RESUMEN
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, underscoring the urgent need for in-depth biological research. The phenomenon of alternative RNA splicing dysregulation is a common hallmark in cancer, including PDAC, presenting new avenues for understanding and developing diagnostic and therapeutic tools. Our research focuses on EIF4A3, a core component of the Exon Junction Complex intimately linked to RNA splicing, and its role in PDAC. EIF4A3 is overexpressed in PDAC tissue and associated to clinical parameters of malignancy and poorer patient survival. Mechanistically, exploration of PDAC RNA-seq data unveiled the link of EIF4A3 to diverse malignancy processes, consistent with its association to key molecular pathways. EIF4A3 targeting in vitro decreased essential functional tumor features such as proliferation, migration, colony formation and sphere formation, while its in vivo targeting reduced tumor growth. EIF4A3 silencing in PDAC cell lines severely altered its transcriptional and spliceosomic landscapes, as shown by RNA-seq analyses, suggesting a role for EIF4A3 in maintaining RNA homeostasis. Our results indicate that EIF4A3 dysregulation in PDAC has a pleiotropic regulatory role on RNA biology, influencing key cellular functions. This paves the way to explore its potential as novel biomarker and actionable target candidate for this lethal cancer.
RESUMEN
CONTEXT.: The neurotrophic tropomyosin receptor kinase (NTRK) family gene rearrangements have been recently incorporated as predictive biomarkers in a "tumor-agnostic" manner. However, the identification of these patients is extremely challenging because the overall frequency of NTRK fusions is below 1%. Academic groups and professional organizations have released recommendations on the algorithms to detect NTRK fusions. The European Society for Medical Oncology proposal encourages the use of next-generation sequencing (NGS) if available, or alternatively immunohistochemistry (IHC) could be used for screening with NGS confirmation of all positive IHC results. Other academic groups have included histologic and genomic information in the testing algorithm. OBJECTIVE.: To apply some of these triaging strategies for a more efficient identification of NTRK fusions within a single institution, so pathologists can gain practical insight on how to start looking for NTRK fusions. DESIGN.: A multiparametric strategy combining histologic (secretory carcinomas of the breast and salivary gland; papillary thyroid carcinomas; infantile fibrosarcoma) and genomic (driver-negative non-small cell lung carcinomas, microsatellite instability-high colorectal adenocarcinomas, and wild-type gastrointestinal stromal tumors) triaging was put forward. RESULTS.: Samples from 323 tumors were stained with the VENTANA pan-TRK EPR17341 Assay as a screening method. All positive IHC cases were simultaneously studied by 2 NGS tests, Oncomine Comprehensive Assay v3 and FoundationOne CDx. With this approach, the detection rate of NTRK fusions was 20 times higher (5.57%) by only screening 323 patients than the largest cohort in the literature (0.30%) comprising several hundred thousand patients. CONCLUSIONS.: Based on our findings, we propose a multiparametric strategy (ie, "supervised tumor-agnostic approach") when pathologists start searching for NTRK fusions.