Biology subjects

Carrier, A.

Publications and source records attributed to Carrier, A..

14 recordsLinked to original sources

bioRxiv2026

A crypt-operating DNA repair checkpoint for uncoupling regeneration and tumorigenesis

The rapid turnover of the intestinal epithelium increases its vulnerability to genomic instability and environmental insults such as irradiation. Defects in DNA damage resolution can compromise epithelial regeneration, promote chronic tissue injury, and predispose to colorectal tumorigenesis. However, the intrinsic mechanisms that coordinate DNA repair with epithelial regeneration at the crypt level remain poorly defined. Here, we identify the Nod-like receptor protein 6 (Nlrp6) as a key epithelial regulator of genome surveillance and regenerative control in intestinal crypts. Nlrp6 is strategically expressed in crypt base columnar cells, where it preserves crypt homeostasis by restraining proliferation under genotoxic stress conditions. Loss of Nlrp6 in crypt base columnar cells results in uncontrolled oncogenic stress, defective epithelial regeneration, and accumulation of unrepaired DNA damage, features associated with poor prognosis in colorectal cancer. Conversely, aberrant Nlrp6 overexpression induces cytoplasmic retention of Csnk2 catalytic subunits, limiting their nuclear availability when DNA repair is required. These findings position Nlrp6 as a non-canonical, cell-intrinsic surveillance mechanism that links DNA damage responses to epithelial regeneration through Csnk2-dependent signaling. Collectively, our study reveals a crypt-intrinsic DNA repair pathway that governs epithelial regeneration and disease outcomes, providing new insight into how genome instability and regenerative failure contribute to colorectal cancer progression.

cell biology↗

bioRxiv2025

The methyl-CpG-binding protein 2 inhibits cGAS-associated signaling

The detection of cytosolic dsDNA is tightly regulated to avoid pathological inflammatory responses. A major pathway involved in their detection relies on the cyclic GMP-AMP synthase (cGAS) that triggers activation of the Stimulator of interferon genes (STING) which subsequently drives the expression of inflammatory genes and type I Interferons (IFNs). Here, we show that the methyl-CpG-binding protein 2 (MECP2), a major transcriptional regulator, controls dsDNA-associated inflammatory responses. We show that the presence of cytosolic dsDNA promotes MECP2 export from the nucleus to the cytosol where it interacts with dsDNA, dampening cGAS activation. Our data also indicate that MECP2 export from the nucleus partially phenocopies MECP2 deficiency, leading to the expression of inflammatory and interferon stimulated genes, enforcing an antiviral state. Finally, we also show that MECP2 displacement from the nucleus following dsDNA stimulation is sufficient to disrupt its canonical function, leading to the reactivation of otherwise repressed genes, such endogenous retroelements of the Long interspersed nuclear element-1 (LINE-1) family. Re-expression of the latter led to the accumulation of DNA species feeding cGAS-dependent signaling and can be dampened by reverse transcriptase inhibitors. We thus establish a previously unforeseen direct role of MECP2 in the regulation of the breadth and nature of dsDNA-associated inflammatory responses. Furthermore, our results suggest that targeting dsDNA-associated pathways or pharmacological inhibition of LINE-1 may bear therapeutic hopes for Rett syndrome (RTT) patients that present with MECP2 deficiency.

immunology↗

bioRxiv2024

FB5P-seq-mAbs: monoclonal antibody production from FB5P-seq libraries for integrative single-cell analysis of B cells

Parallel analysis of phenotype, transcriptome and antigen receptor sequence in single B cells is a useful method for tracking B cell activation and maturation during immune responses. However, in most cases, the specificity and affinity of the B cell antigen receptor cannot be inferred from its sequence. Antibody cloning and expression from single B cells is then required for functional assays. Here we propose a method that integrates FACS-based 5-end single-cell RNA sequencing (FB5P-seq) and monoclonal antibody cloning for integrative analysis of single B cells. Starting from a cell suspension, single B cells are FACS-sorted into 96-well plates for reverse transcription, cDNA barcoding and amplification. A fraction of the single-cell cDNA is used for preparing 5-end RNA-seq libraries that are sequenced for retrieving transcriptome-wide gene expression and paired BCR sequences. The archived cDNA of selected cells of interest is used as input for cloning heavy and light chain variable regions into antibody expression plasmid vectors. The corresponding monoclonal antibodies are produced by transient transfection of a eukaryotic producing cell line and purified for functional assays. We provide detailed step-by-step instructions and describe results obtained on ovalbumin-specific murine germinal center B cells after immunization. Our method is robust, flexible, cost-effective, and applicable to different B cell types and species. We anticipate it will be useful for mapping antigen specificity and affinity of rare B cell subsets characterized by defined gene expression and/or antigen receptor sequence.

