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1.
Cell ; 186(8): 1729-1754, 2023 04 13.
Article in English | MEDLINE | ID: mdl-37059070

ABSTRACT

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers. Significant efforts have largely defined major genetic factors driving PDAC pathogenesis and progression. Pancreatic tumors are characterized by a complex microenvironment that orchestrates metabolic alterations and supports a milieu of interactions among various cell types within this niche. In this review, we highlight the foundational studies that have driven our understanding of these processes. We further discuss the recent technological advances that continue to expand our understanding of PDAC complexity. We posit that the clinical translation of these research endeavors will enhance the currently dismal survival rate of this recalcitrant disease.


Subject(s)
Carcinoma, Pancreatic Ductal , Pancreatic Neoplasms , Humans , Carcinoma, Pancreatic Ductal/diagnosis , Carcinoma, Pancreatic Ductal/drug therapy , Carcinoma, Pancreatic Ductal/pathology , Carcinoma, Pancreatic Ductal/surgery , Pancreatic Neoplasms/diagnosis , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/surgery , Tumor Microenvironment , Early Diagnosis , Prognosis
2.
Immunity ; 55(2): 192-194, 2022 02 08.
Article in English | MEDLINE | ID: mdl-35139348

ABSTRACT

The microbiome affects establishment and growth of tumors as well as response to immune-based therapies. In this issue of Immunity, Hezaveh etĀ al. (2022) reveal that metabolites of dietary tryptophan generated by the gut microbiota activate the aryl hydrocarbon receptor in myeloid cells, promoting an immune suppressive tumor microenvironment and facilitating pancreatic ductal adenocarcinoma growth.


Subject(s)
Gastrointestinal Microbiome , Microbiota , Neoplasms , Gastrointestinal Microbiome/immunology , Humans , Receptors, Aryl Hydrocarbon/metabolism , Tryptophan/metabolism , Tumor Microenvironment
3.
Nature ; 618(7963): 151-158, 2023 Jun.
Article in English | MEDLINE | ID: mdl-37198494

ABSTRACT

Pancreatic ductal adenocarcinoma (PDA) is a lethal disease notoriously resistant to therapy1,2. This is mediated in part by a complex tumour microenvironment3, low vascularity4, and metabolic aberrations5,6. Although altered metabolism drives tumour progression, the spectrum of metabolites used as nutrients by PDA remains largely unknown. Here we identified uridine as a fuel for PDA in glucose-deprived conditions by assessing how more than 175 metabolites impacted metabolic activity in 21 pancreatic cell lines under nutrient restriction. Uridine utilization strongly correlated with the expression of uridine phosphorylase 1 (UPP1), which we demonstrate liberates uridine-derived ribose to fuel central carbon metabolism and thereby support redox balance, survival and proliferation in glucose-restricted PDA cells. In PDA, UPP1 is regulated by KRAS-MAPK signalling and is augmented by nutrient restriction. Consistently, tumours expressed high UPP1 compared with non-tumoural tissues, and UPP1 expression correlated with poor survival in cohorts of patients with PDA. Uridine is available in the tumour microenvironment, and we demonstrated that uridine-derived ribose is actively catabolized in tumours. Finally, UPP1 deletion restricted the ability of PDA cells to use uridine and blunted tumour growth in immunocompetent mouse models. Our data identify uridine utilization as an important compensatory metabolic process in nutrient-deprived PDA cells, suggesting a novel metabolic axis for PDA therapy.


Subject(s)
Glucose , Pancreatic Neoplasms , Ribose , Tumor Microenvironment , Uridine , Animals , Mice , Carcinoma, Pancreatic Ductal/metabolism , Carcinoma, Pancreatic Ductal/pathology , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/pathology , Ribose/metabolism , Uridine/chemistry , Glucose/deficiency , Cell Division , Cell Line, Tumor , MAP Kinase Signaling System , Uridine Phosphorylase/deficiency , Uridine Phosphorylase/genetics , Uridine Phosphorylase/metabolism , Humans
4.
PLoS Genet ; 18(7): e1010315, 2022 07.
Article in English | MEDLINE | ID: mdl-35867772

