Elena
@burlo.trieste.it
IRCCS Burlo Garofolo
Scopus Publications
- Deciphering transcriptional plasticity in pancreatic ductal adenocarcinoma reveals alterations in sensory neuron innervation
Elena Genova, Michele Montrone, Uday Rangaswamy, Francesco Diversi, Irene Schiavo, Denise Ferrarini, Roberta Di Florio, Irene Longo, Michele Coscia, Nicola Zamboni, Giorgia Demontis, Lisa Veghini, Vincenzo Corbo, Remo Sanges, Paul Heppenstall
Molecular Oncology, 2026
Neuronal innervation of the pancreas has historically been characterized using marker‐based classification and physiological studies, but its transcriptomic landscape remains only partially explored. A detailed molecular profile of pancreatic sensory neurons could provide insights into their role in health and disease, particularly in pancreatic ductal adenocarcinoma (PDAC), where neural remodeling influences tumor progression and pain signaling. Wild‐type and PDAC mice were injected with the retrotracer Fast Blue into pancreatic or cancerous tissue. Dorsal root ganglia were dissociated, and Fast Blue‐positive sensory neurons were isolated, lysed, and analyzed using single‐cell RNA sequencing. Data were validated using immunofluorescence, organoid cultures and qPCR. We performed transcriptomic profiling of sensory neurons innervating the pancreatic head and tail under normal and cancer conditions. Our analysis identified neurofilament‐containing neurons as the predominant sensory subtype in both contexts, while non‐peptidergic neurons were underrepresented in tumor‐associated innervation. Differential gene expression analysis revealed a unique subset of genes upregulated in sensory neurons innervating pancreatic tumors, many linked to mitochondrial activity. Further validation also revealed the presence of transcripts transferred via extracellular vesicles (including the Pdx1‐CreERT2 transgene from the KPC mouse model), suggesting a novel mechanism of tumor–neuron interaction. Our findings provide a detailed characterization of pancreatic and pancreatic ductal adenocarcinoma sensory innervation. We identified tumor‐derived RNA within sensory neurons in the PDAC mouse model, suggesting an extracellular vesicle–mediated RNA transfer mechanism that may remodel sensory signaling and open new prospects for diagnostic and therapeutic innovation in PDAC. Impact statement Transcriptomic profiling of pancreatic sensory neurons reveals shifts in neuronal populations, tumor‐specific mitochondrial gene upregulation, and potential extracellular vesicle–mediated transcript transfer. Circulating tumor transcripts in KPC mice provide a reference for pancreatic innervation, tumor–nerve interactions, and therapeutic targets. - Unraveling the cellular mechanisms of thiopurine-induced pancreatitis in pediatric inflammatory bowel disease: Insights from induced pluripotent stem cell models
Paola Rispoli, Elena Genova, Fengming Yue, Kohei Johkura, Martina Franzin, Ute Hofmann, Matthias Schwab, Rosalba Monica Ferraro, Elena Laura Mazzoldi, Silvia Clara Giliani, Giovanna Piovani, Matteo Bramuzzo, Stefano Martelossi, Erasmo Miele, Massimo Martinelli, Federico Marchetti, Marco Pelin, Giuliana Decorti, Marianna Lucafò, Gabriele Stocco
Biomedicine and Pharmacotherapy, 2025
Thiopurines are effective drugs for inflammatory bowel disease, but their use is limited by side effects such as pancreatitis, whose mechanism remains unknown and may be more severe in children. This study investigated in a personalized way thiopurine-induced pancreatitis mechanism using induced pluripotent stem cells from pediatric inflammatory bowel disease patients. Ten pediatric patients, five developing pancreatitis (cases) and five without it (controls), were enrolled. Patient-specific stem cells and their pancreatic differentiated counterparts were used to evaluate thiopurine cytotoxicity, to quantify metabolites levels by liquid chromatography-tandem mass spectrometry, and to assess thiopurine pharmacodynamics by western-blot assay. Statistical analyses were performed applying Student’s t-test or two-way ANOVA followed by Bonferroni’s post-hoc test for multiple comparisons. Cytotoxicity assays revealed higher thioguanine cytotoxicity in stem and pancreatic cells from cases; pancreatic cells from cases were also more sensitive to