immunology↗

bioRxiv2023

PI3Kα activity in PHGDH-low pancreatic epithelial cells limits tissue proliferative regeneration in cancer promoting conditions

ObjectiveIncreased consumption of meat is an epidemiologically validated risk condition for pancreatic cancer development, but the underlying mechanisms and whether it is related to induction of epithelial cell plasticity are unknown. DesignExperimental protocol to test the influence of high consumption of meat was compared to pancreatic inflammation experimental models. To determine the molecular drivers promoting pancreatic cell plasticity, we compared transcriptomics data sets from human samples of pancreatic inflammation and pancreatic cancer (PDAC) prone to plasticity and validated in vivo, ex vivo and in vitro the main identified target. ResultsMeat-enriched diet promoted plasticity of pancreatic acinar cells, that transdifferentiated in duct-like cells, and presented PI3K activation. We identified a selective PI3K activation gene signature enriched with plasticity. In this signature, PHGDH, which encodes an enzyme responsible for amino acid serine synthesis, was differentially expressed. High level of PHGDH in acinar cells was necessary for the proliferative action of PI3K sustained by an increased maximal mitochondrial capacity and decreased cyclin-dependent inhibitor p27 level. PHGDH level was decreased in transdifferentiated acinar cells. In this context, active PI3K promoted cell plasticity but decreased the number of cycling cells. Both epithelial-restricted genetic inactivation of PI3K and full PI3K inhibition by pharmacological dosage reduced inflammation-induced tissue damage, while a pharmacological PI3K activator promoted PanIN precancer lesion development. ConclusionMeat-enriched diet promoted plasticity. Blockage of plasticity by PI3K inhibition provoked an increased rate of acinar cell proliferation that had a beneficial impact on the tissue microenvironment less prone to precancer lesion development. What is already known on this topicIt is now well accepted that inflammatory conditions predispose to pancreatic tumour development; increased consumption of red and processed meat is an epidemiologically validated risk condition, but the underlying mechanisms are unknown. What this study addsWe identify PI3K activation as a common molecular pathway activated by increased consumption of red and processed meat and by inflammatory condition to promote pancreatic plasticity and precancer lesion development. How this study might affect research, practice or policyAs we show that treatments with the clinically available PI3K inhibitor block pancreatic plasticity under inflammatory stress while maintaining pancreas mass and limiting inflammatory reaction damage, they may represent an efficient and safe preventive interception drug in patients at risk of developing pancreatic cancer. PI3K pro-cancer action is exacerbated by the loss of serine synthesis enzyme; hence, diets that alter amino acid synthesis should be tightly controlled in those patients.

pathology↗

bioRxiv2022

Adaptation of redox metabolism in drug-tolerant persister cells is a vulnerability to prevent relapse in pancreatic cancer

Pancreatic Ductal Adenocarcinoma (PDAC) remains a major unresolved disease because of its remarkable therapeutic resistance. Even patients who respond to initial therapy experience relapse in most cases. The mechanisms underlying therapy-acquired resistance supporting relapse are poorly understood. In this study, we aimed to determine the metabolic features of PDAC during relapse, specifically adaptations of mitochondrial and redox metabolism. We used preclinical PDAC mouse models (patient-derived xenografts and murine syngeneic allografts) that present complete regression under initial chemotherapeutic treatment but relapse after a certain time. Relapsed tumors were analyzed ex vivo by flow cytometry to measure mitochondrial and redox characteristics. Molecular mechanisms were investigated by quantification of ATP and antioxidants levels, RT-qPCR and bulk RNA-sequencing. Our findings show that mitochondrial metabolism is reprogrammed during relapse, with increased mitochondrial mass, ATP levels, mitochondrial superoxide anions, and total ROS levels, in relapsed compared to control tumors in both models; mitochondrial membrane potential is increased in the xenografts model only. This mitochondrial metabolic reprogramming occurs during treatment-induced regression and at relapse onset. At the molecular level, antioxidant defenses are increased in relapsed tumors and during treatment. These data suggest that treatment-induced oxidative stress may cause the appearance of treatment-adapted cells, known as drug-tolerant persister (DTP) cells. Finally, the combined treatment of arsenic trioxide (ROS inducer) and buthionine sulfoximine (glutathione synthesis inhibitor) is able to completely prevent relapse in PDAC xenografts. In conclusion, targeting redox metabolism via ROS production and antioxidant inhibition is a very promising approach to prevent relapse in PDAC patients. SignificanceMitochondrial and redox metabolisms are reprogrammed during treatment-acquired resistance in pancreatic cancer promoting the survival of drug-tolerant persister cancer cells, opening up new avenues for better therapeutic management of patients.

