Turning back the clock on disease

Invasive cancer sprouts from an artificial pancreatic duct engineered by Purdue University researchers. The cell bodies are stained magenta, and the nuclei are stained blue. (Purdue University image/Stephanie Venis, Hye-ran Moon and Bumsoo Han)

Imagine if you could build a time machine for medicine, turning back the clock to watch how cells with genetic mutations begin their nefarious path to invasive disease. You then would be able to observe the disease progression over time, reconstructing its twists and turns to test therapeutic interventions and approaches that offer the best treatment strategy.

That’s what we’re doing with pancreatic cancer. This deadly disease is the third-leading cause of cancer deaths in the U.S., with a dreadful 5-year survival rate of just 10 percent. It is anticipated there will be approximately 62,000 new cases in 2022, with a projected $3.2 billion cost to the healthcare system.

The poor treatment outcomes are linked to the difficulty of delivering therapeutic drugs through a dense stroma — the surrounding connective tissue of the tumor that provides a structural role. The stroma accounts for up to 90 percent of the pancreatic tumor volume and has been thought to promote tumor growth, in addition to hampering drug delivery to the tumor.

However, multiple recent studies suggest the stroma also plays a role in restraining tumor growth and invasion. We want to understand these puzzling roles of stroma and modulate them to improve drug delivery and efficacy. To conduct our study, my research team has been developing engineered tumor-stroma models using genetic engineering, microfluidics, and 3D-printing technologies.

The models capture various aspects of pancreatic tumor pathophysiology, including metastasis, intra-tumoral heterogeneity, and tumor-stroma interactions. And we’re not only engineering tumor models for this particular application; more broadly, we have been using the models to study cancer biology, and to ultimately discover innovative drugs and drug delivery systems.

Our lab built a “time machine” that is a lifelike replica of a structure in the pancreas called the acinus. Derived from the Latin word for berry, the acinus produces digestive enzymes and secretes them into the small intestine. Pancreatic cancer can develop from chronic, mutation-induced inflammation, which leads to loss of the enzyme production function. Our goal is to turn back “the hands of time,” reprogramming the cancerous acinar cells back to normal phenotypes that produce those enzymes, which might make it possible to “reset” the pancreas on a healthy path.

Pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer, is characterized by a complex environment of heterogeneous cancer cell populations in the stroma. Furthermore, there are multiple tumor cell subtypes that can interact and strengthen one another’s invasiveness, creating convoluted mechanisms that contribute to drug resistance. This makes it especially difficult to identify singular targets for therapeutic intervention.

We are developing an engineered tumor model to replicate the PDAC tumor microenvironment for deeper analysis and experimentation. This model, named pancreatic ductal adenocarcinoma tumor-microenvironment-on-chip (PDAC TME), is a microfluidic platform in which the genetically-engineered pancreatic cancer cells are embedded inside a collagen matrix that mimics the pancreatic duct. The model allows us to culture cancer cells in channels measuring less than 1 mm in diameter and grow them in a realistic, lifelike environment that simulates a biological system.

Within the glass platform of this microscope slide, researchers recreated two anatomical structures involved in the spread of pancreatic cancer. (Purdue University photo/John Underwood)

Our lab is using the model to study the various invasion properties and characteristics of the cancer cells in their response to treatments. We’ve also been able to activate a gene that shows promise to reprogram the cancerous cells for healthy development — building on the work done by Stephen Konieczny, professor emeritus in Purdue’s Department of Biological Sciences, in studying a gene called PTF1a, which is vital for normal pancreatic development.

It typically takes something like 10 to 20 years for pancreatic cancer to develop. Using an animal model can compress this process to several months. Our engineered model squeezes that timeframe to only two weeks. During that brief period, we can see what happens in real life over a much longer period of time, and test drug treatments against multiple targets to better understand tumor cell resistance and treatment efficacy. Our research is being used to investigate ways to genetically reprogram the cancerous acinar cells back to a normal functional state and to develop new drug compounds to combat this lethal disease.

Bumsoo Han, PhD

Professor, School of Mechanical Engineering, and Weldon School of Biomedical Engineering (by courtesy)

College of Engineering

Program Leader, Purdue Center for Cancer Research

Purdue University

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