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Pancreatic Neoplasms: HELP
Articles by Dannielle D. Engle
Based on 10 articles published since 2010
(Why 10 articles?)
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Between 2010 and 2020, Dannielle Engle wrote the following 10 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Article Organoid Profiling Identifies Common Responders to Chemotherapy in Pancreatic Cancer. 2018

Tiriac, Hervé / Belleau, Pascal / Engle, Dannielle D / Plenker, Dennis / Deschênes, Astrid / Somerville, Tim D D / Froeling, Fieke E M / Burkhart, Richard A / Denroche, Robert E / Jang, Gun-Ho / Miyabayashi, Koji / Young, C Megan / Patel, Hardik / Ma, Michelle / LaComb, Joseph F / Palmaira, Randze Lerie D / Javed, Ammar A / Huynh, Jasmine C / Johnson, Molly / Arora, Kanika / Robine, Nicolas / Shah, Minita / Sanghvi, Rashesh / Goetz, Austin B / Lowder, Cinthya Y / Martello, Laura / Driehuis, Else / LeComte, Nicolas / Askan, Gokce / Iacobuzio-Donahue, Christine A / Clevers, Hans / Wood, Laura D / Hruban, Ralph H / Thompson, Elizabeth / Aguirre, Andrew J / Wolpin, Brian M / Sasson, Aaron / Kim, Joseph / Wu, Maoxin / Bucobo, Juan Carlos / Allen, Peter / Sejpal, Divyesh V / Nealon, William / Sullivan, James D / Winter, Jordan M / Gimotty, Phyllis A / Grem, Jean L / DiMaio, Dominick J / Buscaglia, Jonathan M / Grandgenett, Paul M / Brody, Jonathan R / Hollingsworth, Michael A / O'Kane, Grainne M / Notta, Faiyaz / Kim, Edward / Crawford, James M / Devoe, Craig / Ocean, Allyson / Wolfgang, Christopher L / Yu, Kenneth H / Li, Ellen / Vakoc, Christopher R / Hubert, Benjamin / Fischer, Sandra E / Wilson, Julie M / Moffitt, Richard / Knox, Jennifer / Krasnitz, Alexander / Gallinger, Steven / Tuveson, David A. ·Cold Spring Harbor Laboratory, Cold Spring Harbor, New York. · Johns Hopkins University, Division of Hepatobiliary and Pancreatic Surgery, Baltimore, Maryland. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. · Swiss Federal Institute of Technology Lausanne (EPFL), School of Life Sciences, Swiss Institute for Experimental Cancer Research (ISREC), Laboratory of Tumor Heterogeneity and Stemness in Cancer, Lausanne, Switzerland. · Department of Medicine, Stony Brook University, Stony Brook, New York. · Memorial Sloan Kettering Cancer Center, New York, New York. · University of California, Davis, Comprehensive Cancer Center, Division of Hematology and Oncology, Sacramento, California. · New York Genome Center, New York, New York. · Department of Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania. · SUNY Downstate Medical Center, Department of Medicine, New York, New York. · Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW), Utrecht, the Netherlands. · University Medical Center (UMC), Utrecht, the Netherlands. · Princess Maxime Center (PMC), Utrecht, the Netherlands. · Department of Pathology, Johns Hopkins University, Baltimore, Maryland. · Dana-Farber Cancer Institute, Broad Institute, Boston, Massachusetts. · Department of Surgery, Stony Brook University, Stony Brook, New York. · Department of Pathology, Stony Brook University, Stony Brook, New York. · Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Division of Gastroenterology, Hempstead, New York. · Department of Surgery, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York. · Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, Pennsylvania. · Department of Medicine, University of Nebraska Medical Center, Omaha, Nebraska. · Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska. · University of Nebraska Medical Center, Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffet Cancer Center, Omaha, Nebraska. · Wallace McCain Centre for Pancreatic Cancer, Department of Medical Oncology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada. · Department of Pathology and Laboratory Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York. · Division of Medical Oncology, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York. · Weill Cornell Medical College, New York, New York. · Department of Pathology, University Health Network, University of Toronto, Toronto, Ontario, Canada. · Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. · Department of Biomedical Informatics, Stony Brook University, Stony Brook, New York. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. dtuveson@cshl.edu steven.gallinger@uhn.ca. · Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. · Hepatobiliary/Pancreatic Surgical Oncology Program, University Health Network, Toronto, Ontario, Canada. · Cold Spring Harbor Laboratory, Cold Spring Harbor, New York. dtuveson@cshl.edu steven.gallinger@uhn.ca. ·Cancer Discov · Pubmed #29853643.