cancer biology↗

bioRxiv2022

Integrative study of mitochondrial dysfunction in skeletal muscle during pancreatic cancer cachexia

AimsPancreatic Ductal AdenoCarcinoma (PDAC), the most common pancreatic cancer, is a deadly cancer, often diagnosed late and resistant to current therapies. PDAC patients are frequently affected by cachexia characterized by muscle mass and strength loss (sarcopenia) contributing to patient frailty and poor therapeutic response. The objective of this work was to investigate the mechanisms underlying mitochondrial remodeling in the cachectic skeletal muscle, through an integrative study combining functional, morphological and omics-based evaluation of gastrocnemius muscle from genetically-engineered mice developing autochthonous pancreatic tumor and cachexia (KIC GEMM). ResultsKIC cachectic PDAC mice exhibit severe sarcopenia with loss of muscle mass and strength associated with reduced muscle fibers size and induction of protein degradation processes. Mitochondria in PDAC atrophied muscles show reduced respiratory capacities and structural alterations, associated with deregulation of oxidative phosphorylation and mitochondrial dynamics pathways. Beyond the metabolic pathways known to be altered in sarcopenic muscle (carbohydrates, proteins, and redox), lipid and nucleic acid metabolisms are also affected. While the number of mitochondria per cell is not altered, mitochondrial mass is decreased by a factor of 2 and the mitochondrial DNA by a factor of 3, suggesting a defect in mitochondrial genome homeostasis. InnovationMuscle atrophy is associated with strong mitochondrial metabolic defects that are not limited to carbohydrate, protein and redox metabolism, but concern also lipid and nucleic acid metabolism. ConclusionThis work provides a framework to guide towards the most relevant targets in the clinic to limit PDAC-induced cachexia, in particular mitochondrial fatty acid metabolism.

cancer biology↗

bioRxiv2022

DNA methylome combined with chromosome cluster-oriented analysis provides an early signature for cutaneous melanoma aggressiveness

Aberrant DNA methylation is a well-known feature of tumours and has been associated with metastatic melanoma. However, since melanoma cells are highly heterogeneous, it has been challenging to use affected genes to predict tumour aggressiveness, metastatic evolution, and patients outcomes. We hypothesized that common aggressive hypermethylation signatures should emerge early in tumorigenesis and should be shared in aggressive cells, independent of the physiological context under which this trait arises. We compared paired melanoma cell lines with the following properties: (i) each pair comprises one aggressive counterpart and its parental cell line, and (ii) the aggressive cell lines were each obtained from different host and their environment (human, rat, and mouse), though starting from the same parent cell line. Next, we developed a multi-step genomic pipeline that combines the DNA methylome profile with a chromosome cluster-oriented analysis. A total of 229 differentially hypermethylated genes were commonly found in the aggressive cell lines. Genome localization analysis revealed hypermethylation peaks and clusters, identifying eight hypermethylated gene promoters for validation in tissues from melanoma patients. Five CpG identified in primary melanoma tissues were transformed into a DNA methylation score that can predict survival (Log-rank test, p=0.0008). This strategy is potentially universally applicable to other diseases involving DNA methylation alterations.

cancer biology↗

bioRxiv2022

BIN1 regulates electrical activity and network synchronization in hiPSC-derived neurons