ABSTRACT

Proper Hedgehog (HH) signaling is essential for embryonic development, while aberrant HH signaling drives pediatric and adult cancers. HH signaling is frequently dysregulated in pancreatic cancer, yet its role remains controversial, with both tumor-promoting and tumor-restraining functions reported. Notably, the GLI family of HH transcription factors (GLI1, GLI2, GLI3), remain largely unexplored in pancreatic cancer. We therefore investigated the individual and combined contributions of GLI1-3 to pancreatic cancer progression. At pre-cancerous stages, fibroblast-specific Gli2/Gli3 deletion decreases immunosuppressive macrophage infiltration and promotes T cell infiltration. Strikingly, combined loss of Gli1/Gli2/Gli3 promotes macrophage infiltration, indicating that subtle changes in Gli expression differentially regulate immune infiltration. In invasive tumors, Gli2/Gli3 KO fibroblasts exclude immunosuppressive myeloid cells and suppress tumor growth by recruiting natural killer cells. Finally, we demonstrate that fibroblasts directly regulate macrophage and T cell migration through the expression of Gli-dependent cytokines. Thus, the coordinated activity of GLI1-3 directs the fibroinflammatory response throughout pancreatic cancer progression.


Subject(s)
Hedgehog Proteins , Pancreatic Neoplasms , Adult , Child , Female , Hedgehog Proteins/genetics , Hedgehog Proteins/metabolism , Humans , Kruppel-Like Transcription Factors/genetics , Kruppel-Like Transcription Factors/metabolism , Nerve Tissue Proteins/metabolism , Pancreatic Neoplasms/genetics , Pregnancy , Zinc Finger Protein GLI1/genetics , Zinc Finger Protein Gli2/genetics , Zinc Finger Protein Gli3/genetics
6.
Mol Ther ; 30(9): 2881-2890, 2022 09 07.
Article in English | MEDLINE | ID: mdl-35821636

ABSTRACT

Chimeric antigen receptor (CAR) TĀ cell therapy has created a paradigm shift in the treatment of hematologic malignancies but has not been as effective toward solid tumors. For such tumors, the primary obstacles facing CAR TĀ cells are scarcity of tumor-specific antigens and the hostile and complex tumor microenvironment. Glycosylation, the process by which sugars are post-translationally added to proteins or lipids, is profoundly dysregulated in cancer. Abnormally glycosylated glycoproteins expressed on cancer cells offer unique targets for CAR T therapy as they are specific to tumor cells. Tumor stromal cells also express abnormal glycoproteins and thus also have the potential to be targeted by glycan-binding CAR TĀ cells. This review will discuss the state of CAR TĀ cells in the therapy of solid tumors, the cancer glycoproteome and its potential for use as a therapeutic target, and the landscape and future of glycan-binding CAR TĀ cell therapy.


Subject(s)
Immunotherapy, Adoptive , Neoplasms , Glycoproteins , Humans , Polysaccharides , Receptors, Antigen, T-Cell/metabolism , Tumor Microenvironment
7.
Annu Rev Physiol ; 81: 211-233, 2019 02 10.
Article in English | MEDLINE | ID: mdl-30418798

ABSTRACT

Pancreatic cancer is characterized by an extensive fibroinflammatory reaction that includes immune cells, fibroblasts, extracellular matrix, vascular and lymphatic vessels, and nerves. Overwhelming evidence indicates that the pancreatic cancer microenvironment regulates cancer initiation, progression, and maintenance. Pancreatic cancer treatment has progressed little over the past several decades, and the prognosis remains one of the worst for any cancer. The contribution of the microenvironment to carcinogenesis is a key area of research, offering new potential targets for treating the disease. Here, we explore the composition of the pancreatic cancer stroma, discuss the network of interactions between different components, and describe recent attempts to target the stroma therapeutically. We also discuss current areas of active research related to the tumor microenvironment.


Subject(s)
Epithelial Cells/pathology , Pancreatic Neoplasms/pathology , Stromal Cells/pathology , Animals , Humans , Pancreas/pathology , Tumor Microenvironment/physiology
8.
Genes Dev ; 29(2): 171-83, 2015 Jan 15.
Article in English | MEDLINE | ID: mdl-25593307

ABSTRACT

The initiation of pancreatic ductal adenocarcinoma (PDA) is linked to activating mutations in KRAS. However, in PDA mouse models, expression of oncogenic mutant KRAS during development gives rise to tumors only after a prolonged latency or following induction of pancreatitis. Here we describe a novel mouse model expressing ataxia telangiectasia group D complementing gene (ATDC, also known as TRIM29 [tripartite motif 29]) that, in the presence of oncogenic KRAS, accelerates pancreatic intraepithelial neoplasia (PanIN) formation and the development of invasive and metastatic cancers. We found that ATDC up-regulates CD44 in mouse and human PanIN lesions via activation of Ɵ-catenin signaling, leading to the induction of an epithelial-to-mesenchymal transition (EMT) phenotype characterized by expression of Zeb1 and Snail1. We show that ATDC is up-regulated by oncogenic Kras in a subset of PanIN cells that are capable of invading the surrounding stroma. These results delineate a novel molecular pathway for EMT in pancreatic tumorigenesis, showing that ATDC is a proximal regulator of EMT.


