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Pancreatic Neoplasms: HELP
Articles by Christopher J. Halbrook
Based on 14 articles published since 2010
(Why 14 articles?)
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Between 2010 and 2020, C. Halbrook wrote the following 14 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Review Metabolism and epigenetics of pancreatic cancer stem cells. 2019

Perusina Lanfranca, M / Thompson, J K / Bednar, F / Halbrook, C / Lyssiotis, C / Levi, B / Frankel, T L. ·Department of Surgery, University of Michigan, Ann Arbor, MI, United States. · Department of Surgery, University of Michigan, Ann Arbor, MI, United States; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, United States. · Rogel Cancer Center, University of Michigan, Ann Arbor, MI, United States; Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, United States. · Department of Surgery, University of Michigan, Ann Arbor, MI, United States; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, United States. Electronic address: timofran@med.umich.edu. ·Semin Cancer Biol · Pubmed #30273655.

ABSTRACT: Pancreatic Cancer (PDA) is an aggressive malignancy characterized by early spread and a high mortality. Current studies suggest that a subpopulation of cells exist within tumors, cancer stem cell (CSC), which are capable of self-renewal and give rise to unique progeny which form the major neoplastic cellular component of tumors. While CSCs constitute a small cellular subpopulation within the tumor, their resistance to chemotherapy and radiation make them an important therapeutic target for eradication. Along with distinctive phenotypic properties, CSCs possess a unique metabolic plasticity allowing them to rapidly respond and adapt to environmental changes. These cells and their progeny also display a significantly altered epigenetic state with distinctive patterns of DNA methylation. Several mechanisms of cross-talk between epigenetic and metabolic pathways in PDA exist which ultimately contribute to the observed cellular plasticity and enhanced tumorigenesis. In this review we discuss various examples of this metabolic-epigenetic interplay and how it may constitute a new avenue for therapy specifically targeting CSCs in PDA.

2 Review Tumor cross-talk networks promote growth and support immune evasion in pancreatic cancer. 2018

Halbrook, Christopher J / Pasca di Magliano, Marina / Lyssiotis, Costas A. ·Department of Molecular and Integrative Physiology, University of Michigan , Ann Arbor, Michigan. · Department of Surgery, University of Michigan , Ann Arbor, Michigan. · Comprehensive Cancer Center, University of Michigan , Ann Arbor, Michigan. · Department of Internal Medicine, Division of Gastroenterology, University of Michigan , Ann Arbor, Michigan. ·Am J Physiol Gastrointest Liver Physiol · Pubmed #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.

3 Review Employing Metabolism to Improve the Diagnosis and Treatment of Pancreatic Cancer. 2017

Halbrook, Christopher J / Lyssiotis, Costas A. ·Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA. · Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: clyssiot@med.umich.edu. ·Cancer Cell · Pubmed #28073003.

ABSTRACT: Pancreatic ductal adenocarcinoma is on pace to become the second leading cause of cancer-related death. The high mortality rate results from a lack of methods for early detection and the inability to successfully treat patients once diagnosed. Pancreatic cancer cells have extensively reprogrammed metabolism, which is driven by oncogene-mediated cell-autonomous pathways, the unique physiology of the tumor microenvironment, and interactions with non-cancer cells. In this review, we discuss how recent efforts delineating rewired metabolic networks in pancreatic cancer have revealed new in-roads to develop detection and treatment strategies for this dreadful disease.

4 Article Tissue of origin dictates GOT1 dependence and confers synthetic lethality to radiotherapy. 2020

Nelson, Barbara S / Lin, Lin / Kremer, Daniel M / Sousa, Cristovão M / Cotta-Ramusino, Cecilia / Myers, Amy / Ramos, Johanna / Gao, Tina / Kovalenko, Ilya / Wilder-Romans, Kari / Dresser, Joseph / Davis, Mary / Lee, Ho-Joon / Nwosu, Zeribe C / Campit, Scott / Mashadova, Oksana / Nicolay, Brandon N / Tolstyka, Zachary P / Halbrook, Christopher J / Chandrasekaran, Sriram / Asara, John M / Crawford, Howard C / Cantley, Lewis C / Kimmelman, Alec C / Wahl, Daniel R / Lyssiotis, Costas A. ·1Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109 USA. · 0000000086837370 · grid.214458.e · 2Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215 USA. · 000000041936754X · grid.38142.3c · 3Experimental Therapeutics Core and Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215 USA. · 4Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI 48109 USA. · 5Department of Biomedical Engineering, University of Michigan Medical School, Ann Arbor, MI 48109 USA. · 6Meyer Cancer Center, Weill Cornell Medicine, New York City, NY 10065 USA. · 000000041936877X · grid.5386.8 · 7Agios Pharmaceuticals, Inc., Cambridge, MA 02139 USA. · grid.427815.d · 8Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115 USA. · 0000 0000 9011 8547 · grid.239395.7 · 9Center for Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI 48109 USA. · 10Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109 USA. · 11Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan Medical School, Ann Arbor, MI 48109 USA. · 12Department of Radiation Oncology, Perlmutter Cancer Center, NYU Langone Medical Center, New York, NY 10016 USA. · 0000 0001 2109 4251 · grid.240324.3 ·Cancer Metab · Pubmed #31908776.