ABSTRACT: Pancreatic cancer is the most lethal common solid malignancy. Systemic therapies are often ineffective, and predictive biomarkers to guide treatment are urgently needed. We generated a pancreatic cancer patient-derived organoid (PDO) library that recapitulates the mutational spectrum and transcriptional subtypes of primary pancreatic cancer. New driver oncogenes were nominated and transcriptomic analyses revealed unique clusters. PDOs exhibited heterogeneous responses to standard-of-care chemotherapeutics and investigational agents. In a case study manner, we found that PDO therapeutic profiles paralleled patient outcomes and that PDOs enabled longitudinal assessment of chemosensitivity and evaluation of synchronous metastases. We derived organoid-based gene expression signatures of chemosensitivity that predicted improved responses for many patients to chemotherapy in both the adjuvant and advanced disease settings. Finally, we nominated alternative treatment strategies for chemorefractory PDOs using targeted agent therapeutic profiling. We propose that combined molecular and therapeutic profiling of PDOs may predict clinical response and enable prospective therapeutic selection.

2 Article Macrophage-Derived Granulin Drives Resistance to Immune Checkpoint Inhibition in Metastatic Pancreatic Cancer. 2018

Quaranta, Valeria / Rainer, Carolyn / Nielsen, Sebastian R / Raymant, Meirion L / Ahmed, Muhammad S / Engle, Dannielle D / Taylor, Arthur / Murray, Trish / Campbell, Fiona / Palmer, Daniel H / Tuveson, David A / Mielgo, Ainhoa / Schmid, Michael C. ·Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom. · Cold Spring Harbor Laboratory, Cold Spring Harbor, New York. · Department of Cellular and Molecular Physiology, University of Liverpool, Liverpool, United Kingdom. · Lustgarten Pancreatic Cancer Research Laboratory, Cold Spring Harbor, New York. · Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom. mschmid@liverpool.ac.uk. ·Cancer Res · Pubmed #29789416.

ABSTRACT: The ability of disseminated cancer cells to evade the immune response is a critical step for efficient metastatic progression. Protection against an immune attack is often provided by the tumor microenvironment that suppresses and excludes cytotoxic CD8

3 Article Dynamic changes during the treatment of pancreatic cancer. 2018

Wolff, Robert A / Wang-Gillam, Andrea / Alvarez, Hector / Tiriac, Hervé / Engle, Dannielle / Hou, Shurong / Groff, Abigail F / San Lucas, Anthony / Bernard, Vincent / Allenson, Kelvin / Castillo, Jonathan / Kim, Dong / Mulu, Feven / Huang, Jonathan / Stephens, Bret / Wistuba, Ignacio I / Katz, Matthew / Varadhachary, Gauri / Park, YoungKyu / Hicks, James / Chinnaiyan, Arul / Scampavia, Louis / Spicer, Timothy / Gerhardinger, Chiara / Maitra, Anirban / Tuveson, David / Rinn, John / Lizee, Gregory / Yee, Cassian / Levine, Arnold J. ·Department of Gastrointestinal (GI) Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA. · Division of Oncology, Washington University, St. Louis, MO, USA. · Department of Pathology, MD Anderson Cancer Center, Houston, TX, USA. · Cold Spring Harbor Laboratory, New York, NY, USA. · Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL, USA. · Department of Molecular and Cellular Biology, Harvard University, The Broad Institute, Cambridge, MA, USA. · Department of Translational Molecular Pathology, MD Anderson Cancer Center, Houston, TX, USA. · Department of Radiation Oncology, MD Anderson Cancer Center, Houston, TX, USA. · Department of Surgical Oncology, MD Anderson Cancer Center, Houston, TX, USA. · Center for Translational Pathology, University of Michigan Medical Center, Ann Arbor, MI, USA. · Current address: University of Colorado Boulder, BioFrontiers Institute, Boulder, CO, USA. · Department of Melanoma Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA. · Simons Center for Systems Biology, Institute for Advanced Study, Princeton, NJ, USA. ·Oncotarget · Pubmed #29599906.