BackgroundBridging Integrator 1 (BIN1) is the second most important Alzheimers disease (AD) risk gene, but its physiological roles in neurons and its contribution to brain pathology remain largely elusive. In this work, we show that BIN1 plays a critical role in the regulation of calcium homeostasis, electrical activity, and gene expression of glutamatergic neurons. MethodsWe generated 3D cerebral organoids and 2D enriched neuronal cell cultures from isogenic BIN1 wild-type (WT), heterozygous (HET) and homozygous knockout (KO) human-induced pluripotent stem cells (hiPSCs). Using single-cell RNA-sequencing, biochemical assays, immunocytochemistry and multi-electrode array(MEA) electrophysiology, we characterized the molecular and functional consequences of reduced BIN1 expression in different neural cell types. ResultsWe show that BIN1 is mainly expressed by oligodendrocytes and glutamatergic neurons of cerebral organoids, like in the human brain. Both BIN1 HET and KO cerebral organoids show specific transcriptional alterations, mainly associated with ion transport and synapses in glutamatergic neurons. We then demonstrate that BIN1 cell-autonomously regulates gene expression in glutamatergic neurons by using a novel protocol to generate pure culture of human-derived induced neurons (hiNs). Using this system, we also show that BIN1 plays a key role in the regulation of neuronal calcium transients and electrical activity via its interaction with the L-type voltage-gated calcium channel Cav1.2. BIN1 KO hiNs show reduced activity-dependent internalization and higher Cav1.2 expression compared to WT hiNs. Pharmacological treatment with clinically relevant doses of nifedipine, a calcium channel blocker, partly rescues neuronal electrical and gene expression alterations in BIN1 KO glutamatergic neurons. Further, we show that transcriptional alterations in BIN1 KO hiNs affecting biological processes related to calcium homeostasis are also present in glutamatergic neurons of the human brain at late stages of AD pathology. ConclusionsTogether, our findings suggest that BIN1-dependent alterations in neuronal properties could contribute to AD pathophysiology and that treatment with low doses of clinically approved calcium blockers should be considered as an option to dampen disease onset and progression.

neuroscience↗

bioRxiv2021

Excessive fetal growth affects HSC quiescence maintenance through epigenetic programming of EGR1 transcriptional network

Excessive fetal growth is associated with DNA methylation alterations in human hematopoietic stem and progenitor cells (HSPC), but their functional impact remains elusive. We implemented an integrative analysis combining single-cell epigenomics, single-cell transcriptomics, and in vitro analyses to functionally link DNA methylation changes to putative alterations of HSPC functions. We showed in hematopoietic stem cells (HSC) from large for gestational age neonates that both DNA hypermethylation and chromatin rearrangement target a specific network of transcription factors known to sustain stem cell quiescence. In parallel, we found a decrease expression of key genes regulating HSC differentiation including EGR1, KLF2, SOCS3, and JUNB. Our functional analyses showed that this epigenetic programming was associated with a decreased ability for HSCs to stay quiescent. Taken together, our multimodal approach using single-cell (epi)genomics showed that human fetal overgrowth affects hematopoietic stem cells quiescence maintenance via epigenetic programming.

genomics↗

bioRxiv2021

Copy number variations with adaptive potential in caribou (Rangifer tarandus): genome architecture and new annotated genome assembly

BackgroundRangifer tarandus (caribou and reindeer) has experienced recent drastic population size reductions throughout its circumpolar distribution. In efforts aimed at preserving caribou in North America and reindeer in Eurasia, genetic diversity conservation is of utmost importance, particularly the adaptive genetic diversity. To facilitate genomic studies of the caribou population, we improved genome assembly and annotation by combining long-read, linked-read and RNA sequencing technologies. As copy number variations (CNVs) are known to impact phenotype and are therefore likely to play a key role in adaptation, we investigated CNVs among the genomes of individuals representing three ecotypes of caribou (migratory, boreal and mountain). ResultsUsing de novo transcriptome assembly and similarity with annotated human gene sequences, we identified 17,394 robust gene models embedded in a new highly contiguous genome assembly made of 13,994 scaffolds and presenting the highest N50 reported to date. A BUSCO analysis supported the high accuracy of this assembly, 90% of which being represented by only 131 scaffolds. Genome level comparisons with domestic ruminant species showed high synteny within this clade. A total of 1,698 large CNVs (length > 1kb) were identified, including 332 overlapping coding sequences annotated for functions related to immunity, musculoskeletal development or metabolism regulation and others. While the CNV distribution over the genome revealed 31 CNV hotspots, 43 large CNVs were particularly distinctive of the migratory and sedentary ecotypes and included genes annotated for functions related to cardiac development, fatty acid regulation, cold responses, locomotory behavior or environmental perception (hearing and sight), that can be related to the expected adaptations. ConclusionsThis work includes the first publicly available annotation of the Rangifer tarandus genome and the first genome assembly allowing genome architecture analyses. This robust annotation based on truly expressed sequences showed a distribution overlapping many CNVs that are promising candidates given the annotations supporting their involvement in adaptation. This new highly contiguous assembly will allow relative localization of genetic variations and features and will be a valuable resource for molecular tool development and genomic studies aimed at describing and preserving this species.