Subject(s)
Carcinoma, Pancreatic Ductal/physiopathology , Pancreatic Neoplasms/physiopathology , Proto-Oncogene Proteins p21(ras)/metabolism , Transcription Factors/metabolism , Animals , Disease Models, Animal , Epithelial-Mesenchymal Transition/genetics , Gene Expression Regulation, Neoplastic , Homeodomain Proteins/genetics , Homeodomain Proteins/metabolism , Humans , Hyaluronan Receptors/metabolism , Kruppel-Like Transcription Factors/genetics , Kruppel-Like Transcription Factors/metabolism , Mice , Mice, Transgenic , Neoplasm Invasiveness/genetics , Pancreatic Neoplasms/enzymology , Promoter Regions, Genetic/genetics , Proto-Oncogene Proteins p21(ras)/genetics , Snail Family Transcription Factors , Transcription Factors/genetics , Zinc Finger E-box-Binding Homeobox 1 , beta Catenin/metabolism
9.
Gastroenterology ; 158(5): 1417-1432.e11, 2020 04.
Article in English | MEDLINE | ID: mdl-31843590

ABSTRACT

BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy that invades surrounding structures and metastasizes rapidly. Although inflammation is associated with tumor formation and progression, little is known about the mechanisms of this connection. We investigate the effects of interleukin (IL) 22 in the development of pancreatic tumors in mice. METHODS: We performed studies with Pdx1-Cre;LSL-KrasG12D;Trp53+/-;Rosa26EYFP/+ (PKCY) mice, which develop pancreatic tumors, and PKCY mice with disruption of IL22 (PKCY Il22-/-mice). Pancreata were collectedĀ at different stages of tumor development and analyzed by immunohistochemistry, immunoblotting, real-time polymerase chain reaction, and flow cytometry. Some mice were given cerulean to induce pancreatitis. Pancreatic cancer cell lines (PD2560) were orthotopically injected into C57BL/6 mice or Il22-/-mice, and tumor development was monitored. Pancreatic cells were injected into the tail veins of mice, and lung metastases were quantified. Acini were collected from C57BL/6 mice and resected human pancreata and were cultured. Cell lines and acini cultures were incubated with IL22 and pharmacologic inhibitors, and protein levels were knocked down with small hairpin RNAs. We performed immunohistochemical analyses of 26 PDACs and 5 nonneoplastic pancreas specimens. RESULTS: We observed increased expression of IL22 and the IL22 receptor (IL22R) in the pancreas compared with other tissues in mice; IL22 increased with pancreatitis and tumorigenesis. Flow cytometry indicated that the IL22 was produced primarily by T-helper 22 cells. PKCY Il22-/-mice did not develop precancerous lesions or pancreatic tumors. The addition of IL22 to cultured acinar cells increased their expression of markers of ductal metaplasia; these effects of IL22 were prevented with inhibitors of Janus kinase signaling to signal transducer and activator of transcription (STAT) (ruxolitinib) or mitogen-activated protein kinase kinase (MEK) (trametinib) and with STAT3 knockdown. Pancreatic cells injected into Il22-/- mice formed smaller tumors than those injected into C57BL/6. Incubation of IL22R-expressing PDAC cells with IL22 promoted spheroid formation and invasive activity, resulting in increased expression of stem-associated transcription factors (GATA4, SOX2, SOX17, and NANOG), and increased markers of the epithelial-mesenchymal transition (CDH1, SNAI2, TWIST1, and beta catenin); ruxolitinib blocked these effects. Human PDAC tissues had higher levels of IL22, phosphorylated STAT3, and markers of the epithelial-mesenchymal transition than nonneoplastic tissues. An increased level of STAT3 in IL22R-positive cells was associated with shorter survival times of patients. CONCLUSIONS: We found levels of IL22 to be increased during pancreatitis and pancreatic tumor development and to be required for tumor development and progression in mice. IL22 promotes acinar to ductal metaplasia, stem cell features, and increased expression of markers of the epithelial-mesenchymal transition; inhibitors of STAT3 block these effects. Increased expression of IL22 by PDACs is associated with reduced survival times.