ABSTRACT: This manuscript follows a single patient with pancreatic adenocarcinoma for a five year period, detailing the clinical record, pathology, the dynamic evolution of molecular and cellular alterations as well as the responses to treatments with chemotherapies, targeted therapies and immunotherapies. DNA and RNA samples from biopsies and blood identified a dynamic set of changes in allelic imbalances and copy number variations in response to therapies. Organoid cultures established from biopsies over time were employed for extensive drug testing to determine if this approach was feasible for treatments. When an unusual drug response was detected, an extensive RNA sequencing analysis was employed to establish novel mechanisms of action of this drug. Organoid cell cultures were employed to identify possible antigens associated with the tumor and the patient's T-cells were expanded against one of these antigens. Similar and identical T-cell receptor sequences were observed in the initial biopsy and the expanded T-cell population. Immunotherapy treatment failed to shrink the tumor, which had undergone an epithelial to mesenchymal transition prior to therapy. A warm autopsy of the metastatic lung tumor permitted an extensive analysis of tumor heterogeneity over five years of treatment and surgery. This detailed analysis of the clinical descriptions, imaging, pathology, molecular and cellular evolution of the tumors, treatments, and responses to chemotherapy, targeted therapies, and immunotherapies, as well as attempts at the development of personalized medical treatments for a single patient should provide a valuable guide to future directions in cancer treatment.

4 Article Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. 2017

Öhlund, Daniel / Handly-Santana, Abram / Biffi, Giulia / Elyada, Ela / Almeida, Ana S / Ponz-Sarvise, Mariano / Corbo, Vincenzo / Oni, Tobiloba E / Hearn, Stephen A / Lee, Eun Jung / Chio, Iok In Christine / Hwang, Chang-Il / Tiriac, Hervé / Baker, Lindsey A / Engle, Dannielle D / Feig, Christine / Kultti, Anne / Egeblad, Mikala / Fearon, Douglas T / Crawford, James M / Clevers, Hans / Park, Youngkyu / Tuveson, David A. ·Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724. · Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724. · Department of Surgical and Perioperative Sciences, Surgery, Umeå University, 901 85 Umeå, Sweden. · APC Microbiome Institute and School of Microbiology, University College Cork, Cork, Ireland. · Department of Oncology, Clinica Universidad de Navarra, CIMA, IDISNA, Pamplona 31008, Spain. · ARC-Net centre for applied research on cancer, University and Hospital Trust of Verona, 37134 Verona, Italy. · Department of Diagnostic and Public Health, University and Hospital Trust of Verona, 37134 Verona, Italy. · Graduate Program in Molecular and Cellular Biology, Stony Brook University, Stony Brook, NY 11794. · University of Cambridge, Cancer Research UK, Cambridge Institute, Cambridge, UK. · Hofstra Northwell School of Medicine, Hempstead, NY 11550. · Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW), University Medical Centre Utrecht and CancerGenomics.nl, 3584 CT Utrecht, Netherlands. ·J Exp Med · Pubmed #28232471.