mercaptopurine. Moreover, thioguanine treatment on stem cells produced thioguanosine monophosphate and its methylated form, but their concentration did not differ significantly between the groups. In addition, higher TPMT gene expression was observed in stem cells from cases, but no differences were observed in pancreatic cells. No significant differences were detected in HPRT , NUDT15 , ITPA , or PACSIN2 expression. Lastly, Rac1 protein concentration was similar in stem cells from cases and controls, but pancreatic cells from cases exhibited significantly higher Rac1 expression. These findings suggest that thiopurine cytotoxicity differences might be linked to pharmacokinetics in stem cells, while altered Rac1 expression in pancreatic cells might contribute to pancreatitis, implicating distinct mechanisms between stem and differentiated cells. • iPSCs from pediatric IBD patients were used to model thiopurine-induced toxicity • Higher thioguanine cytotoxicity was observed in iPSCs from pancreatitis cases • Mercaptopurine showed increased cytotoxicity in pancreatic cells from cases • Thioguanine metabolites were similar between groups despite differential cytotoxicity • Rac1 overexpression in pancreatic cells may contribute to pancreatitis risk - Pharmacological evaluation of drug therapies in Aicardi-Goutières syndrome: insights from patient-derived neural stem cells
Stefania Braidotti, Rosalba Monica Ferraro, Raffaella Franca, Elena Genova, Francesco Giambuzzi, Andrea Mancini, Valentina Marinozzi, Letizia Pugnetti, Giulia Zudeh, Alessandra Tesser, Alberto Tommasini, Giuliana Decorti, Silvia Clara Giliani, Gabriele Stocco
Frontiers in Pharmacology, 2025
Aicardi-Goutières syndrome (AGS) is a rare genetic disorder classified among type I interferonopathies. Current pharmacological management of AGS is symptomatic and supportive, with recent clinical applications of JAK inhibitors (JAKi) and antiretroviral therapies (RTIs). To investigate the effects of these therapies, patient-specific induced pluripotent stem cells (iPSCs) were generated by reprogramming fibroblasts from three AGS patients with distinct genetic mutations (AGS1, AGS2, AGS7) and differentiated into neural stem cells (NSCs). iPSCs and NSCs derived from commercial BJ fibroblasts of a healthy donor served as control. The cytotoxic effects of glucocorticoids, thiopurines, JAK inhibitors (ruxolitinib, baricitinib, tofacitinib, pacritinib), and RTIs (abacavir, lamivudine, zidovudine) were evaluated using the MTT assay. Results showed that glucocorticoids did not compromise NSC viability. Among thiopurines, thioguanine, but not mercaptopurine, exhibited cytotoxicity in NSCs. All tested JAK inhibitors, except pacritinib, were non-toxic to iPSCs and NSCs. Interestingly, high concentrations of certain JAK inhibitors (ruxolitinib, baricitinib, tofacitinib) led to an unexpected increase in cell viability in AGS patient-derived cells compared to control, suggesting potential alterations in cell proliferation or stress responses. RTIs demonstrated no cytotoxicity, except for zidovudine, which showed selective toxicity in AGS2-derived iPSCs compared to controls. These findings suggest that glucocorticoids, JAK inhibitors (excluding pacritinib), and RTIs are likely safe for NSCs of AGS patients, while caution is warranted with thioguanine and pacritinib. Further studies are needed to explore the mechanisms underlying increased cell viability at high JAK inhibitor concentrations and the selective sensitivity to zidovudine. - Time-efficient strategies in human iPS cell-derived pancreatic progenitor differentiation and cryopreservation: advancing towards practical applications
Elena Genova, Paola Rispoli, Yue Fengming, Johkura Kohei, Matteo Bramuzzo, Roberta Bulla, Marianna Lucafò, Rosalba Monica Ferraro, Giuliana Decorti, Gabriele Stocco
Stem Cell Research and Therapy, 2024