genomics↗

bioRxiv2021

The Alzheimer's disease genetic risk factor BIN1 induces isoform-dependent neurotoxicity through early endosome defects

The Bridging Integrator 1 (BIN1) gene is a major susceptibility gene for Alzheimers disease (AD). Deciphering its pathophysiological role is challenging due to its numerous isoforms. Here we observed in Drosophila that human BIN1 isoform1 (BIN1iso1) overexpression, contrary to BIN1iso8 and BIN1iso9, induced an accumulation of endosomal vesicles and neurodegeneration. Systematic search for endosome regulators able to prevent BIN1iso1-induced neurodegeneration indicated that a defect at the early endosome level is responsible for the neurodegeneration. In human induced neurons (hiNs) and cerebral organoids, BIN1 knock-out resulted in the narrowing of early endosomes. This phenotype was rescued by BIN1iso1 but not BIN1iso9 expression. Finally, BIN1iso1 overexpression also led to an increase in the size of early endosomes and neurodegeneration in hiNs. Altogether, our data demonstrate that the AD susceptibility gene BIN1, and especially BIN1iso1, contributes to early-endosome size deregulation, which is an early pathophysiological hallmark of AD pathology.

neuroscience↗

bioRxiv2020

Pancreatic Cancer Intrinsic PI3Kα Activity accelerates Metastasis and rewires Macrophage Component

Pancreatic ductal adenocarcinoma (PDAC) patients frequently suffer from undetected micrometastatic disease. This clinical situation would greatly benefit from additional investigation. Therefore, we set out to identify key signalling events that drive metastatic evolution from the pancreas. We researched a gene signature that could discriminate localised PDAC from confirmed metastatic PDAC and devised a preclinical protocol using circulating cell-free DNA (cfDNA) as an early biomarker of micro-metastatic disease to validate the identification of key signalling events. Amongst actionable markers of disease progression, the PI3K pathway and a distinctive PI3K activation signature predict PDAC aggressiveness and prognosis. Pharmacological or tumour-restricted genetic PI3K-selective inhibition prevented macro-metastatic evolution by inhibiting tumoural cell migratory behaviour independently of genetic alterations. We found that PI3K inhibition altered the quantity and the species composition of the lipid second messenger PIP3 produced, with selective reduction of C36:2 PI-3,4,5-P3. PI3K inactivation prevented the accumulation of protumoural CD206-positive macrophages in the tumour-adjacent tissue. Tumour-cell intrinsic PI3K therefore promotes pro-metastatic features that could be pharmacologically targeted to delay macro-metastatic evolution. The paper explainedPROBLEM Pancreatic cancer is one of the most lethal solid cancers characterised by rapid progression after primary tumour detection by imaging. Key signalling events that specifically drives this rapid evolution into macro-metastatic disease are so far poorly understood. RESULT With two unbiased approaches to patient data analysis, higher PI3K pathway and more specifically higher PI3K activation signature can now be identified in the most aggressive pancreatic cancer primary tumours, that lead to earlier patient death. Our in vitro data showed that PI3K is a major positive regulator of tumour cell escape from the primary tumour: tumour-intrinsic PI3K activity enables actin cytoskeleton remodelling to escape the pancreatic tumour. We chose to use two preclinical models of pancreatic cancer to validate that PI3K is a target for delaying evolution of PDAC. The first one mimicked pancreatic patient micrometastatic disease that is undetected by echography and consisted in treating mice presenting echography detected primary tumours combined with increased circulating DNA as a blood biomarker of the most aggressive tumours. The second model consisted in studying the tumour cell implantation and their early proliferation in metastatic organ after injection in blood. We treated both preclinical models with a clinically relevant PI3K -selective inhibitor (BYL-719/Alpelisib), that is currently being tested in pancreatic cancer patients (without any patient selection). We found that PI3K activity drives evolution of micrometastatic disease towards macro-metastatic stage in both models: inhibition of PI3K delayed primary tumour and micro-metastasis evolution. Finally, PI3K activity increases protumoural characteristics in peritumoural immune cells via tumour cell-intrinsic cytokine production that could facilitate metastatic evolution. IMPACT Circulating tumour DNA represents a strong independent biomarker linked to relapse and poor survival in solid cancer patients. A clinical study in resected PDAC patients with micrometastatic disease characterised by high circulating tumoural DNA levels is needed to assess if PI3K-selective inhibitors significantly delay metastatic progression and death. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=103 SRC="FIGDIR/small/307884v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@a5a8b4org.highwire.dtl.DTLVardef@1e6e18dorg.highwire.dtl.DTLVardef@e22859org.highwire.dtl.DTLVardef@1c7148b_HPS_FORMAT_FIGEXP M_FIG Pancreatic ductal adenocarcinoma requires tumour-intrinsic PI3K activity to accelerate inflammatory metastatic disease. Biorender illustration. C_FIG

