Daniel Grasso

University of Buenos Aires

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Juan Iovanna

Inserm

María I. Vaccaro

University of Buenos Aires

María Noé Garcia

Fundación para la Investigación, Docencia y Prevención del Cáncer

Raúl Urrutia

Mayo Clinic

Gwen Lomberk

Medical College of Wisconsin

Alejandro Ropolo

University of Buenos Aires

ÉC

Ézéquiel Calvo

Université Laval

Tewfik Hamidi

The University of Texas MD Anderson Cancer Center

Carla E. Cano

HiFiBiO Therapeutics (France)

Guillermo Velasco

Universidad Complutense de Madrid

Cooperative Institutions

Inserm

175

Centre National de la Recherche Scientifique

153

University of Michigan–Ann Arbor

126

Harvard University

117

Consejo Nacional de Investigaciones Científicas y Técnicas

101

Chinese Academy of Sciences

University of Buenos Aires

Istituti di Ricovero e Cura a Carattere Scientifico

National Institutes of Health

Consejo Superior de Investigaciones Científicas

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Nitric Oxide and Apoptosis Induced in Peyer's Patches by Attenuated Strains ofSalmonella entericaSerovar Enteritidis

Infection and Immunity (2002)

M. Cristina Cerquetti Nora Goren Alejandro Ropolo Daniel Grasso Mónica N. Giacomodonato

ABSTRACT Nitric oxide (NO) is a toxic molecule of the immune system which contributes to the control of microbial pathogens. Additional functions of NO in innate and adaptive immunity have recently been described; these functions include the modulation of the cytokine response of lymphocytes and the regulation of immune cell apoptosis. In addition to direct microbicidal actions, NO has immunoregulatory effects relevant to the control of infections. In turn, infected macrophages and macrophage-regulating lymphocytes may undergo apoptosis during infection by Salmonella spp. In this work we investigated the ability of attenuated strains of Salmonella enterica serovar Enteritidis with different protective capacities to induce intestinal inducible nitric oxide synthase (iNOS) and apoptosis in Peyer's patches (PP) in mice. Results showed that the intestinal iNOS activity correlated with increased apoptosis in PP. Furthermore, the ability to induce intestinal NO production and apoptosis within the first few hours after immunization seemed to correlate with the protective capacity of mutant E/1/3 of S. enterica serovar Enteritidis. It was found that nonprotective mutant C/2/2, which was unable to induce intestinal NO production, also failed to induce apoptosis in PP. Moreover, aminoguanidine treatment at the time of immunization resulted in inhibition of the NO production and apoptosis induced by protective mutant E/1/3 and completely abolished protection against challenge. These results suggest that the induction of iNOS in the intestinal mucosa by attenuated mutant E/1/3 of S. enterica serovar Enteritidis at the time of immunization is necessary to generate a protective immune response.

Salmonella enterica

Salmonella enteritidis

10.1128/iai.70.2.964-969.2002

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Citations (14)

Genetic inactivation ofNupr1acts as a dominant suppressor event in a two-hit model of pancreatic carcinogenesis

Gut (2013)

Carla E. Cano Tewfik Hamidi María Noé Garcia Daniel Grasso Céline Loncle

Nuclear protein 1 (Nupr1) is a major factor in the cell stress response required for Kras(G12D)-driven formation of pancreatic intraepithelial neoplastic lesions (PanINs). We evaluated the relevance of Nupr1 in the development of pancreatic cancer. We investigated the role of Nupr1 in pancreatic ductal adenocarcinoma (PDAC) progression beyond PanINs in Pdx1-cre;LSL-Kras(G12D);Ink4a/Arf(fl/fl)(KIC) mice. Even in the context of the second tumorigenic hit of Ink4a/Arf deletion, Nupr1 deficiency led to suppression of malignant transformation involving caspase 3 activation in premalignant cells of KIC pancreas. Only half of Nupr1-deficient;KIC mice achieved PDAC development, and incident cases survived longer than Nupr1(wt);KIC mice. This was associated with the development of well-differentiated PDACs in Nupr1-deficient;KIC mice, which displayed enrichment of genes characteristic of the recently identified human classical PDAC subtype. Nupr1-deficient;KIC PDACs also shared with human classical PDACs the overexpression of the Kras-activation gene signature. In contrast, Nupr1(wt);KIC mice developed invasive PDACs with enriched gene signature of human quasi-mesenchymal (QM) PDACs. Cells derived from Nupr1-deficient;KIC PDACs growth in an anchorage-independent manner in vitro had higher aldehyde dehydrogenase activity and overexpressed nanog, Oct-4 and Sox2 transcripts compared with Nupr1(wt);KIC cells. Moreover, Nupr1-deficient and Nurpr1(wt);KIC cells differed in their sensitivity to the nucleoside analogues Ly101-4b and WJQ63. Together, these findings show the pivotal role of Nupr1 in both the initiation and late stages of PDAC in vivo, with a potential impact on PDAC cell stemness. According to Nupr1 status, KIC mice develop tumours that phenocopy human classical or QM-PDAC, respectively, and present differential drug sensitivity, thus becoming attractive models for preclinical drug trials.

