Biology subjects

Iovanna, J.

Publications and source records attributed to Iovanna, J..

6 recordsLinked to original sources

bioRxiv2025

The ferroptosis inhibitor NUPR1 coordinates the mitochondrial response to oxidative stress and cell metabolism during COPD pathogenesis in the lung

Chronic obstructive pulmonary disease (COPD) is characterized by chronic injury and oxidative stress leading to progressive lung tissue destruction. Emerging evidence suggests that regulated cell death pathways, particularly ferroptosis, contribute to COPD pathology. We previously identified the stress response protein and known ferroptosis inhibitor nuclear protein 1 (NUPR1) as markedly downregulated in lung tissue from COPD patients. Here, we demonstrate that NUPR1 inhibition exacerbates iron accumulation, enhances lipid peroxidation, impairs mitochondrial function, disrupts cellular metabolism, and increases oxidative stress in lung epithelial cells. Furthermore, Nupr1 knockout mice exhibit mitochondrial abnormalities, increased oxidative damage, and lung tissue changes consistent with COPD pathology. Collectively, our findings establish NUPR1 as a critical regulator of ferroptosis, stress responses, mitochondrial integrity, and metabolic balance in the lung, highlighting its potential contribution to COPD pathogenesis.

cell biology↗

bioRxiv2025

KRAS Inhibition Reverses Chemotherapy Resistance Promoted by Therapy-Induced Senescence-like in Pancreatic Ductal Adenocarcinoma

BackgroundEmerging evidence suggests that chemotherapy can accumulate senescent-like cells within tumor tissues, a phenomenon linked to therapy resistance. The aim of this study is to analyze the senescence-like state of after-treatment persistent cells associated with KRAS mutational status to offer a therapeutic strategy to target these cells in pancreatic ductal adenocarcinoma (PDAC). Experimental DesignThree commercial cell lines and five patient-derived primary cell cultures with different KRAS statuses were studied following gemcitabine treatment. Senescence-like status was assessed using SA-{beta}-gal, together with cell cycle regulators such as p21. Additionally, KRAS mutations were modulated using MRTX1133 and AMG-510, and the signaling pathways ERK and AKT were analyzed and modulated in vitro. Finally, p21 expression, associated with the senescence-like state, on patient outcomes and treatment response was analyzed in publicly available bulk RNA-seq and single-nucleus datasets. ResultsWe observed an overexpression of p21 alongside an increase in SA-{beta}-gal signal in response to gemcitabine treatment, indicating the induction of a senescence-like state. Specific inhibition of KRAS G12D or G12C mutations reduced SA-{beta}-gal signal and sensitized PDAC cells to gemcitabine. Moreover, ERK inhibition but not AKT inhibition decreased SA-{beta}-gal signal. Additionally, we characterized p21 expression levels in relation to patient outcomes and found that they are modulated by treatment. ConclusionsThis dual-targeted therapeutic strategy holds promises for overcoming the challenges posed by KRAS-driven cancers, particularly in addressing the formidable obstacle of pancreatic cancer. Highlights The accumulation of senescent-like cells in tumor tissues because of chemotherapy is linked to treatment resistance, specifically in pancreatic ductal adenocarcinoma (PDAC). Therapy-induced senescence-like in PDAC is influenced by the mutational status of KRAS, affecting the response to chemotherapeutic agents. The expression of the p21 is activated in response to therapy-induced senescence-like, particularly after gemcitabine treatment and is associated with patients outcome. Specifically inhibiting the mutated form of KRAS with small compounds can sensitize PDAC cells to gemcitabine and reduce SA-{beta}-gal signal, acting through the ERK pathway but not the AKT pathway. The study presents a dual-targeted therapeutic strategy that combines KRAS inhibition with cytotoxic agents, potentially improving treatment efficacy and overcoming resistance in KRAS-driven cancers, such as PDAC.

cancer biology↗

bioRxiv2022

PACpAInt: a deep learning approach to identify molecular subtypes of pancreatic adenocarcinoma on histology slides

Pancreatic ductal adenocarcinoma (PAC) is a highly heterogeneous and plastic tumor with different transcriptomic molecular subtypes that hold great prognostic and theranostic values. We developed PACpAInt, a multistep approach using deep learning models to determine tumor cell type and their molecular phenotype on routine histological preparation at a resolution enabling to decipher complete intratumor heterogeneity on a massive scale never achieved before. PACpAInt effectively identified molecular subtypes at the slide level in three validation cohorts and had an independent prognostic value. It identified an interslide heterogeneity within a case in 39% of tumors that impacted survival. Diving at the cell level, PACpAInt identified "pure" classical and basal-like main subtypes as well as an intermediary phenotype and hybrid tumors that co-carried both classical and basal-like phenotypes. These novel artificial intelligence-based subtypes, together with the proportion of basal-like cells within a tumor had a strong prognostic impact.

cancer biology↗

bioRxiv2020

Translatome-based classification reveals a dual metabolic dependency of a new tumor subtype of pancreatic cancer.

