scholarly journals NFATc4 RegulatesSox9Gene Expression in Acinar Cell Plasticity and Pancreatic Cancer Initiation

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Elisabeth Hessmann ◽  
Jin-San Zhang ◽  
Nai-Ming Chen ◽  
Marie Hasselluhn ◽  
Geou-Yarh Liou ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Initial Step ◽  
Pancreatic Tissue ◽  
Tumor Formation ◽  
Egfr Signaling ◽  
Pancreatic Carcinogenesis ◽  
Acinar To Ductal Metaplasia ◽  
Epidermal Growth ◽  
Stress Signals ◽  
Signaling Activation

Acinar transdifferentiation toward a duct-like phenotype constitutes the defining response of acinar cells to external stress signals and is considered to be the initial step in pancreatic carcinogenesis. Despite the requirement for oncogenic Kras in pancreatic cancer (PDAC) development, oncogenic Kras is not sufficient to drive pancreatic carcinogenesis beyond the level of premalignancy. Instead, secondary events, such as inflammation-induced signaling activation of the epidermal growth factor (EGFR) or induction of Sox9 expression, are required for tumor formation. Herein, we aimed to dissect the mechanism that links EGFR signaling to Sox9 gene expression during acinar-to-ductal metaplasia in pancreatic tissue adaptation and PDAC initiation. We show that the inflammatory transcription factor NFATc4 is highly induced and localizes in the nucleus in response to inflammation-induced EGFR signaling. Moreover, we demonstrate that NFATc4 drives acinar-to-ductal conversion and PDAC initiation through direct transcriptional induction ofSox9. Therefore, strategies designed to disrupt NFATc4 induction might be beneficial in the prevention or therapy of PDAC.

scholarly journals Rab8 and Rabin8-Mediated Tumor Formation by Hyperactivated EGFR Signaling via FGFR Signaling

2020 ◽  
Vol 21 (20) ◽  
pp. 7770
Author(s):  
Junghwa Choi ◽  
Jee Young Sung ◽  
Saerom Lee ◽  
Jungyoen Yoo ◽  
Christopher Rongo ◽  
...  
Keyword(s):  
Growth Factor Receptor ◽  
Tumor Model ◽  
Tumor Formation ◽  
Rab Proteins ◽  
Egfr Signaling ◽  
Vulval Development ◽  
C Elegans ◽  
Exon 19 Deletion ◽  
Epidermal Growth ◽  
Egfr Tki

The epidermal growth factor receptor (EGFR) signaling is important for normal development, such as vulval development in Caenorhabditis elegans, and hyperactivation of the EGFR is often associated with cancer development. Our previous report demonstrated the multivulva (Muv) phenotype, a tumor model in C. elegans (jgIs25 strain) by engineering LET-23/EGFR with a TKI-resistant human EGFR T790-L858 mutant. Because Rab proteins regulate vesicle transport, which is important for receptor signaling, we screened the RNAi in the jgIs25 strain to find the Rabs critical for Muv formation. Herein, we show that rab-8 RNAi and the rab-8 (-/-) mutation effectively reduce Muv formation. We demonstrate that RABN-8, an ortholog of Rabin8, known as a GEF for Rab8, is also required for Muv formation by promoting the secretion of EGL-17/FGF from vulval precursor cells. In addition, FGFR inhibitors decreased Muv formation mediated by mutant EGFR. Our data suggest that Rab8 and Rabin8 mediate Muv formation through FGF secretion in the EGFR-TKI-resistant nematode model. Furthermore, FGFR-TKIs more effectively inhibit the growth of lung cancer cell lines in H1975 (EGFR T790M-L858R; EGFR-TKI-resistant) than H522 (wild-type EGFR) and H1650 (EGFR exon 19 deletion; EGFR-TKI-sensitive) cells, suggesting that FGFR-TKIs could be used to control cancers with EGFR-TKI-resistant mutations.

