Biology subjects

Salvia, R.

Publications and source records attributed to Salvia, R..

5 recordsLinked to original sources

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↗

bioRxiv2024

Clonal evolutionary analysis reveals patterns of malignant transformation in pancreatic cancer from Intraductal Papillary Mucinous IPMN Neoplasms (IPMN)

Intraductal papillary mucinous neoplasms (IPMNs) are critical precursors to pancreatic ductal adenocarcinoma (PDAC), a highly lethal cancer due to late detection and rapid progression. Using multi-region whole-genome and transcriptome sequencing, we traced the evolution of PDAC from IPMN, constructing detailed phylogenetic trees to provide insights into subclonal architectures and progression pathways. Our analysis identified two distinct evolutionary trajectories: one driven by a single ancestral clone, and another involving multiple independent ancestral clones, potentially influencing the timing and nature of PDAC onset. We further explored the roles of mutational signatures and structural variants (SVs) in promoting clonal evolution. Complementing these genomic findings, our transcriptomic analysis revealed unique gene expression profiles and variations in the immune landscape, correlating with the different progression stages from IPMN to PDAC. These insights reveal the complex molecular dynamics of IPMN progression to PDAC, highlighting the need to refine early detection and treatment strategies.

cancer biology↗

bioRxiv2023

ecDNA amplification of MYC drives intratumor copy-number heterogeneity and adaptation to stress in PDAC

Intratumor heterogeneity and phenotypic plasticity drive tumour progression and therapy resistance. Oncogene dosage variation contributes to cell state transitions and phenotypic heterogeneity, thereby providing a substrate for somatic evolution. Nonetheless, the genetic mechanisms underlying phenotypic heterogeneity are still poorly understood. Here, we show that extrachromosomal DNA (ecDNA) is a major source of high-level focal amplification in key oncogenes and a major contributor of MYC heterogeneity in pancreatic ductal adenocarcinoma (PDAC). We demonstrate that ecDNA can drive exceptionally high dosage of MYC and afford cancer cells rapid adaptation to microenvironmental changes. The continued maintenance of extrachromosomal MYC is uniquely ensured by the presence of the selective pressure. We also show that MYC dosage affects cell morphology and dependence of cancer cells on stromal niche factors, with the highest MYC levels correlating with squamous-like phenotypes. Our work provides the first detailed analysis of ecDNAs in PDAC and describes a new genetic mechanism driving MYC heterogeneity in PDAC.

cancer biology↗

bioRxiv2023

TGFβ/activin-dependent activation of Torso controls the timing of the metamorphic transition in the red flour beetle Tribolium castaneum

Understanding the mechanisms governing body size attainment during animal development is of paramount importance in biology. In insects, a crucial phase in determining body size occurs at the larva-pupa transition, marking the end of the larval growth period. Central to this process is the attainment of the threshold size (TS), a critical developmental checkpoint that must be reached before the larva can undergo metamorphosis. However, the intricate molecular mechanisms by which the TS orchestrates this transition remain poor understood. In this study, we investigate the role of the interaction between the Torso and TGF{beta}/activin signaling pathways in regulating metamorphic timing in the red flour beetle, Tribolium castaneum. Our results show that Torso signaling is required specifically during the last larval instar and that its activation is mediated not only by the prothoracicotropic hormone (Tc-Ptth) but also by Trunk (Tc-Trk), another ligand of the Tc-Torso receptor. Interestingly, we show that while Torso activation by Tc-Ptth determines the onset of metamorphosis, Tc-Trk promotes growth during the last larval stage. In addition, we found that the expression of Tc-torso correlates with the attainment of the TS and the decay of juvenile hormone (JH) levels, at the onset of the last larval instar. Notably, our data reveals that activation of TGF{beta}/activin signaling pathway at the TS is responsible for repressing the JH synthesis and inducing Tc-torso expression, initiating metamorphosis. Altogether, these findings shed light on the pivotal involvement of the Ptth/Trunk/Torso and TGF{beta}/activin signaling pathways as critical regulatory components orchestrating the TS-driven metamorphic initiation, offering valuable insights into the mechanisms underlying body size determination in insects.

developmental biology↗

bioRxiv2019

Functional insights from the GC-poor genomes of two aphid parasitoids, Aphidius ervi and Lysiphlebus fabarum

BackgroundParasitoid wasps have fascinating life cycles and play an important role in trophic networks, yet little is known about their genome content and function. Parasitoids that infect aphids are an important group with the potential for biocontrol, and infecting aphids requires overcoming both aphid defenses and their defensive endosymbionts. ResultsWe present the de novo genome assemblies, detailed annotation, and comparative analysis of two closely related parasitoid wasps that target pest aphids: Aphidius ervi and Lysiphlebus fabarum (Hymenoptera: Braconidae: Aphidiinae). The genomes are small (139 and 141 Mbp), highly syntenic, and the most AT-rich reported thus far for any arthropod (GC content: 25.8% and 23.8%). This nucleotide bias is accompanied by skewed codon usage, and is stronger in genes with adult-biased expression. AT-richness may be the consequence of reduced genome size, a near absence of DNA methylation, and age-specific energy demands. We identify expansions of F-box/Leucine-rich-repeat proteins, suggesting that diversification in this gene family may be associated with their broad host range or with countering defenses from aphids endosymbionts. The absence of some immune genes (Toll and Imd pathways) resembles similar losses in their aphid hosts, highlighting the potential impact of symbiosis on both aphids and their parasitoids. ConclusionsThese findings are of fundamental interest for insect evolution and beyond. This will provide a strong foundation for further functional studies including coevolution with respect to their hosts, the basis of successful infection, and biocontrol. Both genomes are available at https://bipaa.genouest.org.

genomics↗