Biology subjects

Pedraza-Arevalo, S.

Publications and source records attributed to Pedraza-Arevalo, S..

5 recordsLinked to original sources

bioRxiv2026

Early Progression Cells mark a stem-like state associated with pancreatic cancer initiation and progression

Pancreatic cancer is deemed to progress from microscopic pancreatic intraepithelial neoplasia (PanINs). However, low grade PanINs are frequently detected in the general population without presentation or increased risk of developing cancer, suggesting that many PanINs never progress to tumours. What precisely characterises PanINs that develop into tumours is insufficiently understood. Using a mouse model where pancreatitis-induced tissue injury promotes pancreatic cancer from rare KrasG12D cells, we identify Early Progression Cells (EPCs) as a new entity, a novel population of cancer stem-like cells. Transcriptomic analyses illustrate EPCs as stress-adapted, inflammation responsive stem cells that also upregulate gene programmes indicative of microenvironment remodelling. Using identified EPC protein markers, we show that EPCs are prevalent in early metaplastic stages and in PanIN progression from low grade to high grade but are rarer in tumours. PanIN- and tumour-derived sphere and organoid assays demonstrate that EPCs possess all characteristics of stem cells in vitro and are dependent on Nupr1 stress response pathways for survival and growth. We identify APP-CD74 as a novel cell-cell interaction pathway between EPCs and neighbouring epithelial cells in PanINs and tumours. Inhibition of CD74 activity in vitro induces high-grade PanIN organoid death, suggesting EPCs are critical for high-grade PanINs. Using spatial transcriptomics of human samples, we detect gene signatures of EPCs in distinct regions of human PanIN and PDAC tissues, including APP-CD74 interactions, providing compelling evidence that EPCs are relevant to human disease. Further understanding of EPC biology will likely uncover new knowledge on why rare PanINs progress towards tumours.

cancer biology↗

bioRxiv2026

From Splicing to Survival: Understanding the Molecular Basis of Prognostic Differences in advanced Small Intestine Neuroendocrine Tumors

Small intestine neuroendocrine tumors (SI-NETs) represent a challenging neoplasm due to their high rate of metastasis and the limited availability of effective therapies. Recent evidence has unveiled altered splicing as an influential player in tumor progression, linked to patient prognosis, which provides a powerful source of novel biomarkers and therapeutic targets in cancer. Here, we conducted a comprehensive analysis regarding the possible connection of the spliceosomic landscape of metastatic SI-NETs with patient survival. Initial analyses revealed a distinctive pattern of splicing events between the two conditions, short (< 5 years, n = 17 patients), vs. long survival ([≥] 5 years, n = 26 patients), with strong discrimination capacity. Furthermore, numerous key splicing events were associated with relevant clinical parameters in SI-NETs. The observed impairments in spliceosomic parameters led us to interrogate the integrity of the splicing machinery. This revealed striking changes in the expression of a high proportion of core spliceosome components and splicing factors between short vs. longsurvival groups, suggesting a possible mechanistic link with the distinct profile of splicing events observed. Among them, CPSF2, a core component of the CPSF complex, stands out as its higher expression is associated with worse survival and vascular and perineural invasion. Interestingly, the shifts potentially generated by this factor supported a possible role in tumor plasticity oriented to higher tumor aggressiveness and treatment resistance. In sum, this study offers the first detailed snapshot of the status of the spliceosomic landscape in SI-NETs and its molecular linkage to patient survival, thus offering a new window towards identification of novel candidate biomarkers and/or therapeutic targets.

cancer biology↗

bioRxiv2024

An integrative RNA spliceosomic landscape of pancreatic neuroendocrine tumors unveils novel clinicomolecular associations

Alterations in alternative splicing are emerging as a novel hallmark in cancer biology, offering new insights. However, integrative analyses of splicing are still scarce, particularly in rare cancers such as pancreatic neuroendocrine tumors (PanNETs). These tumors are highly heterogeneous, complicating diagnosis and treatment. This study is the first to comprehensively investigate the RNA splicing landscape in PanNETs, identifying distinct spliceosomic profiles correlated with unique clinical and molecular characteristics. We analyzed RNA-seq data from 174 samples, identifying three distinct spliceosomic groups (SPN1, SPN2, SPN3) with unique clinical and molecular characteristics. SPN1 exhibited intermediate clinical features and specific splicing machinery profile, SPN2 was associated with frequent mutations in MEN1 and DAXX/ATRX genes, and SPN3 showed a prevalence of well-differentiated tumors with distinct splicing patterns. These groups were linked to different clinical outcomes and activated key biological processes like mTOR signaling and hormone secretion pathways. Our findings underscore the significant impact of RNA splicing on PanNET heterogeneity and suggest that detailed splicing profiles could serve as valuable tools for identifying novel biomarkers and therapeutic targets. This study provides crucial insights into PanNET molecular biology and paves the way for personalized therapies based on splicing features.

cancer biology↗

bioRxiv2023

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

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide and further research on its biology is needed to fully understand the disease. Dysregulation of alternative RNA splicing is a common hallmark in cancer, including PDAC, which provides an emerging source of knowledge and of novel biomarkers and therapeutic tools. Here, we examined the role of EIF4A3, a core component of the Exon Junction Complex intimately linked to RNA splicing, in pancreatic cancer biology. 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, in line with its association to key molecular pathways. Accordingly, 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 a novel biomarker and actionable target candidate for this lethal cancer.

cancer biology↗

bioRxiv2022

Spliceosomic dysregulation unveils NOVA1 as an actionable therapeutic target in pancreatic neuroendocrine tumors

Dysregulation of the splicing machinery is emerging as a hallmark in cancer due to its association with multiple dysfunctions in tumor cells. Inappropriate function of this machinery can generate tumor-driving splicing variants and trigger oncogenic actions. However, its role in pancreatic neuroendocrine tumors (PanNETs) is poorly defined. In this study we aimed to characterize the expression pattern of a set of splicing machinery components in PanNETs, and their relationship with aggressiveness features. A qPCR-based array was first deployed to determine the expression levels of components of the major (n=13) and minor spliceosome (n=4) and associated splicing factors (n=27), using a microfluidic technology in 20 PanNETs and non-tumoral adjacent samples. Subsequently, in vivo and in vitro models were applied to explore the pathophysiological role of NOVA1. Expression analysis revealed that a substantial proportion of splicing machinery components was altered in tumors. Notably, key splicing factors were overexpressed in PanNETs samples, wherein their levels correlated with clinical and malignancy features. Using in vivo and in vitro assays, we demonstrate that one of those altered factors, NOVA1, is tightly related to cell proliferation, alters pivotal signaling pathways and interferes with responsiveness to drug treatment in PanNETs, suggesting a role for this factor in the aggressiveness of these tumors and its suitability as therapeutic target. Altogether, our results unveil a severe alteration of the splicing machinery in PanNETs and identify the putative relevance of NOVA1 in tumor development/progression, which could provide novel avenues to develop diagnostic biomarkers and therapeutic tools for this pathology.

cancer biology↗