Pancreatic cancer-derived organoids recapitulate core features of the primary cancer to predict drug response

 

Introduction:

Organotypic cultures derived from pancreatic ductal adenocarcinoma (PDAC) termed pancreatic cancer organoids (PDO) recapitulate the primary cancer and can be derived from primary or metastatic biopsies. Although isolation and culture of patient derived pancreatic organoids have been established several years ago, advantages and constrains for individualized medicine have not been comprehensively investigated yet.

Aims & Methods:

We conducted a feasibility study, systematically comparing head-to-head xenografted primary tissue and xenograft-derived organoids by rigorous immunohistochemical and molecular characterization. Subsequently, a drug testing platform has been set-up and validated in vivo.

Results:

Firstly, PDAC organoids faithfully recapitulate morphology and marker protein expression patterns of the original tumors. Secondly, quantitative proteomes from the patient-derived xenografts as well as from corresponding organoid cultures showed high concordance. Thirdly, genomic alterations as assessed by array-based comparative genomic hybridization revealed similar results in both groups. Fourthly, we established a small-scale, pharmacotyping platform adjusted to operate in parallel considering potential obstacles such as culture conditions, timing, drug dosing and interpretation of the results. In vitropredictions were successfully validated in an in vivoxenograft trial. Finally, the organoid phenotyping outcome was compared with the predictive value of gene mutations obtained by panel sequencing.

Conclusion:

In conclusion, small-scale drug screening in organoids appears a feasible, robust and easy-to-handle method to allow response predictions in parallel to daily clinical routine. PDO based phenotyping faithfully reflects genotypes. Therefore, our fast and cost-efficient assay is a reasonable approach in a predictive clinical setting.