ABSTRACT: Pancreatic stellate cells (PSCs) differentiate into cancer-associated fibroblasts (CAFs) that produce desmoplastic stroma, thereby modulating disease progression and therapeutic response in pancreatic ductal adenocarcinoma (PDA). However, it is unknown whether CAFs uniformly carry out these tasks or if subtypes of CAFs with distinct phenotypes in PDA exist. We identified a CAF subpopulation with elevated expression of α-smooth muscle actin (αSMA) located immediately adjacent to neoplastic cells in mouse and human PDA tissue. We recapitulated this finding in co-cultures of murine PSCs and PDA organoids, and demonstrated that organoid-activated CAFs produced desmoplastic stroma. The co-cultures showed cooperative interactions and revealed another distinct subpopulation of CAFs, located more distantly from neoplastic cells, which lacked elevated αSMA expression and instead secreted IL6 and additional inflammatory mediators. These findings were corroborated in mouse and human PDA tissue, providing direct evidence for CAF heterogeneity in PDA tumor biology with implications for disease etiology and therapeutic development.

5 Article Macrophage-secreted granulin supports pancreatic cancer metastasis by inducing liver fibrosis. 2016

Nielsen, Sebastian R / Quaranta, Valeria / Linford, Andrea / Emeagi, Perpetua / Rainer, Carolyn / Santos, Almudena / Ireland, Lucy / Sakai, Takao / Sakai, Keiko / Kim, Yong-Sam / Engle, Dannielle / Campbell, Fiona / Palmer, Daniel / Ko, Jeong Heon / Tuveson, David A / Hirsch, Emilio / Mielgo, Ainhoa / Schmid, Michael C. ·Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Ashton Street, Liverpool L69 3GE, UK. · Department of Molecular and Clinical Pharmacology, University of Liverpool, Ashton Street, Liverpool L69 3GE, UK. · Aging Intervention Research Center, KRIBB, 125 Gwahak-ro, Yuseong-gu, Deajeon 305-806, Korea. · Korea University of Science and Technology, 217 Gajeong-ro, Yuseong-gu, Daejeon 305-350, Korea. · Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA. · Lustgarten Pancreatic Cancer Research Laboratory, Cold Spring Harbor, New York 11724, USA. · Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. · Department of Molecular Biotechnology and Health Sciences, Center for Molecular Biotechnology, University of Torino, Via Nizza 52, 10126 Turin, Italy. ·Nat Cell Biol · Pubmed #27088855.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a devastating metastatic disease for which better therapies are urgently needed. Macrophages enhance metastasis in many cancer types; however, the role of macrophages in PDAC liver metastasis remains poorly understood. Here we found that PDAC liver metastasis critically depends on the early recruitment of granulin-secreting inflammatory monocytes to the liver. Mechanistically, we demonstrate that granulin secretion by metastasis-associated macrophages (MAMs) activates resident hepatic stellate cells (hStCs) into myofibroblasts that secrete periostin, resulting in a fibrotic microenvironment that sustains metastatic tumour growth. Disruption of MAM recruitment or genetic depletion of granulin reduced hStC activation and liver metastasis. Interestingly, we found that circulating monocytes and hepatic MAMs in PDAC patients express high levels of granulin. These findings suggest that recruitment of granulin-expressing inflammatory monocytes plays a key role in PDAC metastasis and may serve as a potential therapeutic target for PDAC liver metastasis.

6 Article The necrosome promotes pancreatic oncogenesis via CXCL1 and Mincle-induced immune suppression. 2016

Seifert, Lena / Werba, Gregor / Tiwari, Shaun / Giao Ly, Nancy Ngoc / Alothman, Sara / Alqunaibit, Dalia / Avanzi, Antonina / Barilla, Rocky / Daley, Donnele / Greco, Stephanie H / Torres-Hernandez, Alejandro / Pergamo, Matthew / Ochi, Atsuo / Zambirinis, Constantinos P / Pansari, Mridul / Rendon, Mauricio / Tippens, Daniel / Hundeyin, Mautin / Mani, Vishnu R / Hajdu, Cristina / Engle, Dannielle / Miller, George. ·S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA. · Department of Cell Biology, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA. · Department of Pathology, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA. · Cold Spring Harbor Laboratories, Cold Spring Harbor, New York 11724, USA. ·Nature · Pubmed #27049944.