Pancreatic Intraepithelial Neoplasia

10.1136/gutjnl-2013-305221

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Clinical Science (2017)

Bárbara Maiztegui Verónica Boggio Carolina Lisi Román Luis Flores Héctor Del Zotto

The aim of the present study was to demonstrate the role of autophagy and incretins in the fructose-induced alteration of β-cell mass and function. Normal Wistar rats were fed (3 weeks) with a commercial diet without (C) or with 10% fructose in drinking water (F) alone or plus sitagliptin (CS and FS) or exendin-4 (CE and FE). Serum levels of metabolic/endocrine parameters, β-cell mass, morphology/ultrastructure and apoptosis, vacuole membrane protein 1 (VMP1) expression and glucose-stimulated insulin secretion (GSIS) were studied. Complementary to this, islets isolated from normal rats were cultured (3 days) without (C) or with F and F + exendin-4 or chloroquine. Expression of autophagy-related proteins [VMP1 and microtubule-associated protein light chain 3 (LC3)], apoptotic/antiapoptotic markers (caspase-3 and Bcl-2), GSIS and insulin mRNA levels were measured. F rats developed impaired glucose tolerance (IGT) and a significant increase in plasma triacylglycerols, thiobarbituric acid-reactive substances, insulin levels, homoeostasis model assessment (HOMA) for insulin resistance (HOMA-IR) and β-cell function (HOMA-β) indices. A significant reduction in β-cell mass was associated with an increased apoptotic rate and morphological/ultrastructural changes indicative of autophagic activity. All these changes were prevented by either sitagliptin or exendin-4. In cultured islets, F significantly enhanced insulin mRNA and GSIS, decreased Bcl-2 mRNA levels and increased caspase-3 expression. Chloroquine reduced these changes, suggesting the participation of autophagy in this process. Indeed, F induced the increase of both VMP1 expression and LC3-II, suggesting that VMP1-related autophagy is activated in injured β-cells. Exendin-4 prevented islet-cell damage and autophagy development. VMP1-related autophagy is a reactive process against F-induced islet dysfunction, being prevented by exendin-4 treatment. This knowledge could help in the use of autophagy as a potential target for preventing progression from IGT to type 2 diabetes mellitus.

10.1042/cs20170010

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VMP1 dependent selective mitophagy and mitochondrial fragmentation are protective cellular mechanisms in pancreatitis

Pancreatology (2018)

Virginia Vanasco Alejandro Ropolo Daniel Grasso Silvia Álvarez María I. Vaccaro

Fragmentation

10.1016/j.pan.2018.05.234

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Autophagy in Cell Fate and Diseases

InTech eBooks (2015)

Daniel Grasso Alejandro Ropolo María I. Vaccaro

Autophagy pathway has been one of the hot topics during the last decade. From a general notion about its cellular role, autophagy becomes a more sophisticated phenomenon with significant implications in cellular homeostasis. Consequently, autophagy represents an emerging new factor in human diseases. Despite its general task, the bulk degradation of cellular constituents during starvation settings, autophagy possesses important cross talk and interrelationships with several cellular processes such as apoptosis and senescence, among others. This entire panorama gives us a complex but exciting scenario. Consequently, with the aim of encompassing the whole spectrum, in this chapter, we review three main topics: autophagy as a cellular process; autophagy in cell fate; and autophagy in disease. We discuss the emerging role of selective type of autophagy to avoid apoptosis or necrosis and the novel relationship between autophagy and senescence to understand the real extent that autophagy pathway has over cell fate. Finally, we briefly describe the current trends on autophagy in human pancreatic diseases and its role in cancer cell metabolism.

Cell fate determination

Senescence

10.5772/61553

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Citations (4)

[The mRNA vaccine for the treatment of pancreatic cancer is here to stay].

PubMed (2023)

Eduardo Chuluyán Carlos Davio Nelson Dusetti Nicolás A. Fraunhoffer María Noé Garcia

Cancer vaccine

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New Roles of Autophagy Pathways in Cancer

Frontiers research topics (2021)

Daniel Grasso Eugenia Morselli Waleska K. Martins Claudio M. Fader

10.3389/978-2-88971-281-6

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Genetic inactivation of the pancreatitis-inducible gene Nupr1 impairs PanIN formation by modulating KrasG12D-induced senescence

Cell Death and Differentiation (2014)