Subject(s)
Acinar Cells/pathology , Carcinoma, Pancreatic Ductal/immunology , Cell Transformation, Neoplastic/immunology , Interleukins/metabolism , Pancreatic Neoplasms/immunology , STAT3 Transcription Factor/metabolism , Signal Transduction/immunology , Acinar Cells/immunology , Animals , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/mortality , Carcinoma, Pancreatic Ductal/pathology , Cell Line, Tumor/transplantation , Cell Plasticity/drug effects , Cell Plasticity/immunology , Cell Transformation, Neoplastic/drug effects , Disease Models, Animal , Epithelial-Mesenchymal Transition/drug effects , Epithelial-Mesenchymal Transition/immunology , Female , HEK293 Cells , Humans , Interleukins/immunology , Janus Kinases/antagonists & inhibitors , Janus Kinases/metabolism , Male , Metaplasia/immunology , Metaplasia/pathology , Mice , Mice, Knockout , Nitriles , Pancreas/cytology , Pancreas/immunology , Pancreas/pathology , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/mortality , Pancreatic Neoplasms/pathology , Pancreatitis/immunology , Pancreatitis/pathology , Pyrazoles/pharmacology , Pyridones/pharmacology , Pyrimidines , Pyrimidinones/pharmacology , RNA, Small Interfering/metabolism , Receptors, Interleukin/metabolism , STAT3 Transcription Factor/antagonists & inhibitors , Signal Transduction/drug effects , Survival Analysis , Interleukin-22
10.
Am J Pathol ; 190(8): 1735-1751, 2020 08.
Article in English | MEDLINE | ID: mdl-32339496

ABSTRACT

Pancreatic ductal adenocarcinoma (PDA) and chronic pancreatitis are characterized by a dense collagen-rich desmoplastic reaction. Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase activated by collagens that can regulate cell proliferation, migration, adhesion, and remodeling of the extracellular matrix. To address the role of DDR1 in PDA, Ddr1-null (Ddr-/-) mice were crossed with the KrasG12D/+; Trp53R172H/+; Ptf1aCre/+ (KPC) model of metastatic PDA. Ddr1-/-; KPC mice progress to differentiated PDA but resist progression to poorly differentiated cancer compared with KPC control mice. Strikingly, severe pancreatic atrophy accompanied tumor progression in Ddr1-/-; KPC mice. To further explore the effects of Ddr1 ablation, Ddr1-/- mice were crossed with the KrasG12D/+; Ptf1aCre/+ neoplasia model and subjected to cerulein-induced experimental pancreatitis. Similar to KPC mice, tissue atrophy was a hallmark of both neoplasia and pancreatitis models in the absence of Ddr1. Compared with controls, Ddr1-/- models had increased acinar cell dropout and reduced proliferation with no difference in apoptotic cell death between control and Ddr1-/- animals. In most models, organ atrophy was accompanied by increased fibrillar collagen deposition, suggesting a compensatory response in the absence of this collagen receptor. Overall, these data suggest that DDR1 regulates tissue homeostasis in the neoplastic and injured pancreas.


Subject(s)
Acinar Cells/pathology , Carcinoma, Pancreatic Ductal/genetics , Discoidin Domain Receptor 1/genetics , Pancreatic Neoplasms/genetics , Acinar Cells/metabolism , Animals , Carcinoma, Pancreatic Ductal/metabolism , Carcinoma, Pancreatic Ductal/pathology , Cell Line, Tumor , Cell Proliferation/physiology , Discoidin Domain Receptor 1/metabolism , Disease Progression , Homeostasis/physiology , Humans , Mice , Mice, Knockout , Pancreas/metabolism , Pancreas/pathology , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/pathology , Signal Transduction/physiology
11.
Gastroenterology ; 156(7): 2073-2084, 2019 05.
Article in English | MEDLINE | ID: mdl-30716326

ABSTRACT

Pancreatic ductal adenocarcinoma is one of the deadliest cancers, and its incidence on the rise. The major challenges in overcoming the poor prognosis with this disease include late detection and the aggressive biology of the disease. Intratumoral heterogeneity; presence of a robust, reactive, and desmoplastic stroma; and the crosstalk between the different tumor components require complete understanding of the pancreatic tumor biology to better understand the therapeutic challenges posed by this disease. In this review, we discuss the processes involved during tumorigenesis encompassing the inherent plasticity of the transformed cells, development of tumor stroma crosstalk, and enrichment of cancer stem cell population during tumorigenesis.