ABSTRACT: Background: Metabolic programs in cancer cells are influenced by genotype and the tissue of origin. We have previously shown that central carbon metabolism is rewired in pancreatic ductal adenocarcinoma (PDA) to support proliferation through a glutamate oxaloacetate transaminase 1 (GOT1)-dependent pathway. Methods: We utilized a doxycycline-inducible shRNA-mediated strategy to knockdown GOT1 in PDA and colorectal cancer (CRC) cell lines and tumor models of similar genotype. These cells were analyzed for the ability to form colonies and tumors to test if tissue type impacted GOT1 dependence. Additionally, the ability of GOT1 to impact the response to chemo- and radiotherapy was assessed. Mechanistically, the associated specimens were examined using a combination of steady-state and stable isotope tracing metabolomics strategies and computational modeling. Statistics were calculated using GraphPad Prism 7. One-way ANOVA was performed for experiments comparing multiple groups with one changing variable. Student's Results: While PDA exhibits profound growth inhibition upon GOT1 knockdown, we found CRC to be insensitive. In PDA, but not CRC, GOT1 inhibition disrupted glycolysis, nucleotide metabolism, and redox homeostasis. These insights were leveraged in PDA, where we demonstrate that radiotherapy potently enhanced the effect of GOT1 inhibition on tumor growth. Conclusions: Taken together, these results illustrate the role of tissue type in dictating metabolic dependencies and provide new insights for targeting metabolism to treat PDA.

5 Article Hiding in plain sight. 2019

Halbrook, Christopher J / Crawford, Howard C. ·Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA. · Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA. howcraw@med.umich.edu. · Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA. · The Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA. ·Science · Pubmed #31221844.

ABSTRACT: -- No abstract --

6 Article ATDC is required for the initiation of KRAS-induced pancreatic tumorigenesis. 2019

Wang, Lidong / Yang, Huibin / Zamperone, Andrea / Diolaiti, Daniel / Palmbos, Phillip L / Abel, Ethan V / Purohit, Vinee / Dolgalev, Igor / Rhim, Andrew D / Ljungman, Mats / Hadju, Christina H / Halbrook, Christopher J / Bar-Sagi, Dafna / di Magliano, Marina Pasca / Crawford, Howard C / Simeone, Diane M. ·Department of Surgery, New York University School of Medicine, New York, New York 10016, USA. · Perlmutter Cancer Center, NYU Langone Medical Center, New York University, New York, New York 10016, USA. · Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan 48109, USA. · Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA. · Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA. · Department of Gastroenterology, Hepatology, and Nutrition, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. · Department of Pathology, New York University School of Medicine, New York, New York 10016, USA. · Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York 10016, USA. · Department of Medicine, New York University School of Medicine, New York, New York 10016, USA. · Department of Surgery, University of Michigan, Ann Arbor, Michigan 48109, USA. · Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109, USA. ·Genes Dev · Pubmed #31048544.