BACKGROUND: Differentiation of patient-specific induced pluripotent stem cells (iPS) helps researchers to study the individual sensibility to drugs. However, differentiation protocols are time-consuming, and not all tissues have been studied. Few works are available regarding pancreatic exocrine differentiation of iPS cells, and little is known on culturing and cryopreserving these cells. METHODS: We differentiated the iPS cells of two pediatric Crohn's disease patients into pancreatic progenitors and exocrine cells, adapting and shortening a protocol for differentiating embryonic stem cells. We analyzed the expression of key genes and proteins of the differentiation process by qPCR and immunofluorescence, respectively. We explored the possibility of keeping differentiated cells in culture and freezing and thawing them to shorten the time needed for the differentiation. We analyzed the cell cycle of undifferentiated and differentiated cells by flow cytometry. RESULTS: The analysis of mRNA levels of key pancreatic differentiation genes PDX1 and pancreatic amylase indicate that iPS cells were successfully differentiated into pancreatic exocrine cells with expression of PDX1 (one way ANOVA p < 0.0001), and the two isoforms of amylase (one way ANOVA p < 0.05) significantly higher in exocrine cells in comparison to iPS cells. Differentiation efficiency was also confirmed by immunofluorescence analysis of PDX1 and amylase. We confirmed the possibility of shortening the time necessary for obtaining pancreatic cells without losing differentiation efficiency. Pancreatic progenitors and exocrine cells were maintained in culture and cryopreserved. Interestingly, the stemness marker OCT4 resulted significantly lower after subculturing (OCT4 p < 0.001; one-way ANOVA) and after freezing and thawing procedures (p < 0.05, one-way ANOVA) suggesting a reduction of undifferentiated stem cells leading to a purer population of pancreatic progenitor cells. Also, the stemness marker NANOG resulted lower after passaging, corroborating this result. CONCLUSIONS: In this work, we optimized the generation of patient-specific pancreatic differentiated cells and laid the foundation for creating a bank of patient-specific pancreatic lines exploitable for tailored pharmacological assays. TRIAL REGISTRATION: The study was approved by the Ethical Committee of the Institute of Maternal and Child Health IRCCS Burlo Garofolo, with approval number 1556 (internal ID RC 44/22). - Insights into the cellular pharmacokinetics and pharmacodynamics of thiopurine antimetabolites in a model of human intestinal cells
Elena Genova, Marianna Lucafò, Marco Pelin, Veronica Di Paolo, Luigi Quintieri, Giuliana Decorti, Gabriele Stocco
Chemico Biological Interactions, 2021 - Induced pluripotent stem cells as an innovative model to study drug induced pancreatitis
Elena Genova, Gabriele Stocco, Giuliana Decorti
World Journal of Gastroenterology, 2021
models. - In vitro effects of sulforaphane on interferon-driven inflammation and exploratory evaluation in two healthy volunteers
Elena Genova, Maura Apollonio, Giuliana Decorti, Alessandra Tesser, Alberto Tommasini, Gabriele Stocco
Molecules, 2021
Interferonopathies are rare genetic conditions defined by systemic inflammatory episodes caused by innate immune system activation in the absence of pathogens. Currently, no targeted drugs are authorized for clinical use in these diseases. In this work, we studied the contribution of sulforaphane (SFN), a cruciferous-derived bioactive molecule, in the modulation of interferon-driven inflammation in an immortalized human hepatocytes (IHH) line and in two healthy volunteers, focusing on STING, a key-component player in interferon pathway, interferon signature modulation, and GSTM1 expression and genotype, which contributes to SFN metabolism and excretion. In vitro, SFN exposure reduced STING expression as well as interferon signature in the presence of the pro-inflammatory stimulus cGAMP (cGAMP 3 h vs. SFN+cGAMP 3 h p value < 0.0001; cGAMP 6 h vs. SFN+cGAMP 6 h p < 0.001, one way ANOVA), restoring STING expression to the level of unstimulated cells. In preliminary experiments on healthy volunteers, no appreciable variations in interferon signature were identified after SFN assumption, while only in one of them, presenting the GSTM1 wild type genotype related to reduced SFN excretion, could a downregulation of STING be recorded. This study confirmed that SFN inhibits STING-mediated inflammation and interferon-stimulated genes expression in vitro. However, only a trend towards the downregulation of STING could be reproduced in vivo. Results obtained have to be confirmed in a larger group of healthy individuals and in patients with type I interferonopathies to define if the assumption of SFN could be useful as supportive therapy. - Ergothioneine, a dietary amino acid with a high relevance for the interpretation of label-free surface enhanced Raman scattering (SERS) spectra of many biological samples
