AnatomyOrganismsDiseasesChemicals and DrugsAnalytical, Diagnostic and Therapeutic Techniques and EquipmentPhenomena and ProcessesDisciplines and OccupationsInformation ScienceHealth Care
Disease ProgressionCarcinoma, Pancreatic DuctalPancreatic NeoplasmsCell Line, TumorGene Expression Regulation, NeoplasticAdenocarcinomaCell ProliferationCell CycleNeoplasm InvasivenessImmunohistochemistrySignal TransductionNeoplasm MetastasisPrognosisTumor Markers, BiologicalDisease Models, AnimalProto-Oncogene Proteins p21(ras)Cell Transformation, NeoplasticTime FactorsPancreatitis, ChronicMice, NudeRNA, MessengerPancreatic DuctsApoptosisReverse Transcriptase Polymerase Chain ReactionMice, TransgenicTreatment OutcomeProstatic NeoplasmsCarcinoma in SituPrecancerous ConditionsGenes, rasGene Expression ProfilingCell MovementCyclic S-OxidesMutationRNA, Small InterferingAntineoplastic AgentsDeoxycytidineFollow-Up StudiesBlotting, WesternCell Cycle ProteinsEpithelial-Mesenchymal TransitionSurvival AnalysisUp-RegulationTumor Cells, CulturedCathepsin ES PhaseNeoplasm StagingNeoplasm ProteinsG1 PhaseTumor MicroenvironmentBreast NeoplasmsMice, Inbred C57BLKaplan-Meier EstimateMicroRNAsCell DivisionXenograft Model Antitumor AssaysDown-RegulationMice, SCIDGene ExpressionPhosphorylationNeovascularization, PathologicNeoplasmsNeoplasm TransplantationPancreasOligonucleotide Array Sequence AnalysisGene Knockdown TechniquesMitosisProtein-Serine-Threonine KinasesSurvival RatePhenotypeTumor BurdenTissue Array AnalysisMice, KnockoutProto-Oncogene ProteinsRNA InterferenceTransfectionReal-Time Polymerase Chain ReactionCohort StudiesRetrospective StudiesRisk FactorsTumor Suppressor Protein p53Transcription FactorsBiological MarkersCell LineFlow CytometryProspective StudiesDrug Resistance, Neoplasmras ProteinsGene SilencingCells, CulturedCA-19-9 AntigenLung NeoplasmsPredictive Value of TestsTransplantation, HeterologousModels, BiologicalMolecular Sequence DataMelanomaImmunoenzyme TechniquesCell SurvivalAntineoplastic Combined Chemotherapy Protocols
DuctalAdenocarcinomaDisease progressionMetastaticTumorsVivoProliferationInitiation and progressionPrognosisImmunotherapyPhenotypePancreatic intraepithelial neoplasiaOverall survivalPathwaysSurgical resectionMyeloidAntitumorCorrelatesMechanismsMolecularMetastasisFibrosisMiceNeoplasiaFibroblastTherapeuticInhibitionPatientsImmunosuppressiveClinicalMutationsChemotherapyTherapiesSurvival rateKRASDesmoplasticOutcomes
Ductal27
Adenocarcinoma2
  • My primary area of focus is investigating molecular mechanisms involved during the multi-step progression of pancreatic adenocarcinoma (PDAC). (ox.ac.uk)
  • Pancreatic adenocarcinoma (PDAC) is one of the most lethal human cancers with a 5-year survival of less than 5% due mostly to the lack of effective therapy and difficulty of detection at an early stage of development. (brighton.ac.uk)
Disease progression12
  • While TAMs are known to proliferate in cancer tissues, the impact of this on macrophage phenotype and disease progression is poorly understood. (wustl.edu)
  • Here, we show that MUC16 expression is associated with disease progression, basal-like and squamous tumor subtypes, increased tumor metastasis, and short-term survival of PDAC patients. (unc.edu)
  • These two immunotherapies will be administered by intravenous infusions every 2 weeks until disease progression or unacceptable toxicity, for up to 1 year. (medscape.com)
  • Each participant will take a belzutifan tablet and lenvatinib capsule daily until disease progression or discontinuation and receive intravenous pembrolizumab once every 6 weeks for up to 2 years. (medscape.com)
  • Tumor-associated macrophages (TAMs) orchestrate PDAC malignancy, but their dynamics during disease progression remains poorly understood. (biomedcentral.com)
  • The first project in our laboratory seeks to understand how host metabolism impacts disease progression and therapy resistance in pancreatic cancer. (wistar.org)