ABSTRACT: Pancreatic adenocarcinoma (PDA) is an aggressive disease driven by oncogenic KRAS and characterized by late diagnosis and therapeutic resistance. Here we show that deletion of the ataxia-telangiectasia group D-complementing (

7 Article Macrophage-Released Pyrimidines Inhibit Gemcitabine Therapy in Pancreatic Cancer. 2019

Halbrook, Christopher J / Pontious, Corbin / Kovalenko, Ilya / Lapienyte, Laura / Dreyer, Stephan / Lee, Ho-Joon / Thurston, Galloway / Zhang, Yaqing / Lazarus, Jenny / Sajjakulnukit, Peter / Hong, Hanna S / Kremer, Daniel M / Nelson, Barbara S / Kemp, Samantha / Zhang, Li / Chang, David / Biankin, Andrew / Shi, Jiaqi / Frankel, Timothy L / Crawford, Howard C / Morton, Jennifer P / Pasca di Magliano, Marina / Lyssiotis, Costas A. ·Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA. · Cancer Research UK, Beatson Institute, Glasgow G61 1BD, UK. · West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow G61 1QH, UK; Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK. · Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA; University of Michigan Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA. · Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA. · Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA. · University of Michigan Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA; Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA. · Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA; University of Michigan Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA; Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI 48109, USA. · Cancer Research UK, Beatson Institute, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK. · Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA; University of Michigan Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA; Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: clyssiot@med.umich.edu. ·Cell Metab · Pubmed #30827862.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) is characterized by abundant infiltration of tumor-associated macrophages (TAMs). TAMs have been reported to drive resistance to gemcitabine, a frontline chemotherapy in PDA, though the mechanism of this resistance remains unclear. Profiling metabolite exchange, we demonstrate that macrophages programmed by PDA cells release a spectrum of pyrimidine species. These include deoxycytidine, which inhibits gemcitabine through molecular competition at the level of drug uptake and metabolism. Accordingly, genetic or pharmacological depletion of TAMs in murine models of PDA sensitizes these tumors to gemcitabine. Consistent with this, patients with low macrophage burden demonstrate superior response to gemcitabine treatment. Together, these findings provide insights into the role of macrophages in pancreatic cancer therapy and have potential to inform the design of future treatments. Additionally, we report that pyrimidine release is a general function of alternatively activated macrophage cells, suggesting an unknown physiological role of pyrimidine exchange by immune cells.

8 Article Metabolism Drives Carcinogenesis and Maintenance of Pancreatic Tumors. 2019

Halbrook, Christopher J / Nelson, Barbara S / Lysstiotis, Costas A. ·Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan. · Cancer Biology Graduate Program, University of Michigan, Ann Arbor, Michigan. · Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan. clyssiot@med.umich.edu. · Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan. · Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan. ·Cancer Discov · Pubmed #30824487.

ABSTRACT: In this issue of

9 Article Mutant p53R270H drives altered metabolism and increased invasion in pancreatic ductal adenocarcinoma. 2018

Schofield, Heather K / Zeller, Jörg / Espinoza, Carlos / Halbrook, Christopher J / Del Vecchio, Annachiara / Magnuson, Brian / Fabo, Tania / Daylan, Ayse Ece Cali / Kovalenko, Ilya / Lee, Ho-Joon / Yan, Wei / Feng, Ying / Karim, Saadia A / Kremer, Daniel M / Kumar-Sinha, Chandan / Lyssiotis, Costas A / Ljungman, Mats / Morton, Jennifer P / Galbán, Stefanie / Fearon, Eric R / Pasca di Magliano, Marina. ·Department of Surgery. · Program in Cellular and Molecular Biology. · Medical Scientist Training Program. · Department of Internal Medicine. · Center for Molecular Imaging. · Department of Radiology. · Department of Molecular and Integrative Physiology, and. · Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, Michigan, USA. · Harvard University, Cambridge, Massachusetts, USA. · Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom. · Cancer Research UK Beatson Institute, Glasgow, United Kingdom. · Department of Pathology. · Comprehensive Cancer Center. · Department of Radiation Oncology. · Department of Environmental Health Sciences. · Department of Human Genetics, and. · Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA. ·JCI Insight · Pubmed #29367463.

ABSTRACT: Pancreatic cancer is characterized by nearly universal activating mutations in KRAS. Among other somatic mutations, TP53 is mutated in more than 75% of human pancreatic tumors. Genetically engineered mice have proven instrumental in studies of the contribution of individual genes to carcinogenesis. Oncogenic Kras mutations occur early during pancreatic carcinogenesis and are considered an initiating event. In contrast, mutations in p53 occur later during tumor progression. In our model, we recapitulated the order of mutations of the human disease, with p53 mutation following expression of oncogenic Kras. Further, using an inducible and reversible expression allele for mutant p53, we inactivated its expression at different stages of carcinogenesis. Notably, the function of mutant p53 changes at different stages of carcinogenesis. Our work establishes a requirement for mutant p53 for the formation and maintenance of pancreatic cancer precursor lesions. In tumors, mutant p53 becomes dispensable for growth. However, it maintains the altered metabolism that characterizes pancreatic cancer and mediates its malignant potential. Further, mutant p53 promotes epithelial-mesenchymal transition (EMT) and cancer cell invasion. This work generates new mouse models that mimic human pancreatic cancer and expands our understanding of the role of p53 mutation, common in the majority of human malignancies.