Preclinical immunotherapy studies using an orthotopic pancreatic cancer mouse model.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 324-324
Author(s):  
Despina Siolas ◽  
Orlando Aristizabal ◽  
Kate Byrne ◽  
Lawrence P. Leichman ◽  
Robert H. Vonderheide ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Small Animal ◽  
Pancreatic Tissue ◽  
Tumor Formation ◽  
Genetically Engineered ◽  
Therapeutic Interventions ◽  
Cancer Mutations ◽  
Tumor Microenviroment ◽  
Aggressive Clinical Course

324 Background: Pancreatic cancer is well known for its aggressive clinical course and resistance to chemotherapy. The advent of new mouse models of pancreatic cancer have accelerated our understanding of tumorigenesis and enabled preclinical testing of experimental therapeutics with a desire to translate these findings into meaningful clinical treatments. Methods: We have developed a model where pancreatic cells obtained from a KrasG12D;Trp53R172H genetically engineered mouse can be cultivated in two dimensional cell culture and implanted into the pancreas of a immunocompetent syngeneic mouse allowing for tumor formation in situ. In addition, we are using this model to study the effectiveness of new drug combination therapy such as gemcitabine, albumin-bound paclitaxel and CD40 agonist immunotherapy using overall survival as a primary endpoint. Results: These cells generate tumors of five millimeter diameter within two weeks of implantation with 100% efficiency. Because cancer cells are seeded in the context of normal surrounding pancreatic tissue, this model is not hampered by the genetic field effect of expressing cancer mutations in the entire pancreatic organ, allowing for the study of the tumor microenviroment. Responses to therapeutic interventions can be non-invasively monitored through small animal high resolution ultrasound. Conclusions: Our orthotopic pancreatic cancer mouse system is an effective model for pre-clinical studies of tumorigenesis, immunotherapy and examination of the tumor microenvironment. Future experiments will focus on exploiting this system for identifying potent immunotherapy and chemotherapy combinations and for detecting biomarkers of efficiency.

scholarly journals The glycan CA19-9 promotes pancreatitis and pancreatic cancer in mice

Science ◽  
2019 ◽  
Vol 364 (6446) ◽  
pp. 1156-1162 ◽  
Author(s):  
Dannielle D. Engle ◽  
Hervé Tiriac ◽  
Keith D. Rivera ◽  
Arnaud Pommier ◽  
Sean Whalen ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Growth Factor Receptor ◽  
Pancreatic Disease ◽  
Carbohydrate Antigen ◽  
Matricellular Protein ◽  
Egfr Signaling ◽  
Sialyl Lewis ◽  
Egfr Ligands ◽  
Epidermal Growth

Glycosylation alterations are indicative of tissue inflammation and neoplasia, but whether these alterations contribute to disease pathogenesis is largely unknown. To study the role of glycan changes in pancreatic disease, we inducibly expressed human fucosyltransferase 3 and β1,3-galactosyltransferase 5 in mice, reconstituting the glycan sialyl-Lewisa, also known as carbohydrate antigen 19-9 (CA19-9). Notably, CA19-9 expression in mice resulted in rapid and severe pancreatitis with hyperactivation of epidermal growth factor receptor (EGFR) signaling. Mechanistically, CA19-9 modification of the matricellular protein fibulin-3 increased its interaction with EGFR, and blockade of fibulin-3, EGFR ligands, or CA19-9 prevented EGFR hyperactivation in organoids. CA19-9–mediated pancreatitis was reversible and could be suppressed with CA19-9 antibodies. CA19-9 also cooperated with the KrasG12D oncogene to produce aggressive pancreatic cancer. These findings implicate CA19-9 in the etiology of pancreatitis and pancreatic cancer and nominate CA19-9 as a therapeutic target.

scholarly journals Omega-3 Fatty Acids Prevent Early Pancreatic Carcinogenesis via Repression of the AKT Pathway

Nutrients ◽  
2018 ◽  
Vol 10 (9) ◽  
pp. 1289 ◽  
Author(s):  
Yongzeng Ding ◽  
Bhargava Mullapudi ◽  
Carolina Torres ◽  
Emman Mascariñas ◽  
Georgina Mancinelli ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Fatty Acids ◽  
Early Stage ◽  
Disease Incidence ◽  
Tumor Formation ◽  
Early Stage Disease ◽  
Vast Number ◽  
Pancreatic Carcinogenesis ◽  
Ω3 Fatty Acids ◽  
Phosphorylated Akt

