Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive cancer due to the lack of early diagnosis and the low efficacy of available treatments. It is the most prevalent type of pancreatic cancer and accounts for more than 90% of pancreatic cancer cases. It is estimated that the 5-year overall survival is less than 8%. PDAC has been linked to aging, diabetes, obesity but also lifestyle habits such as smoking and alcohol consumption. With the incidence of some of these risk factors in the rise scientists have estimated that the incidence of PDAC and the PDAC-associated deaths will increase two-fold in the next 10 years.
The development of reliable tools for the diagnosis of early stage PDAC is critical for the fight against the lethality of the disease. A team of researchers led by Matthias Meier (Helmholtz Pioneer Campus at Helmholtz Zentrum München and TUM), Meike Hohwieler and Alexander Kleger (Ulm University Medical Center), have developed a newly engineered and unique organoid platform providing urgently needed access to the first steps of human pancreatic duct formation.
Pancreas on chip
Better understanding of the mechanisms of pancreas development and carcinogenesis is critical for the identification of reliable markers and, hence, the development of new diagnostic tools. For this, it is imperative to reliably model the human pancreas in vitro. With the research group's new approach, it tissue from healthy or individuals or patients is no longer required.
“We took on the challenge to replicate human pancreas development on a chip platform. We programmed human pluripotent stem cells to become our source of lineage-committed pancreatic ductal cells. We demonstrated that our platform can serve as a tool to mimic pancreatic development, corroborated through time resolved single cell transcriptomic analysis,” says Matthias Meier, corresponding author of the article.
To better control critical 3D-features of the organoid - such as shape and size - the team designed a new micro-well chip. The new design also improved the reproducibility of the approach. The in-depth functional analysis of developing organoids helped the team differentiate towards the desired human pancreatic ductal fate and ultimately succeed in developing a mature organoid with key features of human pancreatic physiology, including secretion of extracellular matrix components and intercellular communication. “Recapitulation of a healthy ductal fate is critical to draw any conclusions for further downstream analysis with this novel cell resource” says Alexander Kleger also corresponding author of the article.
The researchers used the new chip and the organoids to test its effectiveness in identifying novel biomarkers for early onset of PDAC and the first results were promising. One marker identified was filamin b, a protein which has been linked with carcinogenesis in various tissues. Further validation and analysis in a small cohort of PDAC patients confirmed filamin b as a promising liquid-biopsy biomarker for the detection of early onset of the disease. In addition, the biomarker could be a potential prognostic marker for disease outcome.
“The most compelling application of our technology is that we are now able to assess and identify novel early-detection biomarkers with prognostic value, finally moving towards the detection of early-stage pancreatic cancer which hopefully, in the future, will lead us to the development of novel therapies that can be used at early onset or even as preventive measures,” says Sandra Wiedenmann, first author of the article.
The study was published in Nature Biomedical Engineering.