Subject(s)
Biomarkers, Tumor/metabolism , Carcinoma, Pancreatic Ductal/metabolism , Cell Plasticity , Cell Transformation, Neoplastic/metabolism , Pancreatic Neoplasms/metabolism , Animals , Biomarkers, Tumor/genetics , Cancer-Associated Fibroblasts/metabolism , Cancer-Associated Fibroblasts/pathology , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/secondary , Carcinoma, Pancreatic Ductal/therapy , Cell Communication , Cell Movement , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/pathology , Humans , Inflammation Mediators/metabolism , Mutation , Neoplasm Invasiveness , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/pathology , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/therapy , Phenotype , Signal Transduction , Tumor Microenvironment
12.
Am J Physiol Gastrointest Liver Physiol ; 315(1): G27-G35, 2018 07 01.
Article in English | MEDLINE | ID: mdl-29543507

ABSTRACT

In the event of an injury, normal tissues exit quiescent homeostasis and rapidly engage a complex stromal and immune program. These tissue repair responses are hijacked and become dysregulated in carcinogenesis to form a growth-supportive tumor microenvironment. In pancreatic ductal adenocarcinoma (PDA), which remains one of the deadliest major cancers, the microenvironment is a key driver of tumor maintenance that impedes many avenues of therapy. In this review, we outline recent efforts made to uncover the microenvironmental cross-talk mechanisms that support pancreatic cancer cells, and we detail the strategies that have been undertaken to help overcome these barriers.


Subject(s)
Pancreatic Neoplasms , Carcinogenesis/immunology , Humans , Pancreatic Neoplasms/immunology , Pancreatic Neoplasms/pathology , Tumor Escape , Tumor Microenvironment/immunology
13.
Immunity ; 30(4): 508-20, 2009 Apr 17.
Article in English | MEDLINE | ID: mdl-19345119

ABSTRACT

Pax5 is an essential regulator of B cell identity and function. Here, we used transgenesis and deletion mapping to identify a potent enhancer in intron 5 of the Pax5 locus. This enhancer in combination with the promoter region was sufficient to recapitulate the B lymphoid expression of Pax5. The enhancer was silenced by DNA methylation in embryonic stem cells, but became activated in multipotent hematopoietic progenitors. It contained functional binding sites for the transcription factors PU.1, IRF4, IRF8, and NF-kappaB, suggesting that these regulators contribute to sequential enhancer activation in hematopoietic progenitors and during B cell development. In contrast, the promoter region was repressed by Polycomb group proteins in non-B cells and was activated only at the onset of pro-B cell development through induction of chromatin remodeling by the transcription factor EBF1. These experiments demonstrate a stepwise activation of Pax5 in early lymphopoiesis and provide mechanistic insights into the process of B cell commitment.


Subject(s)
B-Lymphocytes/immunology , Enhancer Elements, Genetic , Gene Expression Regulation , Lymphopoiesis/physiology , PAX5 Transcription Factor , Promoter Regions, Genetic , Transgenes/genetics , Animals , B-Lymphocytes/cytology , Base Sequence , Chromosomes, Artificial, Bacterial/genetics , Flow Cytometry , Humans , Mice , Molecular Sequence Data , PAX5 Transcription Factor/genetics , PAX5 Transcription Factor/metabolism , Trans-Activators/genetics , Up-Regulation
14.
Gut ; 66(1): 124-136, 2017 01.
Article in English | MEDLINE | ID: mdl-27402485