10 Article PDX1 dynamically regulates pancreatic ductal adenocarcinoma initiation and maintenance. 2016

Roy, Nilotpal / Takeuchi, Kenneth K / Ruggeri, Jeanine M / Bailey, Peter / Chang, David / Li, Joey / Leonhardt, Laura / Puri, Sapna / Hoffman, Megan T / Gao, Shan / Halbrook, Christopher J / Song, Yan / Ljungman, Mats / Malik, Shivani / Wright, Christopher V E / Dawson, David W / Biankin, Andrew V / Hebrok, Matthias / Crawford, Howard C. ·Diabetes Center, Department of Medicine, University of California at San Francisco, San Francisco, California 94143, USA. · Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA. · Wolfson Wohl Cancer Research Center, University of Glasgow, Glasgow G61 1BD, Scotland. · Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York 11794, USA. · Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan 48109, USA. · Department of Medicine/ Hematology and Oncology, University of California at San Francisco, San Francisco, California 94143, USA. · Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee 37240, USA. · Department of Pathology and Laboratory Medicine, University of California at Los Angeles, Los Angeles, California 90095, USA. ·Genes Dev · Pubmed #28087712.

ABSTRACT: Aberrant activation of embryonic signaling pathways is frequent in pancreatic ductal adenocarcinoma (PDA), making developmental regulators therapeutically attractive. Here we demonstrate diverse functions for pancreatic and duodenal homeobox 1 (PDX1), a transcription factor indispensable for pancreas development, in the progression from normal exocrine cells to metastatic PDA. We identify a critical role for PDX1 in maintaining acinar cell identity, thus resisting the formation of pancreatic intraepithelial neoplasia (PanIN)-derived PDA. Upon neoplastic transformation, the role of PDX1 changes from tumor-suppressive to oncogenic. Interestingly, subsets of malignant cells lose PDX1 expression while undergoing epithelial-to-mesenchymal transition (EMT), and PDX1 loss is associated with poor outcome. This stage-specific functionality arises from profound shifts in PDX1 chromatin occupancy from acinar cells to PDA. In summary, we report distinct roles of PDX1 at different stages of PDA, suggesting that therapeutic approaches against this potential target need to account for its changing functions at different stages of carcinogenesis. These findings provide insight into the complexity of PDA pathogenesis and advocate a rigorous investigation of therapeutically tractable targets at distinct phases of PDA development and progression.

11 Article Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion. 2016

Sousa, Cristovão M / Biancur, Douglas E / Wang, Xiaoxu / Halbrook, Christopher J / Sherman, Mara H / Zhang, Li / Kremer, Daniel / Hwang, Rosa F / Witkiewicz, Agnes K / Ying, Haoqiang / Asara, John M / Evans, Ronald M / Cantley, Lewis C / Lyssiotis, Costas A / Kimmelman, Alec C. · ·Nature · Pubmed #27509858.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease characterized by an intense fibrotic stromal response and deregulated metabolism. The role of the stroma in PDAC biology is complex and it has been shown to play critical roles that differ depending on the biological context. The stromal reaction also impairs the vasculature, leading to a highly hypoxic, nutrient-poor environment. As such, these tumours must alter how they capture and use nutrients to support their metabolic needs. Here we show that stroma-associated pancreatic stellate cells (PSCs) are critical for PDAC metabolism through the secretion of non-essential amino acids (NEAA). Specifically, we uncover a previously undescribed role for alanine, which outcompetes glucose and glutamine-derived carbon in PDAC to fuel the tricarboxylic acid (TCA) cycle, and thus NEAA and lipid biosynthesis. This shift in fuel source decreases the tumour’s dependence on glucose and serum-derived nutrients, which are limited in the pancreatic tumour microenvironment. Moreover, we demonstrate that alanine secretion by PSCs is dependent on PSC autophagy, a process that is stimulated by cancer cells. Thus, our results demonstrate a novel metabolic interaction between PSCs and cancer cells, in which PSC-derived alanine acts as an alternative carbon source. This finding highlights a previously unappreciated metabolic network within pancreatic tumours in which diverse fuel sources are used to promote growth in an austere tumour microenvironment.

