Related Experiment Video
Updated: Jul 17, 2026
Isolation and Characterization of Patient-derived Pancreatic Ductal Adenocarcinoma Organoid Models
Published on: January 14, 2020
Screening Splice-Switching Antisense Oligonucleotides in Pancreas-Cancer Organoids
Ledong Wan1,2, Alexander J Kral1,2, Dillon Voss1,2
1Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA.
Abstract:
Aberrant alternative splicing is emerging as a cancer hallmark and a potential therapeutic target. It is the result of dysregulated or mutated splicing factors, or genetic alterations in splicing-regulatory cis-elements. Targeting individual altered splicing events associated with cancer-cell dependencies is a potential therapeutic strategy, but several technical limitations need to be addressed. Patient-derived organoids are a promising platform to recapitulate key aspects of disease states, and to facilitate drug development for precision medicine. Here, we report an efficient antisense-oligonucleotide (ASO) lipofection method to systematically evaluate and screen individual splicing events as therapeutic targets in pancreatic ductal adenocarcinoma organoids. This optimized delivery method allows fast and efficient screening of ASOs, e.g., those that reverse oncogenic alternative splicing. In combination with advances in chemical modifications of oligonucleotides and ASO-delivery strategies, this method has the potential to accelerate the discovery of antitumor ASO drugs that target pathological alternative splicing.
Insights
Aberrant alternative splicing in cancer can be targeted therapeutically. We developed an efficient method using antisense oligonucleotides (ASOs) in pancreatic cancer organoids to screen these splicing events for drug development.
Area of Science:
- Molecular Biology
- Cancer Research
- Drug Discovery
Background:
- Aberrant alternative splicing is a recognized hallmark of cancer, driven by splicing factor dysregulation or genetic alterations in cis-elements.
- Targeting cancer-specific splicing events presents a therapeutic strategy, but faces technical challenges in efficient screening and delivery.
- Patient-derived organoids offer a valuable preclinical model for recapitulating disease states and advancing precision medicine.
Purpose of the Study:
- To develop and optimize an efficient antisense oligonucleotide (ASO) lipofection method for screening therapeutic targets in pancreatic ductal adenocarcinoma organoids.
- To systematically evaluate individual aberrant alternative splicing events as potential drug targets.
- To facilitate the discovery of novel antisense oligonucleotide drugs for cancer therapy.
Main Methods:
- Development of an efficient antisense oligonucleotide (ASO) lipofection protocol for pancreatic ductal adenocarcinoma organoids.
- Systematic screening of individual splicing events modulated by ASOs.
- Evaluation of ASOs designed to reverse oncogenic alternative splicing.
Main Results:
- An optimized lipofection method enables fast and efficient delivery of ASOs into pancreatic cancer organoids.
- The method allows for the systematic evaluation and screening of aberrant alternative splicing events as therapeutic targets.
- Demonstrated potential for reversing oncogenic alternative splicing through ASO intervention.
Conclusions:
- The developed ASO lipofection method provides an efficient platform for targeting aberrant alternative splicing in pancreatic cancer.
- This approach, combined with oligonucleotide chemical modifications and delivery strategies, can accelerate the development of ASO-based cancer drugs.
- Highlights the potential of targeting pathological alternative splicing for novel antitumor therapies.