ABSTRACT: Neoplastic pancreatic epithelial cells are believed to die through caspase 8-dependent apoptotic cell death, and chemotherapy is thought to promote tumour apoptosis. Conversely, cancer cells often disrupt apoptosis to survive. Another type of programmed cell death is necroptosis (programmed necrosis), but its role in pancreatic ductal adenocarcinoma (PDA) is unclear. There are many potential inducers of necroptosis in PDA, including ligation of tumour necrosis factor receptor 1 (TNFR1), CD95, TNF-related apoptosis-inducing ligand (TRAIL) receptors, Toll-like receptors, reactive oxygen species, and chemotherapeutic drugs. Here we report that the principal components of the necrosome, receptor-interacting protein (RIP)1 and RIP3, are highly expressed in PDA and are further upregulated by the chemotherapy drug gemcitabine. Blockade of the necrosome in vitro promoted cancer cell proliferation and induced an aggressive oncogenic phenotype. By contrast, in vivo deletion of RIP3 or inhibition of RIP1 protected against oncogenic progression in mice and was associated with the development of a highly immunogenic myeloid and T cell infiltrate. The immune-suppressive tumour microenvironment associated with intact RIP1/RIP3 signalling depended in part on necroptosis-induced expression of the chemokine attractant CXCL1, and CXCL1 blockade protected against PDA. Moreover, cytoplasmic SAP130 (a subunit of the histone deacetylase complex) was expressed in PDA in a RIP1/RIP3-dependent manner, and Mincle--its cognate receptor--was upregulated in tumour-infiltrating myeloid cells. Ligation of Mincle by SAP130 promoted oncogenesis, whereas deletion of Mincle protected against oncogenesis and phenocopied the immunogenic reprogramming of the tumour microenvironment that was induced by RIP3 deletion. Cellular depletion suggested that whereas inhibitory macrophages promote tumorigenesis in PDA, they lose their immune-suppressive effects when RIP3 or Mincle is deleted. Accordingly, T cells, which are not protective against PDA progression in mice with intact RIP3 or Mincle signalling, are reprogrammed into indispensable mediators of anti-tumour immunity in the absence of RIP3 or Mincle. Our work describes parallel networks of necroptosis-induced CXCL1 and Mincle signalling that promote macrophage-induced adaptive immune suppression and thereby enable PDA progression.

7 Article TLR9 ligation in pancreatic stellate cells promotes tumorigenesis. 2015

Zambirinis, Constantinos P / Levie, Elliot / Nguy, Susanna / Avanzi, Antonina / Barilla, Rocky / Xu, Yijie / Seifert, Lena / Daley, Donnele / Greco, Stephanie H / Deutsch, Michael / Jonnadula, Saikiran / Torres-Hernandez, Alejandro / Tippens, Daniel / Pushalkar, Smruti / Eisenthal, Andrew / Saxena, Deepak / Ahn, Jiyoung / Hajdu, Cristina / Engle, Dannielle D / Tuveson, David / Miller, George. ·Department of Surgery, New York University School of Medicine, New York, NY 10016. · New York University College of Dentistry, New York, NY 10016. · Department of Population Health, New York University School of Medicine, New York, NY 10016. · Department of Pathology, New York University School of Medicine, New York, NY 10016. · Cold Spring Harbor Laboratories, Cold Spring Harbor, NY 11724. · Department of Surgery, New York University School of Medicine, New York, NY 10016 Department of Cell Biology, New York University School of Medicine, New York, NY 10016 george.miller@nyumc.org. ·J Exp Med · Pubmed #26481685.