  • Reprogramming cancer cells to pluripotency by induced pluripotent stem cell (iPSC) technology, which can be then programmed back to their original cellular state, allows for studying the dynamic events in the course of the disease progression. (elsevierpure.com)
  • Enhanced neutrophil infiltration into the TME with disease progression was previously observed in my lab. (unmc.edu)
  • The remaining 11 patients (78.6%) experienced disease progression. (medicaltrend.org)
  • Only one MSI-H, locally advanced PDAC patient showed a partial response lasting 10.5 months before disease progression. (medicaltrend.org)
  • Archival gene expression data revealed a modest elevation of AIF transcript levels in subsets of pancreatic tumor specimens, suggesting a possible role in disease progression. (biomedcentral.com)
  • Progression Free Survival (PFS) [Time Frame: From date of first dose/randomisation until disease progression or death in the absence of progression (approximately 2 years). (who.int)
Metastatic7
  • The tumor microenvironment (TME) is recognized as an important factor in metastatic progression across cancers. (stanford.edu)
  • Adult patients (aged ≥18 years) with histologically or cytologically confirmed metastatic PDAC, and had tumor progression following prior standard first-line 5-FU-containing or gemcitabine-containi. (clinicaltrialsregister.eu)
  • PDAC most often presents at an advanced stage and with metastatic disease, which precludes resection, and is often associated with marked chemoresistance and intense desmoplasia that may interfere with tumor blood flow and hinder drug penetration into the pancreatic tumor mass [ 2 - 5 ]. (oncotarget.com)
  • Moreover, the patients diagnosed for PDAC are mostly presented at advanced stage with metastatic disease. (ox.ac.uk)
  • and Singh, Rakesh, "Metastatic PDAC Cell - Neutrophil Interaction Regulates their Proliferation and Survival" (2023). (unmc.edu)
  • A phase 1b study (NCT02734160) explored the combination of Galunisertib and anti-PD-L1 antibody Durvalumab in 32 patients with metastatic PDAC. (medicaltrend.org)
  • Participants diagnosed with histologically confirmed metastatic or advanced PDAC. (who.int)
Tumors11
  • Herein, we also demonstrate that compounds developed to target mutant IDH1 can be repurposed as wild-type IDH1 inhibitors, because these drugs surprisingly become potent inhibitors of wtIDH1 in cancer cells under conditions present in tumors: specifically, we found that wtIDH1 is critical for PDAC cell survival under low-glucose conditions, and allosteric IDH inhibitors effectively block wtIDH1 activity under low magnesium. (nature.com)
  • Despite extensive study of the TME in PDAC, the cellular and molecular signaling networks remain poorly understood, largely due to the tremendous heterogeneity across tumors. (stanford.edu)
  • Aberrant epigenetic modifications play a vital role in the progression of digestive system tumors. (ijbs.com)
  • Aberrant changes in epigenetic mechanisms regulating DNA methylation, histone methylation and acetylation, expression of noncoding RNAs, and mRNA methylation are associated with the initiation, growth, and progression of digestive system tumors [ 2 , 4 ]. (ijbs.com)
  • Critical obstacles to immunotherapy in PDAC tumors include the dense desmoplastic stroma that acts as a barrier to T cell infiltration and high numbers of tumor-associated immunosuppressive cells, such as MDSCs and regulatory T cells (Tregs). (biomedcentral.com)
  • Of the pathways evaluated, we found that focal adhesion kinase (FAK) activity is elevated in human PDAC and that FAK activity correlates with highly fibrotic tumors with poor CD8 + T cell infiltration. (biomedcentral.com)
  • We postulated that the desirable effects of FAK inhibition on the tumor microenvironment might render PDAC tumors more sensitive to immunotherapy. (biomedcentral.com)
  • Importantly, the FAK inhibitor VS-4718 and FAK shRNA in the tumor cells were each effective in increasing CD8+ cytotoxic T cell infiltration into the PDAC tumors in vivo . (biomedcentral.com)