Pancreatic cancer remains a daunting foe despite a vast number of accumulating molecular analyses regarding the mutation and expression status of a variety of genes. Indeed, most pancreatic cancer cases uniformly present with a mutation in the KRAS allele leading to enhanced RAS activation. Yet our understanding of the many epigenetic/environmental factors contributing to disease incidence and progression is waning. Epidemiologic data suggest that diet may be a key factor in pancreatic cancer development and potentially a means of chemoprevention at earlier stages. While diets high in ω3 fatty acids are typically associated with tumor suppression, diets high in ω6 fatty acids have been linked to increased tumor development. Thus, to better understand the contribution of these polyunsaturated fatty acids to pancreatic carcinogenesis, we modeled early stage disease by targeting mutant KRAS to the exocrine pancreas and administered diets rich in these fatty acids to assess tumor formation and altered cell-signaling pathways. We discovered that, consistent with previous reports, the ω3-enriched diet led to reduced lesion penetrance via repression of proliferation associated with reduced phosphorylated AKT (pAKT), whereas the ω6-enriched diet accelerated tumor formation. These data provide a plausible mechanism underlying previously observed effects of fatty acids and suggest that administration of ω3 fatty acids can reduce the pro-survival, pro-growth functions of pAKT. Indeed, counseling subjects at risk to increase their intake of foods containing higher amounts of ω3 fatty acids could aid in the prevention of pancreatic cancer.

scholarly journals New Aspects of the Epigenetics of Pancreatic Carcinogenesis

Epigenomes ◽  
2020 ◽  
Vol 4 (3) ◽  
pp. 18
Author(s):  
Murat Toruner ◽  
Martin E. Fernandez-Zapico ◽  
Christopher L. Pin
Keyword(s):  
Pancreatic Cancer ◽  
Dna Methylation ◽  
Survival Rate ◽  
Epigenetic Mechanisms ◽  
Therapeutic Approaches ◽  
Cancer Epigenetics ◽  
Pancreatic Carcinogenesis ◽  
New Therapeutic Approaches ◽  
Environmental Events ◽  
Underlying Pathogenesis

Pancreatic cancer remains among the deadliest forms of cancer with a 5 year survival rate less than 10%. With increasing numbers being observed, there is an urgent need to elucidate the pathogenesis of pancreatic cancer. While both contribute to disease progression, neither genetic nor environmental factors completely explain susceptibility or pathogenesis. Defining the links between genetic and environmental events represents an opportunity to understand the pathogenesis of pancreatic cancer. Epigenetics, the study of mitotically heritable changes in genome function without a change in nucleotide sequence, is an emerging field of research in pancreatic cancer. The main epigenetic mechanisms include DNA methylation, histone modifications and RNA interference, all of which are altered by changes to the environment. Epigenetic mechanisms are being investigated to clarify the underlying pathogenesis of pancreatic cancer including an increasing number of studies examining the role as possible diagnostic and prognostic biomarkers. These mechanisms also provide targets for promising new therapeutic approaches for this devastating malignancy.

scholarly journals Updated Insights on EGFR Signaling Pathways in Glioma

2021 ◽  
Vol 22 (2) ◽  
pp. 587
Author(s):  
Alexandru Oprita ◽  
Stefania-Carina Baloi ◽  
Georgiana-Adeline Staicu ◽  
Oana Alexandru ◽  
Daniela Elise Tache ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Treatment Strategies ◽  
Growth Factor Receptor ◽  
Standard Of Care ◽  
Egfr Signaling ◽  
Current Standard ◽  
Egfr Amplification ◽  
Epidermal Growth ◽  
New Diagnosis ◽  
Clear Clinical Benefit

Nowadays, due to recent advances in molecular biology, the pathogenesis of glioblastoma is better understood. For the newly diagnosed, the current standard of care is represented by resection followed by radiotherapy and temozolomide administration, but because median overall survival remains poor, new diagnosis and treatment strategies are needed. Due to the quick progression, even with aggressive multimodal treatment, glioblastoma remains almost incurable. It is known that epidermal growth factor receptor (EGFR) amplification is a characteristic of the classical subtype of glioma. However, targeted therapies against this type of receptor have not yet shown a clear clinical benefit. Many factors contribute to resistance, such as ineffective blood–brain barrier penetration, heterogeneity, mutations, as well as compensatory signaling pathways. A better understanding of the EGFR signaling network, and its interrelations with other pathways, are essential to clarify the mechanisms of resistance and create better therapeutic agents.