Molecular profiling of Pancreatic Ductal Adenocarcinoma (PDA), based on transcriptomic analyses, identifies two main prognostic subtypes (basal-like and classical), but does not allow personalized first-line treatment. To date, tumors have not been profiled based on protein synthesis rates, yet the step of mRNA translation is highly deregulated in both PDA cancer cells and their microenvironment. Using a collection of twenty-seven pancreatic Patient-Derived Xenografts (PDX), we performed genome-wide analysis of translated mRNA (translatome). Unsupervised bioinformatics analysis revealed a new tumor subtype harboring a low protein synthesis rate, but associated with a robust translation of mRNAs encoding effectors of the integrated stress response (ISR), including the transcription factor ATF4. Functional characterization of the "ISR-activated" human cancer cells revealed a high resistance to drugs, low autophagic capacities, and importantly, metabolic impairments in the serine synthesis and transsulfuration pathways. Overall, our study highlights the strength of translatomic profiling on PDA, which here revealed an unforeseen drug-resistant cancer cell phenotype, whose auxotrophy to both serine and cysteine may be amenable to targeted therapy.

cancer biology↗

bioRxiv2020

E-cadherin: Unexpected actor of invadopodia formation in pancreatic cancer

Graphical abstract BackgroundThe appearance of hybrid epithelial-mesenchymal (E/M) cells expressing E-cadherin is favourable for the establishment of pro-invasive function. However, the molecular mechanism and potential roles of E-cadherin in cancer cell invasion stay unexplored. MethodsWe used models of E/M hybrid cell lines, tissues sections and patient-derived xenografts from a multi-center clinical trial. E-cadherin involvement in invadopodia formation was assessed using a gelatin-FITC degradation assay. Mechanistic studies were performed by using proteomic analysis, siRNA strategy and proximity ligation assay. ResultsWe showed that E-cadherin is a critical component of invadopodia. This unexpected localization results from a synergistic trafficking of E-cadherin and MT1-MMP through Rab vesicle-dependent pathway. Modulation of E-cadherin expression or activation impacted invadopodia formation. Moreover, colocalization of E-cadherin and Actin in [-]ring structures|| as precursor of invadopodia reveals that E-cadherin is required for invadopodia structuration. ConclusionE-cadherin, initially localized in the adherens junctions could be recycled to nascent invadopodia where it will interact with several components such as Arp2/3, Cortactin or MT1-MMP. The trans-adhesive properties of E-cadherin are therefore essential for structuring invadopodia. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=152 SRC="FIGDIR/small/332783v2_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@13b08e8org.highwire.dtl.DTLVardef@c5d19eorg.highwire.dtl.DTLVardef@14511cforg.highwire.dtl.DTLVardef@19436eb_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2018

SMAP: exploiting high-throughput sequencing data of patient derived xenografts

BackgroundPatient-derived xenograft is the model of reference in oncology fordrug response analyses. Xenografts samples have the specificity to be composedof cells from both the graft and the host species. Sequencing analysis ofxenograft samples therefore requires specific processing methods to properlyreconstruct genomic profiles of both the host and graft compartments.\n\nResultsWe propose a novel xenograft sequencing process pipeline termedSMAP for Simultaneous mapping. SMAP integrates the distinction of host andgraft sequencing reads to the mapping process by simultaneously aligning to bothgenome references. We show that SMAP increases accuracy of species-assignmentwhile reducing the number of discarded ambiguous reads compared to otherexisting methods. Moreover, SMAP includes a module called SMAP-fuz toimprove the detection of chimeric transcript fusion in xenograft RNAseq data. Finally, we apply SMAP on a real dataset and show the relevance of pathway andcell population analysis of the tumoral and stromal compartments.\n\nConclusionsIn high-throughput sequencing analysis of xenografts, our resultsshow that: i. the use of ad hoc sequence processing methods is essential, ii. highsequence homology does not introduce a significant bias when proper methodsare used and iii. the detection of fusion transcripts can be improved using ourapproach. SMAP is available on GitHub: cit-bioinfo.github.io/SMAP.

genomics↗