  • Taken together, these data suggest that FAK inhibition increases immune surveillance programs in PDAC tumors by overcoming the fibrotic and inflammatory microenvironment rendering tumors more responsive to immunotherapy. (biomedcentral.com)
  • What makes the response of PDAC to immunotherapy different from the responses of other solid tumors is the specific host tissue. (biomedcentral.com)
  • We isolated CSCs from low passage PDAC cell lines derived from human tumors and commercially available cell lines. (amegroups.org)
Vivo4
  • Finally, by modeling p21 expression levels in TAMs, we found that p21-driven macrophage immunosuppression in vivo drove tumor progression. (wustl.edu)
  • Delayed Tgfbeta1 activation in vivo suppressed PDAC progression. (tum.de)
  • Moreover, ruxolitinib blocks mitogenic EC/PCC cross-talk, and suppresses endothelial p-STAT3 and HDAC9, and PDAC progression and angiogenesis in vivo , while markedly prolonging survival of KRC mice. (oncotarget.com)
  • The interaction between RAGE-S100P stimulates pancreatic tumor proliferation, survival, invasion and metastasis progression in vitro and tumor metastasis in vivo. (brighton.ac.uk)
Proliferation7
  • We showed that in PDAC, proliferation of TAMs could be driven by colony stimulating factor-1 (CSF1) produced by cancer-associated fibroblasts. (wustl.edu)
  • The proliferation and growth of PDAC cells were detected by Celigo analysis, MTT, and clone formation assay. (jcancer.org)
  • Using CRC cell lines with different TP53 gene status such as HCT116 (TP53wt/wt), HCT116 (TP53-/-), SW48 and DLD-1 cells, proliferation, cell cycle progression and apoptosis, as well as the effect of RYBP on oxaliplatin sensitivity, were assessed. (bvsalud.org)
  • Our working hypothesis is that neutrophil-PDAC interaction increases PDAC proliferation, survival, and metastasis. (unmc.edu)
  • We observed concentration-dependent increase in PDAC cell proliferation following treatment with neutrophil-conditioned media. (unmc.edu)
  • Together, our data suggest that PDAC-neutrophil interaction differentially modulates of neutrophil and PDAC cells survival/proliferation. (unmc.edu)
  • The complex PDAC pathobiology is established predominantly through KRAS mutations and the associated cellular signaling that contributes to cell proliferation and dedifferentiation ( 5 , 6 ). (amegroups.org)
Initiation and progression2
  • The role of TGFbeta signalling in pancreatic cancer initiation and progression is still unclear. (tum.de)
  • Research toward understanding this disease led to the identification of major risk factors and important molecular changes underlying pancreatic cancer initiation and progression. (oncotarget.com)
Prognosis8
  • Finally, compared with known biomarkers, the model was more accurate in predicting the prognosis of PDAC. (aging-us.com)
  • However, postoperative patients with PDAC often frequently relapse and have poor prognosis because of micro-infiltration and micro-metastasis in the lesions. (aging-us.com)
  • We also aim to highlight the importance of PDAC patient stratification based on cell of origin for better prognosis. (ox.ac.uk)
  • This dismal prognosis is mostly because PDAC is usually diagnosed at an advanced stage and is resistant to therapy [ 3 ]. (biomedcentral.com)
  • Impaired immune effector cell infiltration and inactivation of the immune response contribute to the poor prognosis of PDAC patients. (biomedcentral.com)
  • In this pilot study, we aimed to identify differentially regulated proteins in plasma and plasma derived microparticles from PDAC patients with poor and good prognosis. (edu.au)
  • Protein tyrosine phosphatases, PTPRM and PTPRB, were decreased in plasma of patients with poor PDAC prognosis, while proteasomal subunit PSMD11 was increased in microparticles of patients with poor prognosis. (edu.au)
  • Conclusion and general significance: A novel blood-based biomarker signature for PDAC prognosis was identified. (edu.au)
Immunotherapy1
