However, the shortage of healthy and early disease-affected primary ductal material greatly limits the development of novel diagnostic tools and effective drugs. Now, a transregional team around HPC PI Matthias Meier took upon this challenge and reported in Nature Biomedical Engineering the use of lineage-committed pancreatic ductal cells generated from human induced pluripotent stem cells (hiPSCs) as a source of pancreatic organoids to create a suitable, donor-independent model system for pancreatic carcinogenesis.
Building upon the groups insights published recently in Cell Stem Cell, Sandra Wiedenmann from the Meier group at the Helmholtz Pioneer Campus and her colleagues from the University Hospital Ulm under the leadership of Prof. Alexander Kleger, together with additional team members from Helmholtz Zentrum München, the German Center for Diabetes Research as well as the Technical University of Munich moved the system to a newly designed microwell chip format allowing them to control key features of the developing organoids such as shape and size, and most importantly, increase the reproducibility of the approach.
The study further stands out by its thorough and comprehensive validation of the generated ductal organoids, reaching an so far unmatched level of cellular purity. Using extensive time-resolved single-cell transcriptional profiling, secretome and proteome analysis as well as immunofluorescence imaging of the forming organoids, the team identified crucial developmental markers of the human pancreatic ductal fate and ultimately succeeded in developing a mature organoid with key features of human pancreatic physiology, including secretion of extracellular matrix components and intercellular communication.
“The most compelling application of our technology is that we are now able to assess and identify novel 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”,
-states the senior authors of the study.
Indeed, in an initial, very promising pilot approach, the authors were already able to identify a number of unfavorable prognostic markers for PDAC, amongst them filamin b (FLNB), a protein that has been linked to convey cancerous properties in various tissues. Further validation and analysis in a small cohort of PDAC patients confirmed FLNB as a promising liquid biopsy-based biomarker for the detection of early onset of the disease.
Taken together, the study is of immense clinical value as it provides clinician-scientists with a very powerful differentiation pipeline to functionally understand - and eventually prevent - the rapid progression of PDAC, that is predicted to be the second most common cause of cancer-related deaths in the Western World within the next ten years.
Link to Press Release Helmholtz Zentrum München