Daniel Grasso María Noé Garcia Tewfik Hamidi Carla E. Cano Ézéquiel Calvo

Nuclear protein 1 (Nupr1), a small chromatin protein, has a critical role in cancer development, progression and resistance to therapy. Previously, we had demonstrated that Nupr1 cooperates with KrasG12D to induce pancreas intraepithelial neoplasias (PanIN) formation and pancreatic ductal adenocarcinoma development in mice. However, the molecular mechanisms by which Nupr1 influences Kras-mediated preneoplastic growth remain to be fully characterized. In the current study, we report evidence supporting a role for Nupr1 as a gene modifier of KrasG12D-induced senescence, which must be overcome to promote PanIN formation. We found that genetic inactivation of Nupr1 in mice impairs Kras-induced PanIN, leading to an increase in β-galactosidase-positive cells and an upregulation of surrogate marker genes for senescence. More importantly, both of these cellular and molecular changes are recapitulated by the results of mechanistic experiments using RNAi-based inactivation of Nupr1 in human pancreatic cancer cell models. In addition, the senescent phenotype, which results from Nupr1 inactivation, is accompanied by activation of the FoxO3a-Skp2-p27Kip1-pRb-E2F pathway in vivo and in vitro. Thus, combined, these results show, for the first time, that Nupr1 aids oncogenic Kras to bypass senescence in a manner that cooperatively promotes PanIN formation. Besides its mechanistic importance, this new knowledge bears medical relevance as it delineates early pathobiological events that may be targeted in the future as a means to interfere with the formation of preneoplastic lesions early during pancreatic carcinogenesis.

Senescence

10.1038/cdd.2014.74

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Citations (44)

IER3 supports KRASG12D-dependent pancreatic cancer development by sustaining ERK1/2 phosphorylation

Journal of Clinical Investigation (2014)

María Noé Garcia Daniel Grasso Belén López‐Millán Tewfik Hamidi Céline Loncle

Activating mutations in the KRAS oncogene are prevalent in pancreatic ductal adenocarcinoma (PDAC). We previously demonstrated that pancreatic intraepithelial neoplasia (PanIN) formation, which precedes malignant transformation, associates with the expression of immediate early response 3 (Ier3) as part of a prooncogenic transcriptional pathway. Here, we evaluated the role of IER3 in PanIN formation and PDAC development. In human pancreatic cancer cells, IER3 expression efficiently sustained ERK1/2 phosphorylation by inhibiting phosphatase PP2A activity. Moreover, IER3 enhanced KrasG12D-dependent oncogenesis in the pancreas, as both PanIN and PDAC development were delayed in IER3-deficient KrasG12D mice. IER3 expression was discrete in healthy acinar cells, becoming highly prominent in peritumoral acini, and particularly high in acinar ductal metaplasia (ADM) and PanIN lesions, where IER3 colocalized with phosphorylated ERK1/2. However, IER3 was absent in undifferentiated PDAC, which suggests that the IER3-dependent pathway is an early event in pancreatic tumorigenesis. IER3 expression was induced by both mild and severe pancreatitis, which promoted PanIN formation and progression to PDAC in KrasG12D mice. In IER3-deficient mice, pancreatitis abolished KrasG12D-induced proliferation, which suggests that pancreatitis enhances the oncogenic effect of KRAS through induction of IER3 expression. Together, our data indicate that IER3 supports KRASG12D-associated oncogenesis in the pancreas by sustaining ERK1/2 phosphorylation via phosphatase PP2A inhibition.

Pancreatic Intraepithelial Neoplasia

10.1172/jci76037

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SUFU promotes GLI activity in a Hedgehog-independent manner in pancreatic cancer

Biochemical Journal (2023)

Brooke D. Paradise Vladimir G. Gainullin Luciana L. Almada Ashley N. Sigafoos Sandhya Sen

Aberrant activation of the Hedgehog (Hh) signaling pathway, through which the GLI family of transcription factors (TF) is stimulated, is commonly observed in cancer cells. One well-established mechanism of this increased activity is through the inactivation of Suppressor of Fused (SUFU), a negative regulator of the Hh pathway. Relief from negative regulation by SUFU facilitates GLI activity and induction of target gene expression. Here, we demonstrate a novel role for SUFU as a promoter of GLI activity in pancreatic ductal adenocarcinoma (PDAC). In non-ciliated PDAC cells unresponsive to Smoothened agonism, SUFU overexpression increases GLI transcriptional activity. Conversely, knockdown (KD) of SUFU reduces the activity of GLI in PDAC cells. Through array PCR analysis of GLI target genes, we identified B-cell lymphoma 2 (BCL2) among the top candidates down-regulated by SUFU KD. We demonstrate that SUFU KD results in reduced PDAC cell viability, and overexpression of BCL2 partially rescues the effect of reduced cell viability by SUFU KD. Further analysis using as a model GLI1, a major TF activator of the GLI family in PDAC cells, shows the interaction of SUFU and GLI1 in the nucleus through previously characterized domains. Chromatin immunoprecipitation (ChIP) assay shows the binding of both SUFU and GLI1 at the promoter of BCL2 in PDAC cells. Finally, we demonstrate that SUFU promotes GLI1 activity without affecting its protein stability. Through our findings, we propose a novel role of SUFU as a positive regulator of GLI1 in PDAC, adding a new mechanism of Hh/GLI signaling pathway regulation in cancer cells.

GLI1

Smoothened

Chromatin immunoprecipitation

10.1042/bcj20220439

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Citations (3)