  • However, chimeric antigen receptor T (CAR-T) cell immunotherapy and immune checkpoint blockade (ICB), which have produced unprecedented clinical benefits in a variety of different cancers, produce promising results in only some highly selected patients with PDAC. (biomedcentral.com)
Phenotype1
  • Particularly, I am interested in looking at the role of an oncogene, YAP, which could potentially drive early precursor lesions into aggressive phenotype in PDAC. (ox.ac.uk)
Pancreatic intraepithelial neoplasia2
  • Similarly, an absence of ATF3 reduced spontaneous pancreatic intraepithelial neoplasia (PanIN) formation and PDAC in Ptf1acreERT/+KrasG12D/+ mice. (bepress.com)
  • We showed that when an iPS-like cell line, designated 10-22, derived from human recurrent PDAC, was injected into immunodeficient mice, the cells consistently recapitulated preinvasive, pancreatic intraepithelial neoplasia (PanIN) to invasive stages of human PDAC. (elsevierpure.com)
Overall survival5
  • Using Univariable Cox regression analysis and Lasso regression analysis method in the training dataset, it was found that the four DNA methylation markers ( CCNT1 , ITGB3 , SDS , and HMOX2 ) were significantly correlated with the overall survival of patients with PDAC. (aging-us.com)
  • The median overall survival was 5.72 months, and the median progression-free survival was 1.87 months. (medicaltrend.org)
  • Phase 1 data from an early clinical trial (NCT02699515) in 30 pretreated biliary tract cancer patients showed an objective response rate of 20% (6/30), with median progression-free and overall survival of 2.5 and 12.7 months, respectively. (medicaltrend.org)
  • Surgical resection and adjuvant therapy have limited effects on the overall survival of PDAC patients. (biomedcentral.com)
  • In this cohort study of 94 patients with resected melanoma brain metastases that underwent targeted DNA sequencing, BRAF V600E variant lesions were associated with worse intracranial progression-free survival and overall survival. (cdc.gov)
Pathways4
  • Serendipitously, the same p21-driven pathways that drive tumor progression also drove response to CD40 agonist. (wustl.edu)
  • In summary, early simultaneous targeting of 5-LOX-COX- and EGFR pathways may provide additive inhibitory effects leading to complete suppression of PDAC. (oncotarget.com)
  • This project seeks to identify the metabolic pathways by which the gut microbiome influences antitumor immune responses, impacting PDAC burden and therapy response. (wistar.org)
  • To understand which signaling pathways in pancreatic tumor cells might drive this suppressive tumor microenvironment, we analyzed the correlation between hyper-activated signaling molecules and tumor infiltrating leukocytes using 50 human PDAC tumor tissues. (biomedcentral.com)
Surgical resection3
  • Currently, surgical resection is the only chance of cure for early-stage PDAC [ 3 ]. (jcancer.org)
  • Currently, surgical resection is the most effective method for PDAC treatment. (aging-us.com)
  • Methods: Plasma and plasma derived microparticle samples were obtained before surgical resection from PDAC patients. (edu.au)
Myeloid5
  • In patient samples, we identified a transition from PGD 2 to PGE 2 -producing enzymes in the epithelium during the transition to PDAC, fibroblast/tumor expression of PTGIS, and myeloid/tumor cell expression of TBXAS1. (nih.gov)
  • Distinct lymphoid, myeloid, and stromal cell types in the TME exert opposing influences on PDAC tumor trajectory, suggesting a more complex organization than the classical "hot" versus "cold" tumor distinction. (stanford.edu)
  • We demonstrated myeloid compartment was an interactive hub of tumor microenvironment (TME) essential for PDAC progression. (biomedcentral.com)
  • This alteration in tumor progression was associated with dramatically reduced tumor fibrosis, decreased numbers of FOXP3 + Tregs and tumor-infiltrating myeloid cells, and anti-tumor polarization of tumor-associated macrophages. (biomedcentral.com)