ABSTRACT

BACKGROUND: Pancreatic cancer is characterised by the accumulation of a fibro-inflammatory stroma. Within this stromal reaction, myeloid cells are a predominant population. Distinct myeloid subsets have been correlated with tumour promotion and unmasking of anti-tumour immunity. OBJECTIVE: The goal of this study was to determine the effect of myeloid cell depletion on the onset and progression of pancreatic cancer and to understand the relationship between myeloid cells and T cell-mediated immunity within the pancreatic cancer microenvironment. METHODS: Primary mouse pancreatic cancer cells were transplanted into CD11b-diphtheria toxin receptor (DTR) mice. Alternatively, the iKras* mouse model of pancreatic cancer was crossed into CD11b-DTR mice. CD11b+ cells (mostly myeloid cell population) were depleted by diphtheria toxin treatment during tumour initiation or in established tumours. RESULTS: Depletion of myeloid cells prevented KrasG12D-driven pancreatic cancer initiation. In pre-established tumours, myeloid cell depletion arrested tumour growth and in some cases, induced tumour regressions that were dependent on CD8+ T cells. We found that myeloid cells inhibited CD8+ T-cell anti-tumour activity by inducing the expression of programmed cell death-ligand 1 (PD-L1) in tumour cells in an epidermal growth factor receptor (EGFR)/mitogen-activated protein kinases (MAPK)-dependent manner. CONCLUSION: Our results show that myeloid cells support immune evasion in pancreatic cancer through EGFR/MAPK-dependent regulation of PD-L1 expression on tumour cells. Derailing this crosstalk between myeloid cells and tumour cells is sufficient to restore anti-tumour immunity mediated by CD8+ T cells, a finding with implications for the design of immune therapies for pancreatic cancer.


Subject(s)
B7-H1 Antigen/metabolism , CD8-Positive T-Lymphocytes/immunology , Carcinoma, Pancreatic Ductal/immunology , Myeloid Cells/immunology , Pancreatic Neoplasms/immunology , Programmed Cell Death 1 Receptor/metabolism , Tumor Microenvironment/immunology , Animals , CD11b Antigen/analysis , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/metabolism , Carcinoma, Pancreatic Ductal/pathology , Cell Cycle Checkpoints , Cell Line, Tumor , Cell Transformation, Neoplastic/immunology , Cell Transformation, Neoplastic/metabolism , ErbB Receptors/metabolism , Humans , Immune Tolerance , Immunity, Cellular , Lymphocyte Activation , Lymphocytes, Tumor-Infiltrating , MAP Kinase Signaling System , Mice , Mitogen-Activated Protein Kinases/metabolism , Myeloid Cells/chemistry , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/pathology , Proto-Oncogene Proteins p21(ras)/genetics , Tumor Escape
15.
Carcinogenesis ; 36(7): 730-8, 2015 Jul.
Article in English | MEDLINE | ID: mdl-25939753

ABSTRACT

Epigenetic dysregulation is involved in the initiation and progression of many epithelial cancers. BMI1, a component of the polycomb protein family, plays a key role in these processes by controlling the histone ubiquitination and long-term repression of multiple genomic loci. BMI1 has previously been implicated in pancreatic homeostasis and the function of pancreatic cancer stem cells. However, no work has yet addressed its role in the early stages of pancreatic cancer development. Here, we show that BMI1 is required for the initiation of murine pancreatic neoplasia using a novel conditional knockout of Bmi1 in combination with a Kras(G12D)-driven pancreatic cancer mouse model. We also demonstrate that the requirement for Bmi1 in pancreatic carcinogenesis is independent of the Ink4a/Arf locus and at least partially mediated by dysregulation of reactive oxygen species. Our data provide new evidence of the importance of this epigenetic regulator in the genesis of pancreatic cancer.


Subject(s)
Cyclin-Dependent Kinase Inhibitor p16/metabolism , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/pathology , Polycomb Repressive Complex 1/metabolism , Proto-Oncogene Proteins/metabolism , Animals , Cell Transformation, Neoplastic/genetics , Cyclin-Dependent Kinase Inhibitor p16/genetics , Mice, Knockout , Mice, Mutant Strains , Mice, Transgenic , Neoplasms, Experimental/genetics , Neoplasms, Experimental/pathology , Pancreas/metabolism , Pancreas/pathology , Pancreatic Neoplasms/genetics , Polycomb Repressive Complex 1/genetics , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins p21(ras)/genetics , Reactive Oxygen Species/metabolism
16.
Gastroenterology ; 146(3): 822-834.e7, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24315826

