Screening Splice-Switching Antisense Oligonucleotides in Pancreas-Cancer Organoids

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.