cancer biology↗

bioRxiv2018

Combining population genomics and forward simulations to investigate stocking impacts: A case study of Muskellunge (Esox masquinongy) from the St. Lawrence River basin

Understanding the genetic and evolutionary impacts of fish stocking on wild populations has long been of interest as negative consequences such as reduced fitness and loss of genetic resources are commonly reported. Nearly five decades of extensive stocking of over a million Muskellunge (Esox masquinongy) in the Lower St. Lawrence River (Quebec, Canada) was implemented by managers in an attempt to sustain a fishery. We investigated the effect of stocking on this native species genetic structure and allelic diversity in the St. Lawrence river and its tributaries as well as several stocked inland lakes. Using Genotype-By-Sequencing (GBS), we genotyped 643 individuals representing 22 sampling sites and combined this information with forward simulations to investigate the genetic consequences of stocking. Individuals native to the St. Lawrence watershed were genetically divergent from the sources used for stocking and both the St. Lawrence tributaries and inland lakes were also naturally divergent from the main stem. Empirical data and simulations revealed weak effects of stocking on admixture patterns within the St. Lawrence despite intense stocking in the past, whereas footprints of admixture were higher in the smaller stocked populations from tributaries and lakes. Altogether, our data suggests that selection against introgression has been relatively efficient within the large St. Lawrence River. In contrast, the smaller populations from adjacent tributaries and lakes still displayed stocking related admixture which apparently resulted in higher genetic diversity, suggesting that, while stocking stopped at the same time, its impact remained higher in these populations. Finally, the origin of populations from inland lakes that were established by stocking confirmed their close affinity with these source populations. This study illustrates the benefit of combining extensive genomic data with forward simulations for improved inferences regarding outcomes of population enhancement by stocking, as well as its relevance for fishery management decision making.

evolutionary biology↗

bioRxiv2018

Inactivation of NUPR1 promotes cell death by coupling ER-stress responses with necrosis

Genetic inhibition of NUPR1 induces tumor growth arrest. Inactivation of NUPR1 expression in pancreatic cancer cells results in lower ATP production, higher consumption of glucose with a significant switch from OXPHOS to glycolysis followed by necrotic cell death. Importantly, induction of necrosis is independent of the caspase activity. We demonstrated that NUPR1 inactivation triggers a massive release of Ca2+ from the endoplasmic reticulum (ER) to the cytosol and a strong increase in ROS production by mitochondria with a concomitant relocalization of mitochondria to the vicinity of the ER. In addition, transcriptomic analysis of NUPR1-deficient cells shows the induction of an ER stress which is associated to a decrease in the expression of some ER stress response-associated genes. Indeed, during ER stress induced by the treatment with thapsigargin, brefeldin A or tunicamycin, an increase in the mitochondrial malfunction with higher induction of necrosis was observed in NUPR1-defficent cells. Finally, activation of NUPR1 during acute pancreatitis protects acinar cells of necrosis in mice. Altogether, these data enable us to describe a model in which inactivation of NUPR1 in pancreatic cancer cells results in an ER stress that induces a mitochondrial malfunction, a deficient ATP production and, as consequence, the cell death by necrosis.\n\nHighlightsNUPR1 expression promotes pancreatic cancer development and progression\n\nNUPR1-depletion is a promising therapeutic strategy to be used for treating cancers\n\nNUPR1-depletion induces ER stress, mitochondrial malfunction and a significant switch from OXPHOS to glycolysis followed by necrotic cell death\n\nInactivation of NUPR1 antagonizes cell growth by coupling a defective ER-stress response and a caspase-independent necrosis.

cell biology↗