ABSTRACT

BACKGROUND & AIMS: Kras signaling via mitogen-activated protein kinase (MAPK) is highly up-regulated in pancreatic cancer cells. We investigated whether MAPK signaling is required for the initiation and maintenance of pancreatic carcinogenesis in mice. METHODS: We studied the formation and maintenance of pancreatic intraepithelial neoplasia (PanINs) in p48Cre; TetO-KrasG12D; Rosa26(rtTa-IRES-EGFP) (iKras*) mice and LSL-KrasG12D mice bred with p48Cre mice (KC). Mice were given oral PD325901, a small-molecule inhibitor of MEK1 and MEK2 (factors in the MAPK signaling pathway), along with injections of cerulein to induce pancreatitis. Other mice were given PD325901 only after PanINs developed. Pancreatic tissues were collected and evaluated using histologic, immunohistochemical, immunofluorescence, and electron microscopy analyses. Acinar cells were isolated from the tissues and the effects of MEK1 and 2 inhibitors were assessed. RESULTS: PD325901 prevented PanIN formation, but not pancreatitis, in iKras* and KC mice. In iKras* or KC mice given PD325901 at 5 weeks after PanINs developed, PanINs regressed and acinar tissue regenerated. The regression occurred through differentiation of the PanIN cells to acini, accompanied by re-expression of the acinar transcription factor Mist1. CONCLUSIONS: In iKras* and KC mice, MAPK signaling is required for the initiation and maintenance of pancreatic cancer precursor lesions. MAPK signaling promotes formation of PanINs by enabling dedifferentiation of acinar cells into duct-like cells that are susceptible to transformation.


Subject(s)
Acinar Cells/pathology , Carcinoma in Situ/physiopathology , Cell Dedifferentiation/physiology , Mitogen-Activated Protein Kinase Kinases/physiology , Pancreatic Neoplasms/physiopathology , Signal Transduction/physiology , Acinar Cells/physiology , Animals , Carcinoma in Situ/pathology , Disease Models, Animal , Female , MAP Kinase Kinase 1/physiology , MAP Kinase Kinase 2/physiology , MAP Kinase Signaling System/physiology , Male , Mice , Mice, Mutant Strains , Pancreatic Neoplasms/pathology , Pancreatitis/physiopathology , Up-Regulation/physiology
17.
J Biol Chem ; 288(17): 11786-94, 2013 Apr 26.
Article in English | MEDLINE | ID: mdl-23482563

ABSTRACT

Although the biological role of KRAS is clearly established in carcinogenesis, the molecular mechanisms underlying this phenomenon are not completely understood. In this study, we provide evidence of a novel signaling network regulated by the transcription factor GLI1 mediating KRAS-induced carcinogenesis. Using pancreatic cancer (a disease with high prevalence of KRAS mutations) as a model, we show that loss of GLI1 blocks the progression of KRAS-induced pancreatic preneoplastic lesions in mice with pancreas-specific Cre-activated oncogenic mutant kras. Mice lacking GLI1 develop only low-grade lesions at low frequency, and in most cases, the pancreata are histologically normal. Further characterization of the phenotype showed a decrease in the activation of STAT3 in pancreatic preneoplastic lesions; STAT3 is a transcription factor required for the development of premalignant lesions and their progression into pancreatic cancer. Analysis of the mechanisms revealed a key role for GLI1 in maintaining the levels of activated STAT3 through the modulation of IL-6 signaling. GLI1 binds to the IL-6 mouse promoter and regulates the activity and expression of this cytokine. This newly identified GLI1/IL-6 axis is active in fibroblasts, a known source of IL-6 in the tumor microenvironment. Sonic hedgehog induces GLI1 binding to the IL-6 promoter and increases IL-6 expression in fibroblasts in a paracrine manner. Finally, we demonstrate that mutant KRAS initiates this cascade by inducing the expression of Sonic hedgehog in cancer cells. Collectively, these results define a novel role for GLI1 in carcinogenesis acting as a downstream effector of oncogenic KRAS in the tumor microenvironment.


Subject(s)
Cell Transformation, Neoplastic/metabolism , Gene Expression Regulation, Neoplastic , Kruppel-Like Transcription Factors/metabolism , Pancreatic Neoplasms/metabolism , Proto-Oncogene Proteins p21(ras)/biosynthesis , Tumor Microenvironment , Animals , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/pathology , Fibroblasts/metabolism , Fibroblasts/pathology , Hedgehog Proteins/genetics , Hedgehog Proteins/metabolism , Interleukin-6/biosynthesis , Interleukin-6/genetics , Kruppel-Like Transcription Factors/genetics , Mice , Mice, Knockout , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/pathology , Proto-Oncogene Proteins p21(ras)/genetics , STAT3 Transcription Factor/genetics , STAT3 Transcription Factor/metabolism , Zinc Finger Protein GLI1
18.
BMC Cancer ; 14: 862, 2014 Nov 22.
Article in English | MEDLINE | ID: mdl-25416148

