黑料吃瓜资源

Pancreatic ductal adenocarcinoma (PDAC) is the most lethal form of pancreas cancer. It鈥檚 also the most common form of the disease. Potential treatments typically target a key mutated oncogene called KRAS. In some cases, PDAC tumors with these mutations have resisted therapeutic efforts. However, combination therapies involving alternative drug targets may one day help clinicians overwhelm these defenses.

In 2023, 黑料吃瓜资源 (CSHL) Professor Adrian Krainer鈥檚 lab discovered how the protein SRSF1 jumpstarts PDAC tumor development. Now, after revisiting data from that study, a team led by former CSHL graduate student Alexander Kral has found that SRSF1 doesn鈥檛 act alone. Instead, the protein is one of three pillars in a key circuit promoting aggressive PDAC progression.

鈥淥ur theory was that some of the changes caused by increased levels of SRSF1 were playing a role in the accelerated tumor growth we were seeing,鈥� Kral explains. 鈥淲e homed in on a molecule we thought could be an important driver of this called Aurora kinase A (AURKA). We found it鈥檚 part of a complex regulatory circuit that includes not only AURKA and SRSF1, but another key oncogene called MYC.鈥�

In this circuit, SRSF1 regulates AURKA through a process called alternative splicing. This increases AURKA production, which allows it to stabilize and protect the MYC protein. MYC then increases SRSF1 levels, restarting the loop.

鈥淏its and pieces of this circuit were known previously, but we didn鈥檛 have the full picture until now,鈥� Krainer says. 鈥淥nce we figured out alternative splicing of AURKA was involved, we could start looking into ways to disrupt it.鈥�

The team developed an antisense oligonucleotide (ASO) to alter the process. These molecules are a specialty of the Krainer lab. They previously developed an ASO called Spinraza, the first-ever FDA-approved treatment for spinal muscular atrophy. Based on their observations, the team hoped their new ASO could obstruct AURKA鈥檚 alternative splicing. Remarkably, in pancreatic cancer, the ASO didn鈥檛 just interfere. It collapsed the entire oncogenic circuit. This reduced tumor cells鈥� overall viability and triggered a programmed cell death called apoptosis.

鈥淚t鈥檚 like killing three birds with one stone,鈥� Krainer explains. 鈥淪RSF1, AURKA, and MYC are all oncogenes contributing to PDAC progression. Just by targeting AURKA splicing with our ASO, we see the loss of these other two molecules as well.

The Krainer lab is now working to refine their ASO. Potential clinical applications are still a long way off. However, Krainer says every clinical breakthrough begins with such basic research. That was true of Spinraza, which has saved thousands of lives. So, hopefully, it will be for the next lifesaving cancer treatment.

Written by: Nick Wurm, Communications Specialist | [email protected] | 516-367-5940

Funding

National Cancer Institute

Citation

Kral, A.J., et al., 鈥淪plice-switching ASOs targeting the AURKA 5鈥橴TR collapse an SRSF1-AURKA-MYC oncogenic circuit in pancreatic cancer鈥�, Molecular Cell, December 30, 2025. DOI:

Core Facilites

鈥淭丑别 Antibody Core Facility produces monoclonal and polyclonal antibodies for research use. It鈥檚 our mission to provide the resources and expertise to generate these reagents in a highly efficient and cost-effective manner.鈥� 鈥� Director Johannes Yeh, Ph.D.

鈥淭丑别 Microscopy Core Facility provides training, consultation, experimental design and technical assistance to investigators at CSHL in widefield, spinning disk laser scanning or point laser scanning confocal fluorescence microscopy, and super-resolution microscopy. In addition, the Microscopy Shared Resource provides customized state-of-the-art optical imaging and quantitative image analysis applications to support a wide range of scientific endeavors.鈥� 鈥� Director Erika Wee, Ph.D.

鈥淭丑别 Organoid Shared Resource provides Cancer Center members with access to the reagents, equipment, and expertise needed to culture and perform experiments with three-dimensional organoid models. We offer centralized access to protocols for generating and working with Patient Derived Organoid (PDO) cultures, standardized culture reagents, and Droplet Digital PCR (ddPCR) Technology, as well as training and equipment for performing high-throughput chemical screens on either two-dimensional cell lines or organoid cultures.鈥� 鈥� Facility Manager Hardik Patel

鈥淭丑别 Sequencing Technologies and Analysis Shared Resource provides access to an array of high throughput Next Generation Sequencing (NGS) technologies. We offer cutting-edge technology alongside convenient in-house services for a broad range of genetic analysis.鈥� 鈥� NGS Director Sara Goodwin, Ph.D.