Researchers developed a three-dimensional organoid culture model to grow both normal and cancerous pancreatic tissue in the lab, providing a window into the molecular underpinnings of tumor progression and a potential path to identifying new drug targets for pancreatic cancer.
Researchers in the Netherlands and the United States have developed a culture system for pancreatic cancer capable of rapidly generating three-dimensional (3-D) organoid models from normal and diseased pancreatic tissue, providing a window into the molecular underpinnings of tumor progression and a potential path to identifying new drug targets.
In a recent study, researchers established normal and neoplastic pancreatic organoids—tiny 3-D organ-like structures comprised of hundreds to thousands of cells—from mouse and human pancreatic ductal cells (Cell 2015;160:324–38). The 3-D culture strategy enabled researchers to grow normal pancreatic cells—which has not been possible in 2-D culture conditions—and study them alongside diseased pancreatic cells in order to analyze the molecular pathways that correlate with disease progression.
“By growing the cancer as an organoid we were able to capture the earliest stages of disease,” says study co–senior author Hans Clevers, MD, PhD, professor of molecular genetics at the Hebrecht Institute, Royal Netherlands Academy of Arts and Sciences, who first developed organoids representing a variety of tissues, including the small intestine, colon, stomach, liver, and prostate. “Furthermore, this allows us to identify molecular pathways that are altered in the cancer compared to normal cells.”
When the cancerous organoid cells were transplanted into mice, they successfully replicated the full spectrum of pancreatic tumor development, allowing researchers to isolate and analyze each stage of disease.
“Using this progression model is very different from implanting cancer cell lines into mouse models and watching them grow as cancer cells,” says study co–senior author David Tuveson, MD, PhD, director of the Lustgarten Foundation Pancreatic Cancer Research Laboratory at Cold Spring Harbor Laboratory in New York. “With this new system, the cells appear to be reprogrammed so that they start out as a low-grade and become, over time, a high-grade neoplasm.”
The model also allows organoids to be generated rapidly from tiny needle biopsies, eliminating a barrier for researchers. To date, there has been limited access to tissue samples because 85% of pancreatic cancer patients are ineligible for surgical resection due to the advanced stage of their disease at diagnosis or because their tumor is enmeshed in critical vasculature.
Gene expression and proteomic analyses conducted as part of the study revealed that nucleoporins—a family of proteins that make up the nuclear core complex—were broadly upregulated in the neoplastic mouse organoid models and that the expression increased measurably along with cancer progression, says Tuveson. The unexpected finding suggests that nucleoporins, which have been previously implicated in cancer, should be a focus of future pancreatic cancer research.
The investigators also established an organoid with a wild-type KRAS gene, an uncommon manifestation of pancreas cancer, says Clevers. Studying these organoids may help identify new driver genes and molecular pathways with therapeutic relevance.
“We're hoping that organoid technology will provide a platform from which researchers will be able to identify actionable mutations for pancreas cancer,” says Clevers. Concurring, Tuveson notes that “the organoid model may be a way to actually deliver on the promise of personalized medicine.”
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