ABSTRACT: Modulation of Toll-like receptor (TLR) signaling can have protective or protumorigenic effects on oncogenesis depending on the cancer subtype and on specific inflammatory elements within the tumor milieu. We found that TLR9 is widely expressed early during the course of pancreatic transformation and that TLR9 ligands are ubiquitous within the tumor microenvironment. TLR9 ligation markedly accelerates oncogenesis, whereas TLR9 deletion is protective. We show that TLR9 activation has distinct effects on the epithelial, inflammatory, and fibrogenic cellular subsets in pancreatic carcinoma and plays a central role in cross talk between these compartments. Specifically, TLR9 activation can induce proinflammatory signaling in transformed epithelial cells, but does not elicit oncogene expression or cancer cell proliferation. Conversely, TLR9 ligation induces pancreatic stellate cells (PSCs) to become fibrogenic and secrete chemokines that promote epithelial cell proliferation. TLR9-activated PSCs mediate their protumorigenic effects on the epithelial compartment via CCL11. Additionally, TLR9 has immune-suppressive effects in the tumor microenvironment (TME) via induction of regulatory T cell recruitment and myeloid-derived suppressor cell proliferation. Collectively, our work shows that TLR9 has protumorigenic effects in pancreatic carcinoma which are distinct from its influence in extrapancreatic malignancies and from the mechanistic effects of other TLRs on pancreatic oncogenesis.

8 Article Pancreatic Cancer Cell Migration and Metastasis Is Regulated by Chemokine-Biased Agonism and Bioenergetic Signaling. 2015

Roy, Ishan / McAllister, Donna M / Gorse, Egal / Dixon, Kate / Piper, Clinton T / Zimmerman, Noah P / Getschman, Anthony E / Tsai, Susan / Engle, Dannielle D / Evans, Douglas B / Volkman, Brian F / Kalyanaraman, Balaraman / Dwinell, Michael B. ·Department of Microbiology & Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin. · Department of Microbiology & Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin. Department of Biophysics, Medical College of Wisconsin, Milwaukee, Wisconsin. · Department of Microbiology & Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin. MCW Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin. · Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin. · MCW Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin. Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin. · Cold Spring Harbor Laboratory, Cold Spring Harbor, New York. · Department of Biophysics, Medical College of Wisconsin, Milwaukee, Wisconsin. MCW Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin. · Department of Microbiology & Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin. MCW Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin. mdwinell@mcw.edu. ·Cancer Res · Pubmed #26330165.

ABSTRACT: Patients with pancreatic ductal adenocarcinoma (PDAC) invariably succumb to metastatic disease, but the underlying mechanisms that regulate PDAC cell movement and metastasis remain little understood. In this study, we investigated the effects of the chemokine gene CXCL12, which is silenced in PDAC tumors, yet is sufficient to suppress growth and metastasis when re-expressed. Chemokines like CXCL12 regulate cell movement in a biphasic pattern, with peak migration typically in the low nanomolar concentration range. Herein, we tested the hypothesis that the biphasic cell migration pattern induced by CXCL12 reflected a biased agonist bioenergetic signaling that might be exploited to interfere with PDAC metastasis. In human and murine PDAC cell models, we observed that nonmigratory doses of CXCL12 were sufficient to decrease oxidative phosphorylation and glycolytic capacity and to increase levels of phosphorylated forms of the master metabolic kinase AMPK. Those same doses of CXCL12 locked myosin light chain into a phosphorylated state, thereby decreasing F-actin polymerization and preventing cell migration in a manner dependent upon AMPK and the calcium-dependent kinase CAMKII. Notably, at elevated concentrations of CXCL12 that were insufficient to trigger chemotaxis of PDAC cells, AMPK blockade resulted in increased cell movement. In two preclinical mouse models of PDAC, administration of CXCL12 decreased tumor dissemination, supporting our hypothesis that chemokine-biased agonist signaling may offer a useful therapeutic strategy. Our results offer a mechanistic rationale for further investigation of CXCL12 as a potential therapy to prevent or treat PDAC metastasis.

