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Pancreatic Cancer Study Uncovers Prognostic Splicing Signature

NEW YORK – A team from Italy and Germany has tracked down an alternative messenger RNA splicing signature that coincides with poorer clinical outcomes and chemotherapy resistance in individuals with a basal-like subtype of pancreatic ductal adenocarcinoma (PDAC).

"Comparing pancreatic tumors of different subtypes, we observed that the therapy-resistant cancer is associated with a specific splicing regulation, leading to the synthesis of proteins associated with resistance to chemotherapies," Claudio Sette, a neuroscience researcher at the Catholic University of the Sacred Heart and organoids facility director at the General Hospital Gemelli, said in a statement, noting that the finding "opens up new treatment possibilities for a type of tumor that generally does not respond to existing therapies."

As they reported in Cell Reports Medicine on Tuesday, Sette and colleagues started with transcriptome data for 45 classical and 32 basal-like PDAC tumors profiled through the Cancer Genome Atlas project, searching for gene expression or gene splicing signatures associated with clinical outcomes.

"It was already known that basal-like PDAC has worse prognosis and is more refractory to chemotherapy," Sette said in an email. "However, it was unknown whether splicing variants contribute to these features."

Past research has shown that classical PDACs are more prognostically favorable than tumors from the basal-like PDAC subtype, the team explained. While tumors from that subtype tend to respond well to modified FOLFIRINOX chemotherapy treatment, tumors from the basal-like PDAC subtype show poorer chemotherapy responses and patient outcomes and are marked by features linked to an epithelial-to-mesenchymal transition.

The team's tumor transcriptome analyses led to 184 genes with higher-than-usual expression in the basal-like tumors, including genes in pathways implicated in everything from stemness to tumor aggressiveness and metastasis. On the other hand, the classical tumors had enhanced expression of 342 genes, along with almost three-dozen gene splicing distinctions compared to the basal-like tumors.

When the investigators looked at sequence-specific RNA-binding proteins that might influence splicing in the PDAC subtypes, they flagged splicing factors such as Quaking (QKI) that are found at higher levels in basal-like tumors.

Findings from their follow-up gene knockdown experiments in PDAC cell lines and patient-derived organoids, together with published single-cell transcriptome data from PDAC samples, suggested QKI contributes to gene splicing patterns with ties to chemotherapy treatment resistance in aggressive PDAC cases from the basal-like subtype.

For example, the team reported that basal-like cases marked by enhanced QKI activity have altered RNA regulation and splicing that prompts increased cell plasticity, cell migration, and chemotherapy resistance, along with reduced production of messenger RNA isoforms found in the classical PDAC subtype.

While boosting QKI expression led to reduced chemotherapy sensitivity in classical subtype cell line experiments, the team found that dialing down QKI levels led to improved response to a topoisomerase I inhibitor drug called irinotecan (part of the FOLFIRINOX chemotherapy treatment for PDAC) when it targeted the prognostic splice variants, Sette noted.

Based on these and other findings, the team suggested that the QKI splicing factor or the related splicing signature may serve as markers for stratifying patients and finding the most effective treatment options for individuals with basal-like PDAC tumors.

"Our study shows that some splicing variants are specific of basal-like PDAC and by themselves predict worse prognosis with high accuracy," Sette explained, noting that "identification of the basal-like and classical phenotype requires high-throughput RNA sequencing and bioinformatics analysis, which are both time consuming and very expensive, thus limiting their application to routine clinical decisions."

"Our study shows that some splice variants, which can be easily detected by routine PCR analyses, are highly predictive of the molecular phenotype of the tumor and … could be also detected in endoscopic biopsies," he said, "thus potentially opening this investigation to all cases of PDAC."