Organ Model heralds first insights into Early Diagnosis of PDAC

A study carried out by a team of researchers from Helmholtz Zentrum München, the Technical University of Munich (TUM) and Ulm University Medical Center, have  engineered a new organoid on chip platform that provides urgently needed access to the first steps of human pancreatic duct formation.

Pancreatic ductal adenocarcinoma (PDAC) accounts for more than 90% of cases with this form of cancer; its aggressiveness is due to the lack of early diagnosis and the low efficacy of available treatments.

To obtain a better understanding of the mechanisms of pancreas development and carcinogenesis, research led by Matthias Meier (Helmholtz Pioneer Campus at Helmholtz Zentrum München and TUM), Meike Hohwieler and Alexander Kleger (Ulm University Medical Center) worked on a way of reliably modelling the human organoid in vitro.

“We took on the challenge to replicate human pancreas development on a chip platform and 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,” said Matthias Meier, corresponding author of the article.

The team designed a new micro-well chip to have more control over critical 3D-features of the organoid - such as shape and size – which also improved the reproducibility of the approach.  Following functional analysis of developing organoids the team 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” added Alexander Kleger also corresponding author of the article.

The researchers tested the chip and the organoids’s effectiveness in identifying novel biomarkers for early onset of PDAC and found the first results 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,” commented Sandra Wiedenmann, first author of the article.

Wiedenmann et al, 2021: Single-cell-resolved differentiation of human induced pluripotent stem cells into pancreatic duct-like organoids on a microwell chip. Nature Biomedical Engineering. DOI: 10.1038/s41551-021-00757-2

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