  • The infiltration of multiple types of tumor-promoting immune cells, including myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), regulatory T cells (Tregs) and other immune cells, mediates immune evasion and tumor progression [ 9 ]. (biomedcentral.com)
Antitumor1
  • We review the pro- and antitumor immune processes found in PDAC and briefly discuss their leverage for the development of novel therapeutic approaches in the field. (stanford.edu)
Correlates1
Mechanisms4
  • As my research is mainly focussed on looking at the underlying mechanisms during early stages of PDAC development, it might be beneficial in identifying patients with high-risk neoplastic precursor lesions. (ox.ac.uk)
  • Although, exact mechanisms of this neutrophil-PDAC interaction remain relatively unknown. (unmc.edu)
  • This finding indicates that targeting immune network signals is a promising strategy, but the immunoregulatory mechanisms in PDAC are more complex than expected and need more exploration. (biomedcentral.com)
  • Although studies have identified unique transcription factors in the selection of normal pancreatic lineages, the cells of origin and molecular mechanisms arbitrating PDAC growth are poorly defined. (amegroups.org)
Molecular4
  • Together, our work deciphered a comprehensive single-cell atlas of the macrophage compartment of PDAC and provided novel macrophage-tumor interaction features with potential value in developing targeted immunotherapies and molecular diagnostics for predicting patient outcome. (biomedcentral.com)
  • By profiling molecular spectrums of intracellular tumor-macrophage communication, we are able to design targeted molecular therapies to tackle PDAC. (biomedcentral.com)
  • However, PDAC is characterized by an abundant tumor stroma that includes a heterogeneous mixture of immune cells, fibroblasts, endothelial cells, neurons and some molecular events. (biomedcentral.com)
  • Given the lethality of PDAC, there is a need to identify new molecular targets for effective treatment. (uab.edu)
Metastasis2
  • It has been shown in previous research that neutrophils aid in PDAC progression and metastasis. (unmc.edu)
  • The specific objective of this project is to determine the role of tumor-associated neutrophils in PDAC progression and metastasis. (unmc.edu)
Fibrosis1
  • Compared to Ptf1acreERT/+KrasG12D/+ mice, APK mice exhibited a significant decrease in pancreatic and total body weight, did not progress through to PDAC, and showed altered pancreatic fibrosis and immune cell infiltration. (bepress.com)
Mice3
  • To target COX-2, 5-LOX, and EGFR simultaneously, we tested effects of licofelone (dual 5-LOX-COX inhibitor), and gefitinib (EGFR inhibitor), individually and in combination, on pancreatic intraepithelial neoplasms (PanINs) and their progression to PDAC using genetically engineered mice. (oncotarget.com)
  • Using data from The Cancer Genome Atlas we demonstrate that a subset of PDACs exhibits a strong pro-angiogenic signature that includes 37 genes, such as HDAC9, that are overexpressed in PDAC arising in KRC mice, which express mutated Kras and lack RB. (oncotarget.com)
  • Single agent VS-4718 dramatically limited tumor progression resulting in a doubling of survival in the p48-CRE/Kras G12D /p53 flox/+ PDAC mouse model (KPC mice). (biomedcentral.com)
Neoplasia1
  • This study successfully uncovers cell behaviors that promote the transition from ADM to neoplasia, offering novel avenues to inhibit PDAC progression. (uab.edu)
Fibroblast2
  • Specifically, elevated expression of HIF-1a and podoplanin predicted worse outcome while inflammatory gene expression correlated with increased survival, suggesting future interventions targeting proximal fibroblast populations to mitigate against PDAC. (elifesciences.org)
  • The procedure to derive iPSCs from human PDAC is principally the same as the procedure to generate iPSCs from normal human fibroblast. (elsevierpure.com)
Therapeutic2
  • Therefore, exploration of the interactions between the stroma and immune cells may offer new therapeutic opportunities for PDAC. (biomedcentral.com)
