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Take it from the top
WEST LAFAYETTE, Ind.—Much of the focus on catching cancer early is based on the hope that prompt, tailored treatment can head things off at the pass. But catching cancer in its earliest stages in models also sheds light on how exactly cancer develops and spreads, and that offers new understanding as well as the potential for new therapeutic avenues.
In pursuit of that understanding, a research team at Purdue University has developed what they call a pancreatic cancer “time machine,” a tumor model that shortens the development of pancreatic cancer—generally a matter of 10 to 20 years in humans and several months in animal models—into the span of two weeks. Their findings were published in the journal Small, in a paper titled “A Biomimetic Tumor Model of Heterogeneous Invasion in Pancreatic Ductal Adenocarcinoma.”
“We can observe what happens over a long period of time. This helps us to see trends that we wouldn’t normally see,” said Bumsoo Han, a Purdue professor of mechanical engineering who builds models for studying how cancer cells move in biological systems.
The tumor model consists of a hollow tube of collagen that recreates the microanatomy of a pancreatic duct. Cancer cell lines are injected into microfluidic channels in the duct, and tumor growth can be tracked from then on.
The mimicry of the natural pancreatic environment is important, as it gives a more accurate recreation of how cancer spreads and interacts with the cells around it. And by setting up imaging equipment to monitor the artificial pancreatic duct, it’s possible to rewind the footage to track how the cancer progresses step by step.
The pancreatic cell line was developed in a mouse model by Stephen Konieczny, a professor of biological sciences at Purdue, and his team. Pancreatic cancer has four major driver mutations, and as noted in the paper, “The cancer cells used carry two of the three mutations of KRAS, CDKN2A, and TP53, which are key driver mutations of human [pancreatic ductal adenocarcinoma]. The intratumoral heterogeneity is mimicked by co-culturing these cancer cells.” Han and his lab then injected the cell line into the artificial duct.
“The curvature of the pancreatic duct affects the behavior of cells. We could culture these cancer cells on a petri dish, but because the dish is flat, we wouldn’t see the same behavior,” explained Han, who is the program leader of the Purdue University Center for Cancer Research and has a courtesy appointment in biomedical engineering.
What they found was that two different cancer cell types merged in the artificial duct—referred to as the ductal tumor‐microenvironment‐on‐chip (dT‐MOC)—and consequently become more invasive, proceeding to sprout out of the duct and form tumors.
Han adds that this new technique could also be used to identify new drug targets.
Moving forward, Han and his team intend to investigate how pancreatic cancer’s main driver mutations interact with each other.
Konieczny’s lab is working on transgenic mouse tumor models, with a focus on the transcription factors MIST1 and SOX9, which are affected differently by KRAS, one of the four key drivers in pancreatic cancer.
“MIST1 expression is normally restricted to pancreatic acinar cells, whereas SOX9 is found exclusively in duct cells. However, when oncogenic KRAS is expressed in acinar cells, the MIST1 gene is rapidly silenced while the SOX9 gene is activated in this cell type,” as reported on the Konieczny lab website. “Interestingly, expression of KRAS in a MIST1KO background greatly accelerates pancreatic tumor formation whereas activation of KRAS in a SOX9KO background completely prevents tumor formation. These findings suggest that MIST1 is needed to prevent pancreatic cancer development whereas SOX9 is essential to tumor formation. Using a variety of genetically engineered mouse models as well as in-vitro strategies using shRNA, we are dissecting the pathways that are controlled by the MIST1 and SOX9 networks. Additionally, we are taking a genomics approach of identifying downstream gene targets of MIST1 and SOX9 to decipher their importance to pancreatic disease initiation.”
Pancreatic cancer has one of the lowest survival rates, due in part to the aforementioned gestation period—given how long it takes the disease to develop, by the time it is diagnosed, the cancer is generally in its late stages when treatment is less effective. Five-year survival rates after diagnosis can be as low as 9 percent, and pancreatic cancer accounts for approximately 7 percent of all cancer deaths. The American Cancer Society estimates that some 57,600 people will be diagnosed with pancreatic cancer this year, and roughly 47,050 individuals will die from it in 2020.