ABSTRACT

BACKGROUND: Pancreatic cancer is one of the deadliest human malignancies, with few therapeutic options. Re-activation of embryonic signaling pathways is commonly in human pancreatic cancer and provided rationale to explore inhibition of these pathways therapeutically. Notch signaling is important during pancreatic development, and it is re-activated in pancreatic cancer. The functional role of Notch signaling during pancreatic carcinogenesis has been previously characterized using both genetic and drug-based approaches. However, contrasting findings were reported based on the study design. In fact, Notch signaling has been proposed to act as tumor-promoter or tumor-suppressor. Given the availability of Notch inhibitors in the clinic, understanding how this signaling pathway contributes to pancreatic carcinogenesis has important therapeutic implications. Here, we interrogated the role of Notch signaling specifically in the epithelial compartment of the pancreas, in the context of a genetically engineered mouse model of pancreatic cancer. METHODS: To inhibit Notch signaling in the pancreas epithelium, we crossed a mouse model of pancreatic cancer based on pancreas-specific expression of mutant Kras with a transgenic mouse that conditionally expresses a dominant negative form of the Mastermind-like 1 gene. MAML is an essential co-activator of the canonical Notch signaling-mediated transcription. DNMAML encodes a truncated MAML protein that represses all canonical Notch mediated transcription in a cell autonomous manner, independent of which Notch receptor is activated. As a result, in mice co-expressing mutant Kras and DNMAML, Notch signaling is inhibited specifically in the epithelium upon Cre-mediated recombination. We explored the effect of epithelial-specific DNMAML expression on Kras-driven carcinogenesis both during normal aging and following the induction of acute pancreatitis. RESULTS: We find that DNMAML expression efficiently inhibits epithelial Notch signaling and delays PanIN formation. However, over time, loss of Notch inhibition allows PanIN formation and progression. CONCLUSIONS: Epithelial-specific Notch signaling is important for PanIN initiation. Our findings indicate that PanIN formation can only occur upon loss of epithelial Notch inhibition, thus supporting an essential role of this signaling pathway during pancreatic carcinogenesis.


Subject(s)
Pancreatic Neoplasms/metabolism , Receptors, Notch/metabolism , Signal Transduction/physiology , Animals , Epithelium/chemistry , Epithelium/metabolism , Female , Male , Mice , Mice, Transgenic , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Pancreas/chemistry , Pancreas/metabolism , Pancreatic Neoplasms/genetics , Pancreatitis , Receptors, Notch/genetics , Signal Transduction/genetics , Transcription Factors/genetics , Transcription Factors/metabolism
19.
Cancer Res ; 84(18): 2944-2946, 2024 Sep 16.
Article in English | MEDLINE | ID: mdl-39279377

ABSTRACT

Published in Cancer Research in 2007, Clark and colleagues first introduced the concept that the immune microenvironment evolves in lockstep with the progression of pancreatic cancer. Leveraging genetically engineered mouse models of the disease that were described a few years earlier, Clark and colleagues used a combination of approaches to describe the dynamics of immune evolution in precursor lesions all the way to overt malignancy. They discovered that immunosuppression is established at the earliest stages of carcinogenesis. Here, we discuss their findings, how they led to a wealth of functional work, and how they have been expanded upon since the advent of -omics technologies. See related article by Clark and colleagues, Cancer Res 2007;67:9518-27.


Subject(s)
Pancreatic Neoplasms , Tumor Microenvironment , Pancreatic Neoplasms/immunology , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/genetics , Tumor Microenvironment/immunology , Animals , Humans , Mice , Immune Tolerance , Disease Progression
20.
Cancer Immunol Res ; 12(9): 1130-1131, 2024 Sep 03.
Article in English | MEDLINE | ID: mdl-38990149

ABSTRACT

IL17 signaling promotes pancreatic cancer development, yet the cell compartment responsible for the protumorigenic function of IL17 has not been defined. In this article, Castro-Pando and colleagues demonstrate that IL17/IL17 receptor A signaling in the pancreatic epithelium is critical for pancreatic cancer initiation and for establishing immunosuppression, whereas its signaling in the immune compartment is dispensable. This work provides an important mechanistic insight on the role of IL17 signaling and identifies a potential new immune checkpoint as a target in pancreatic cancer. See related article by Castro-Pando et al., p. 1170.


Subject(s)
Interleukin-17 , Pancreatic Neoplasms , Signal Transduction , Humans , Interleukin-17/metabolism , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/immunology , Animals , Carcinogenesis/metabolism , Epithelium/metabolism , Epithelium/immunology , Receptors, Interleukin-17/metabolism , Pancreas/metabolism , Pancreas/pathology , Pancreas/immunology , Mice
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