  • We also predict potential therapeutic strategies to target signals in the immune network in the abundant stromal microenvironment of PDAC. (biomedcentral.com)
Inhibition3
  • The combination drug treatment produced complete inhibition of PDAC in both genders. (oncotarget.com)
  • TGF-β is a known driver of immune evasion in PDAC, and TGF-β inhibition has been shown to enhance the response to ICIs in preclinical disease models. (medicaltrend.org)
  • Consequently, combined TGF-β and PD-1/PD-L1 inhibition is currently under clinical investigation in PDAC. (medicaltrend.org)
Patients10
  • Tumor tissues and adjacent normal pancreatic tissues were collected from 89 patients with PDAC. (jcancer.org)
  • Gu M , Sun J , Zhang S , Chen J , Wang G , Ju S , Wang X , . A novel methylation signature predicts inferior outcome of patients with PDAC. (aging-us.com)
  • This study evaluated the methylation array data of 184 patients with PDAC in The Cancer Genome Atlas database to explore methylation biomarkers related to patient outcome. (aging-us.com)
  • Owing to the deep anatomical location of the pancreas and the lack of specific markers of PDAC, most patients are diagnosed at the advanced tumor stage [ 3 , 4 ]. (aging-us.com)
  • Therefore, to improve the clinical outcome of PDAC, identifying novel biomarkers that can stratify the risk of patients and predict their survival time is valuable for guiding therapy for PDAC. (aging-us.com)
  • In this study, patients with PDAC were divided into high-risk and low-risk groups according to the risk index. (aging-us.com)
  • The establishment of a specific model that identifies high-risk patients is urgent for clinical management of PDAC. (aging-us.com)
  • The survival rate of PDAC patients is extremely low, with only 3% patients making it to 5-year survival period in the UK. (ox.ac.uk)
  • This model was recently validated by revealing a new biomarker that can classify early resectable PDAC patients from healthy subjects. (elsevierpure.com)
  • Data on Bintrafusp alfa in PDAC are limited, with a recent phase 1 trial (NCT02517398) including 5 PDAC patients among 19 heavily pretreated cancer patients. (medicaltrend.org)
Immunosuppressive3
  • The oral FAK kinase inhibitor VS-4718, currently in Phase I clinical evaluation, was tested to determine if it could overcome the immunosuppressive tumor microenvironment of PDAC. (biomedcentral.com)
  • PDAC exhibits an immunosuppressive microenvironment, the immune response predicts survival, and activation of immune system has the potential to produce an efficacious PDAC therapy. (biomedcentral.com)
  • The immunosuppressive TME of PDAC is characterized by T cell exhaustion resulting in the loss of cytotoxic effector functions. (biomedcentral.com)
Clinical1
  • The second part of the review discusses potential host-directed interventional strategies based on existing translational and clinical knowledge of infection-induced inflammation, as well as cancer initiation/progression models. (frontiersin.org)
Mutations1
  • The carcinogenesis and progression of PDAC is universally driven by "undruggable" mutations in oncogenes. (foxchase.org)
Chemotherapy1
  • Thus, the best available treatments against PDAC (that is, chemotherapy) are less effective under tumor-associated conditions. (nature.com)
Therapies1
  • The tumor microenvironment ( TME ), consisting of stroma, immune cells and extracellular matrix, is a key determinant of cancer initiation, progression and resistance to therapies. (wistar.org)
Survival rate1
KRAS1
  • When any of the genes KRAS, SMAD4 , TP53 , and BRCA2 are heavily mutated, they correlate with PDAC progression. (emerginginvestigators.org)
Desmoplastic1
  • However, the poorly immunogenic nature of PDAC is more likely due to the pronounced desmoplastic microenvironment. (biomedcentral.com)
Outcomes1
  • Primary outcomes are overall response rate (ORR) and progression-free survival (PFS). (medscape.com)