now, a “time machine” constructed by Purdue College engineers has proven a method to reverse the course of most cancers earlier than it spreads all through the pancreas.

“These findings open up the potential of designing a brand new gene remedy or drug as a result of now we are able to convert cancerous cells again into their regular state,” mentioned Bumsoo Han, a Purdue professor of mechanical engineering and program chief of the Purdue Center for Cancer Research. Han has a courtesy appointment in biomedical engineering.

The time machine that Han’s lab constructed is a lifelike replica of a pancreatic construction known as the acinus, which produces and secretes digestive enzymes into the small gut. Pancreatic most cancers tends to develop from power irritation that occurs when a mutation has triggered these digestive enzymes to digest the pancreas itself.

If there have been a approach to return in time to reprogram the cancerous acinar cells that produce these enzymes, then it is likely to be attainable to utterly reset the pancreas.

For the previous decade, Stephen Konieczny, professor emeritus in Purdue’s Department of Biological Sciences, has studied a possible reset button: a gene known as PTF1a.

“The PTF1a gene is totally essential for regular pancreas growth. For those who lack the PTF1a gene, you don’t develop a pancreas,” Konieczny mentioned. “So, our complete thought was, if we flip the PTF1a gene again on in a pancreatic most cancers cell, what occurs? Will we revert the most cancers phenotype? Certainly, that’s precisely what occurs.”

Konieczny collaborated with Han’s lab to take these findings in molecular biology studies to the following stage by testing them in a practical mannequin of the acinus – the time machine. The printed research is featured on the quilt of the Oct. 7 situation of Lab on a Chip, a journal by the Royal Society of Chemistry.

Inside the glass platform of this microscope slide, researchers recreated two anatomical buildings concerned within the unfold of pancreatic most cancers. (Purdue College picture/John Underwood)
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Researchers sometimes examine attainable pancreatic most cancers remedy approaches in animal fashions, however it could take months for pancreatic most cancers to develop in an animal. Having a method to research most cancers growth and remedy ideas in a microenvironment that’s simply as sensible would save time and provides researchers extra management over the mannequin.

The mannequin that Purdue researchers developed overcomes a significant problem in precisely capturing the anatomical complexity of the acinus, a round cavity lined with cells.

“From an engineering perspective, creating this sort of three-dimensional cavity just isn’t trivial. So, determining a method to construct this cavity is an innovation in itself,” Han mentioned.

Han’s lab already had expertise constructing a practical mannequin of another pancreatic structure, the duct, the place most cancers grows after rising from the acinus. The researchers took this data and developed a brand new method that builds each the duct and acinus in a two-step “viscous fingering” course of.

Right here’s the way it works: The mannequin, a postage stamp-size glass platform on high of a microscope slide, has two interconnected chambers. Loading a collagen answer into one chamber fills the finger-like form of a pancreatic duct, which bulges after which expands to create the cavity construction of the acinus within the second chamber.

Dropping cancerous human cells into the acinar chamber made the mannequin much more sensible. Konieczny’s lab engineered the PTF1a gene of a pancreatic most cancers cell line to activate within the presence of doxycycline, a compound generally utilized in antibiotics. As soon as the gene was activated, the cells began setting up the remainder of the acinus in Han’s mannequin, indicating that they have been now not cancerous and had been reprogrammed.

“On this mannequin, not solely do the cancerous cells change into reprogrammed, however for the primary time, we’re in a position to present the conventional three-dimensional structure of the acinus, which appears similar to the identical buildings we see in a wholesome pancreas,” Konieczny mentioned.

Han’s lab is presently conducting experiments exploring a attainable gene remedy based mostly on these findings.

This research was partially supported by grants from the Nationwide Institutes of Well being, the Walther Embedding Program in Bodily Sciences in Oncology, and the Purdue Heart for Most cancers Analysis, which is one in every of solely seven Nationwide Most cancers Institute Primary Laboratory Most cancers Facilities within the nation.

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Author, Media contact: Kayla Wiles, 765-494-2432, wiles5@purdue.edu

Sources: Bumsoo Han, bumsoo@purdue.edu

Stephen Konieczny, sfk@purdue.edu

ABSTRACT

Engineering of a useful pancreatic acinus with reprogrammed most cancers cells by induced PTF1a expression

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 pancreatic acinus is a useful unit of the exocrine pancreas producing digest enzymes. Its pathobiology is essential to pancreatic ailments together with pancreatitis and pancreatic most cancers, which might provoke from pancreatic acini. Nevertheless, analysis on pancreatic acini has been considerably hampered as a result of problem of culturing regular acinar cells in vitro. On this research, an in vitro mannequin of the conventional acinus, named pancreatic acinus-on-chip (PAC), is developed utilizing reprogrammed pancreatic most cancers cells. The developed mannequin is a microfluidic platform with an epithelial duct and acinar sac geometry microfabricated by a newly developed two-step managed “viscous-fingering” method. On this mannequin, human pancreatic most cancers cells, Panc-1, reprogrammed to revert to the conventional state upon induction of PTF1a gene expression, are cultured. Bioinformatic analyses recommend that, upon induced PTF1a expression, Panc-1 cells transition right into a extra regular and differentiated acinar phenotype. The microanatomy and exocrine features of the mannequin are characterised to verify the conventional acinus phenotypes. The developed mannequin offers a brand new and dependable testbed to review the initiation and development of pancreatic cancers.