12 Article PI3K regulation of RAC1 is required for KRAS-induced pancreatic tumorigenesis in mice. 2014

Wu, Chia-Yen C / Carpenter, Eileen S / Takeuchi, Kenneth K / Halbrook, Christopher J / Peverley, Louise V / Bien, Harold / Hall, Jason C / DelGiorno, Kathleen E / Pal, Debjani / Song, Yan / Shi, Chanjuan / Lin, Richard Z / Crawford, Howard C. ·Department of Physiology and Biophysics, Stony Brook University, Stony Brook, New York. · Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York. · Department of Cancer Biology, Mayo Clinic Florida, Jacksonville, Florida. · Department of Cancer Biology, Mayo Clinic Florida, Jacksonville, Florida; Department of Chemistry, Stony Brook University, Stony Brook, New York. · Division of Hematology/Oncology, Stony Brook University, Stony Brook, New York. · Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York; Department of Cancer Biology, Mayo Clinic Florida, Jacksonville, Florida. · Department of Cancer Biology, Mayo Clinic Florida, Jacksonville, Florida; Molecular Genetics and Microbiology Graduate Program, Stony Brook University, Stony Brook, New York. · Molecular and Cellular Biology Graduate Program, Stony Brook University, Stony Brook, New York. · Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee. · Department of Physiology and Biophysics, Stony Brook University, Stony Brook, New York; Medical Service, Northport VA Medical Center, Northport, New York. Electronic address: richard.lin@stonybrook.edu. · Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York; Department of Cancer Biology, Mayo Clinic Florida, Jacksonville, Florida. Electronic address: crawford.howard@mayo.edu. ·Gastroenterology · Pubmed #25311989.

ABSTRACT: BACKGROUND & AIMS: New drug targets are urgently needed for the treatment of patients with pancreatic ductal adenocarcinoma (PDA). Nearly all PDAs contain oncogenic mutations in the KRAS gene. Pharmacological inhibition of KRAS has been unsuccessful, leading to a focus on downstream effectors that are more easily targeted with small molecule inhibitors. We investigated the contributions of phosphoinositide 3-kinase (PI3K) to KRAS-initiated tumorigenesis. METHODS: Tumorigenesis was measured in the Kras(G12D/+);Ptf1a(Cre/+) mouse model of PDA; these mice were crossed with mice with pancreas-specific disruption of genes encoding PI3K p110α (Pik3ca), p110β (Pik3cb), or RAC1 (Rac1). Pancreatitis was induced with 5 daily intraperitoneal injections of cerulein. Pancreata and primary acinar cells were isolated; acinar cells were incubated with an inhibitor of p110α (PIK75) followed by a broad-spectrum PI3K inhibitor (GDC0941). PDA cell lines (NB490 and MiaPaCa2) were incubated with PIK75 followed by GDC0941. Tissues and cells were analyzed by histology, immunohistochemistry, quantitative reverse-transcription polymerase chain reaction, and immunofluorescence analyses for factors involved in the PI3K signaling pathway. We also examined human pancreas tissue microarrays for levels of p110α and other PI3K pathway components. RESULTS: Pancreas-specific disruption of Pik3ca or Rac1, but not Pik3cb, prevented the development of pancreatic tumors in Kras(G12D/+);Ptf1a(Cre/+) mice. Loss of transformation was independent of AKT regulation. Preneoplastic ductal metaplasia developed in mice lacking pancreatic p110α but regressed. Levels of activated and total RAC1 were higher in pancreatic tissues from Kras(G12D/+);Ptf1a(Cre/+) mice compared with controls. Loss of p110α reduced RAC1 activity and expression in these tissues. p110α was required for the up-regulation and activity of RAC guanine exchange factors during tumorigenesis. Levels of p110α and RAC1 were increased in human pancreatic intraepithelial neoplasias and PDAs compared with healthy pancreata. CONCLUSIONS: KRAS signaling, via p110α to activate RAC1, is required for transformation in Kras(G12D/+);Ptf1a(Cre/+) mice.

