Splicing alterations in pancreatic ductal adenocarcinoma: a new molecular landscape with translational potential

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal cancers worldwide, mainly due to its late diagnosis and lack of effective therapies, translating into a low 5-year 12% survival rate, despite extensive clinical efforts to improve outcomes. International cooperative studies have provided informative multiomic landscapes of PDAC, but translation of these discoveries into clinical advances are lagging. Likewise, early diagnosis biomarkers and new therapeutic tools are sorely needed to tackle this cancer. The study of poorly explored molecular processes, such as splicing, can provide new tools in this regard. Alternative splicing of pre-RNA allows the generation of multiple RNA variants from a single gene and thereby contributes to fundamental biological processes by finely tuning gene expression. However, alterations in alternative splicing are linked to many diseases, and particularly to cancer, where it can contribute to tumor initiation, progression, metastasis and drug resistance. Splicing defects are increasingly being associated with PDAC, including both mutations or dysregulation of components of the splicing machinery and associated factors, and altered expression of specific relevant gene variants. Such disruptions can be a key element enhancing pancreatic tumor progression or metastasis, while they can also provide suitable tools to identify potential candidate biomarkers and discover new actionable targets. In this review, we aimed to summarize the current information about dysregulation of splicing-related elements and aberrant splicing isoforms in PDAC, and to describe their relationship with the development, progression and/or aggressiveness of this dismal cancer, as well as their potential as therapeutic tools and targets.

The Exon Junction Complex component EIF4A3 plays a splicing-linked oncogenic role in Pancreatic Ductal Adenocarcinoma

“…Pioneer reports showing two decades ago an altered expression of abnormal CD44 variants and other “spliceoforms” in PDAC [41] heralded the current bloom of experimental evidence supporting a major role of splicing dysregulation in this deadly cancer [12]. Subsequent work reinforced this notion by showing that the splicing machinery itself is dysregulated in PDAC, and can thereby contribute to trigger some of its typical pathological features, from its precursor pancreatitis [11], to increased cell proliferation and metastasis [7, 10], reviewed in [12]. Further, recent evidence is helping to dissect key molecular players that interact with and mediate the pathological impact of dysregulated splicing components, such as hnRNPK [9], SF3B1 [7], RBFOX2 [10], SRSF1 [11], and others, including core oncogenic hallmarks of PDAC like KRAS and TP53 [2].…”

“…Pioneer reports showing two decades ago an altered expression of abnormal CD44 variants and other “spliceoforms” in PDAC [41] heralded the current bloom of experimental evidence supporting a major role of splicing dysregulation in this deadly cancer [12]. Subsequent work reinforced this notion by showing that the splicing machinery itself is dysregulated in PDAC, and can thereby contribute to trigger some of its typical pathological features, from its precursor pancreatitis [11], to increased cell proliferation and metastasis [7, 10], reviewed in [12].…”

“…Hence, novel research avenues are sorely required to find new molecular players that facilitate a better understanding of PDAC and provide new biomarkers and therapeutic targets to tackle this pathology. In this vein, studies from our group and others have shown that dysregulation of RNA splicing plays a key role in PDAC, which leverages this still limitedly known mechanism as a source of novel molecular tools [7][8][9][10][11][12].…”

“…Alternative splicing is therefore a capital step within the central dogma of Biology (DNA->RNA->protein) and its dysregulation is linked to the appearance of many diseases including cancer [15]. Altered splicing can lead to the generation of oncogenic splice variants and/or changes in signaling pathways, which contribute to cancer development, progression, aggressiveness, metastasis and drug resistance [16, 12].…”

The Many Roads from Alternative Splicing to Cancer: Molecular Mechanisms Involving Driver Genes

“…These examples highlight the significant potential for developing targeted therapies that exploit alternative splicing mechanisms to improve cancer treatment outcomes. Actually, the pharmacological correction of splicing errors is a promising possibility and some compounds are in advanced preclinical stages [ 187 , 188 , 189 , 190 ].…”