scholarly journals Dominant Enhancers of Egfr in Drosophila melanogaster: Genetic Links Between the Notch and Egfr Signaling Pathways

Genetics ◽  
1997 ◽  
Vol 147 (3) ◽  
pp. 1139-1153 ◽  
Author(s):  
James V Price ◽  
Edward D Savenye ◽  
David Lum ◽  
Ashton Breitkreutz
Keyword(s):  
Notch Signaling ◽  
Signaling Pathways ◽  
Growth Factor Receptor ◽  
Compound Eyes ◽  
Egfr Signaling ◽  
Wing Vein ◽  
Developmental Context ◽  
Epidermal Growth ◽  
Hypomorphic Alleles ◽  
Complex Signaling

The Drosophila epidermal growth factor receptor (EGFR) is a key component of a complex signaling pathway that participates in multiple developmental processes. We have performed and F1 screen for mutations that cause dominant enhancement of wing vein phenotypes associated with mutations in Egfr. With this screen, we have recovered mutations in Hairless (H), vein, groucho (gro), and three apparently novel loci. All of the E(Egfr)s we have identified show dominant interactions in transheterozygous combinations with each other and with alleles of N or Su(H), suggesting that they are involved in cross-talk between the N and EGFR signaling pathways. Further examination of the phenotypic interactions between Egfr, H, and gro revealed that reductions in Egfr activity enhanced both the bristle loss associated with H mutations, and the bristle hyperplasia and ocellar hypertrophy associated with gro mutations. Double mutant combinations of Egfr and gro hypomorphic alleles led to the formation of ectopic compound eyes in a dosage sensitive manner. Our findings suggest that these E(Egfr)s represent links between the Egfr and Notch signaling pathways, and that Egfr activity can either promote or suppress Notch signaling, depending on its developmental context.

scholarly journals Mdm2-Mediated Downmodulation of GRK2 Restricts Centrosome Separation for Proper Chromosome Congression

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 729
Author(s):  
Clara Reglero ◽  
Belén Ortiz del Castillo ◽  
Verónica Rivas ◽  
Federico Mayor ◽  
Petronila Penela
Keyword(s):  
Hippo Pathway ◽  
Growth Factor Receptor ◽  
Receptor Kinase ◽  
Egfr Signaling ◽  
Polyubiquitin Chains ◽  
Centrosome Separation ◽  
Chromosome Congression ◽  
Epidermal Growth ◽  
The Hippo Pathway ◽  
G Protein Coupled

The timing of centrosome separation and the distance moved apart influence the formation of the bipolar spindle, affecting chromosome stability. Epidermal growth factor receptor (EGFR) signaling induces early centrosome separation through downstream G protein-coupled receptor kinase GRK2, which phosphorylates the Hippo pathway component MST2 (Mammalian STE20-like protein kinase 2), in turn allowing NIMA kinase Nek2A activation for centrosomal linker disassembly. However, the mechanisms that counterbalance centrosome disjunction and separation remain poorly understood. We unveil that timely degradation of GRK2 by the E3 ligase Mdm2 limits centrosome separation in the G2. Both knockout expression and catalytic inhibition of Mdm2 result in GRK2 accumulation and enhanced centrosome separation before mitosis onset. Phosphorylation of GRK2 on residue S670 enables a complex pattern of non-K48-linked polyubiquitin chains assembled by Mdm2, which correlate with kinase protein degradation. Remarkably, GRK2-S670A protein fails to phosphorylate MST2 despite overcoming Mdm2-dependent degradation, which results in defective centrosome separation, shorter spindles, and abnormal chromosome congression. Conversely, extra levels of wild-type kinase in the G2 cause increased inter-centrosome distances with longer spindles, also converging in congression issues. Our findings show that the signals enabling activity of the GRK2/MST2/Nek2A axis for separation also switches on Mdm2 degradation of GRK2 to ensure accurate centrosome dynamics and proper mitotic spindle functionality.

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