Stefano Fornasaro, Elisa Gurian, Sofia Pagarin, Elena Genova, Gabriele Stocco, Giuliana Decorti, Valter Sergo, Alois Bonifacio
Spectrochimica Acta Part A Molecular and Biomolecular Spectroscopy, 2021 - Induced pluripotent stem cells to model adverse drug reactions in pediatric patients
Elena Genova, Gabriele Stocco, Giuliana Decorti
Pharmacogenomics, 2020
No abstract available - Biomarkers and Precision Therapy for Primary Immunodeficiencies: An In Vitro Study Based on Induced Pluripotent Stem Cells From Patients
Elena Genova, Federica Cavion, Marianna Lucafò, Marco Pelin, Gaetana Lanzi, Stefania Masneri, Rosalba Monica Ferraro, Elisa Maria Fazzi, Simona Orcesi, Giuliana Decorti, Alberto Tommasini, Silvia Giliani, Gabriele Stocco
Clinical Pharmacology and Therapeutics, 2020
Ataxia telangiectasia (AT) and Aicardi–Goutières syndrome (AGS) are inherited disorders of immunity with prevalent neurological phenotype. Available treatments are only partially effective, and the prognosis is poor. Induced pluripotent stem cells (iPSCs) are obtained by reprogramming patient somatic cells, preserving the donor individual genetic heritage and creating patient‐specific disease models, useful to investigate pathogenesis and drug effects and to develop precision therapies. The aim is to investigate the cytotoxicity of a panel of immunomodulators using iPSCs of patients with AT or different forms of AGS (AGS1, AGS2, and AGS7). iPSCs were obtained by reprogramming AT and AGS patients’ cells and, as a control, the BJ normal human fibroblast line, using Sendai virus. Cytotoxic effects of two drugs proposed to treat respectively AT and AGS (dexamethasone and mepacrine) were tested by the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assay after 72 hours' exposure. Data were obtained also for other immunomodulatory drugs (thioguanine, mercaptopurine, thalidomide, and lenalidomide). Relative expression of genes involved in the tested drug pathways was analyzed. AGS7‐derived iPSCs displayed altered viability when treated with a low dose of mepacrine and higher expression of cyclic guanosine monophosphate–adenosine monophosphate synthase, which is the main target for mepacrine action. AGS7‐derived iPSCs were also more sensitive to thioguanine, while AGS2 and AT iPSCs were less sensitive to this medication than the BJ‐iPSC. All iPSCs were equally sensitive to mercaptopurine and resistant to dexamethasone, thalidomide, and lenalidomide. This work establishes an innovative in vitro model that is useful to investigate the mechanisms of drugs potentially effective in AT and AGS. - Induced pluripotent stem cells for therapy personalization in pediatric patients: Focus on drug-induced adverse events
Elena Genova, Federica Cavion, Marianna Lucafò, Luigina De Leo, Marco Pelin, Gabriele Stocco, Giuliana Decorti
World Journal of Stem Cells, 2019 - Generation of 3 clones of induced pluripotent stem cells (iPSCs) from a patient affected by Crohn's disease
Gaetana Lanzi, Stefania Masneri, Rosalba Monica Ferraro, Elena Genova, Giovanna Piovani, Chiara Barisani, Marco Pelin, Gabriele Stocco, Giuliana Decorti, Matteo Bramuzzo, Silvia Giliani
Stem Cell Research, 2019 - SERS of cells: What can we learn from cell lysates?
E. Genova, M. Pelin, G. Decorti, G. Stocco, V. Sergo, A. Ventura, A. Bonifacio
Analytica Chimica Acta, 2018 - Induced pluripotent stem cells as a model for therapy personalizationof pediatric patients: Disease modeling and drug adverse effects prevention
Elena Genova, Marco Pelin, Katsunori Sasaki, Fengming Yue, Gaetana Lanzi, Stefania Masneri, Alessandro Ventura, Gabriele Stocco, Giuliana Decorti
Current Medicinal Chemistry, 2018 - Pharmacokinetics and pharmacodynamics of thiopurines in an in vitro model of human hepatocytes: Insights from an innovative mass spectrometry assay
Marco Pelin, Elena Genova, Laura Fusco, Monzer Marisat, Ute Hofmann, Diego Favretto, Marianna Lucafò, Andrea Taddio, Stefano Martelossi, Alessandro Ventura, Gabriele Stocco, Matthias Schwab, Giuliana Decorti
Chemico Biological Interactions, 2017