13 Article Identification and manipulation of biliary metaplasia in pancreatic tumors. 2014

Delgiorno, Kathleen E / Hall, Jason C / Takeuchi, Kenneth K / Pan, Fong Cheng / Halbrook, Christopher J / Washington, M Kay / Olive, Kenneth P / Spence, Jason R / Sipos, Bence / Wright, Christopher V E / Wells, James M / Crawford, Howard C. ·Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York; Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida. · Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida; Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York. · Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida. · Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee. · Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee. · Departments of Medicine and Pathology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York. · Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan. · Department of Pathology, University Hospital Tubingen, Tubingen, Germany. · Department of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. · Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York; Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida. Electronic address: crawford.howard@mayo.edu. ·Gastroenterology · Pubmed #23999170.

ABSTRACT: BACKGROUND & AIMS: Metaplasias often have characteristics of developmentally related tissues. Pancreatic metaplastic ducts are usually associated with pancreatitis and pancreatic ductal adenocarcinoma. The tuft cell is a chemosensory cell that responds to signals in the extracellular environment via effector molecules. Commonly found in the biliary tract, tuft cells are absent from normal murine pancreas. Using the aberrant appearance of tuft cells as an indicator, we tested if pancreatic metaplasia represents transdifferentiation to a biliary phenotype and what effect this has on pancreatic tumorigenesis. METHODS: We analyzed pancreatic tissue and tumors that developed in mice that express an activated form of Kras (Kras(LSL-G12D/+);Ptf1a(Cre/+) mice). Normal bile duct, pancreatic duct, and tumor-associated metaplasias from the mice were analyzed for tuft cell and biliary progenitor markers, including SOX17, a transcription factor that regulates biliary development. We also analyzed pancreatic tissues from mice expressing transgenic SOX17 alone (ROSA(tTa/+);Ptf1(CreERTM/+);tetO-SOX17) or along with activated Kras (ROSAtT(a/+);Ptf1a(CreERTM/+);tetO-SOX17;Kras(LSL-G12D;+)). RESULTS: Tuft cells were frequently found in areas of pancreatic metaplasia, decreased throughout tumor progression, and absent from invasive tumors. Analysis of the pancreatobiliary ductal systems of mice revealed tuft cells in the biliary tract but not the normal pancreatic duct. Analysis for biliary markers revealed expression of SOX17 in pancreatic metaplasia and tumors. Pancreas-specific overexpression of SOX17 led to ductal metaplasia along with inflammation and collagen deposition. Mice that overexpressed SOX17 along with Kras(G12D) had a greater degree of transformed tissue compared with mice expressing only Kras(G12D). Immunofluorescence analysis of human pancreatic tissue arrays revealed the presence of tuft cells in metaplasia and early-stage tumors, along with SOX17 expression, consistent with a biliary phenotype. CONCLUSIONS: Expression of Kras(G12D) and SOX17 in mice induces development of metaplasias with a biliary phenotype containing tuft cells. Tuft cells express a number of tumorigenic factors that can alter the microenvironment. Expression of SOX17 induces pancreatitis and promotes Kras(G12D)-induced tumorigenesis in mice.

14 Article EGF receptor is required for KRAS-induced pancreatic tumorigenesis. 2012

Ardito, Christine M / Grüner, Barbara M / Takeuchi, Kenneth K / Lubeseder-Martellato, Clara / Teichmann, Nicole / Mazur, Pawel K / Delgiorno, Kathleen E / Carpenter, Eileen S / Halbrook, Christopher J / Hall, Jason C / Pal, Debjani / Briel, Thomas / Herner, Alexander / Trajkovic-Arsic, Marija / Sipos, Bence / Liou, Geou-Yarh / Storz, Peter / Murray, Nicole R / Threadgill, David W / Sibilia, Maria / Washington, M Kay / Wilson, Carole L / Schmid, Roland M / Raines, Elaine W / Crawford, Howard C / Siveke, Jens T. ·Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11794, USA. ·Cancer Cell · Pubmed #22975374.

ABSTRACT: Initiation of pancreatic ductal adenocarcinoma (PDA) is definitively linked to activating mutations in the KRAS oncogene. However, PDA mouse models show that mutant Kras expression early in development gives rise to a normal pancreas, with tumors forming only after a long latency or pancreatitis induction. Here, we show that oncogenic KRAS upregulates endogenous EGFR expression and activation, the latter being dependent on the EGFR ligand sheddase, ADAM17. Genetic ablation or pharmacological inhibition of EGFR or ADAM17 effectively eliminates KRAS-driven tumorigenesis in vivo. Without EGFR activity, active RAS levels are not sufficient to induce robust MEK/ERK activity, a requirement for epithelial transformation.