9 Article Organoid models of human and mouse ductal pancreatic cancer. 2015

Boj, Sylvia F / Hwang, Chang-Il / Baker, Lindsey A / Chio, Iok In Christine / Engle, Dannielle D / Corbo, Vincenzo / Jager, Myrthe / Ponz-Sarvise, Mariano / Tiriac, Hervé / Spector, Mona S / Gracanin, Ana / Oni, Tobiloba / Yu, Kenneth H / van Boxtel, Ruben / Huch, Meritxell / Rivera, Keith D / Wilson, John P / Feigin, Michael E / Öhlund, Daniel / Handly-Santana, Abram / Ardito-Abraham, Christine M / Ludwig, Michael / Elyada, Ela / Alagesan, Brinda / Biffi, Giulia / Yordanov, Georgi N / Delcuze, Bethany / Creighton, Brianna / Wright, Kevin / Park, Youngkyu / Morsink, Folkert H M / Molenaar, I Quintus / Borel Rinkes, Inne H / Cuppen, Edwin / Hao, Yuan / Jin, Ying / Nijman, Isaac J / Iacobuzio-Donahue, Christine / Leach, Steven D / Pappin, Darryl J / Hammell, Molly / Klimstra, David S / Basturk, Olca / Hruban, Ralph H / Offerhaus, George Johan / Vries, Robert G J / Clevers, Hans / Tuveson, David A. ·Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW), University Medical Centre Utrecht and CancerGenomics.nl, 3584 CT Utrecht, the Netherlands; foundation Hubrecht Organoid Technology (HUB), 3584 CT Utrecht, the Netherlands. · Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724, USA. · Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW), University Medical Centre Utrecht and CancerGenomics.nl, 3584 CT Utrecht, the Netherlands. · Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724, USA; Graduate Program in Molecular and Cellular Biology, Stony Brook University, Stony Brook, NY 11794, USA. · Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724, USA; Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Weill Medical College at Cornell University, New York, NY 10065, USA. · Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. · Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724, USA; Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. · Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724, USA; Graduate Program in Genetics, Stony Brook University, Stony Brook, NY 11794, USA. · Department of Pathology, University Medical Centre Utrecht, 3584 CX Utrecht, the Netherlands. · Department of Surgery, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands. · Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. · Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. · The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. · Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW), University Medical Centre Utrecht and CancerGenomics.nl, 3584 CT Utrecht, the Netherlands. Electronic address: h.clevers@hubrecht.eu. · Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724, USA; Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: dtuveson@cshl.edu. ·Cell · Pubmed #25557080.

ABSTRACT: Pancreatic cancer is one of the most lethal malignancies due to its late diagnosis and limited response to treatment. Tractable methods to identify and interrogate pathways involved in pancreatic tumorigenesis are urgently needed. We established organoid models from normal and neoplastic murine and human pancreas tissues. Pancreatic organoids can be rapidly generated from resected tumors and biopsies, survive cryopreservation, and exhibit ductal- and disease-stage-specific characteristics. Orthotopically transplanted neoplastic organoids recapitulate the full spectrum of tumor development by forming early-grade neoplasms that progress to locally invasive and metastatic carcinomas. Due to their ability to be genetically manipulated, organoids are a platform to probe genetic cooperation. Comprehensive transcriptional and proteomic analyses of murine pancreatic organoids revealed genes and pathways altered during disease progression. The confirmation of many of these protein changes in human tissues demonstrates that organoids are a facile model system to discover characteristics of this deadly malignancy.

10 Article Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy. 2014

Sherman, Mara H / Yu, Ruth T / Engle, Dannielle D / Ding, Ning / Atkins, Annette R / Tiriac, Herve / Collisson, Eric A / Connor, Frances / Van Dyke, Terry / Kozlov, Serguei / Martin, Philip / Tseng, Tiffany W / Dawson, David W / Donahue, Timothy R / Masamune, Atsushi / Shimosegawa, Tooru / Apte, Minoti V / Wilson, Jeremy S / Ng, Beverly / Lau, Sue Lynn / Gunton, Jenny E / Wahl, Geoffrey M / Hunter, Tony / Drebin, Jeffrey A / O'Dwyer, Peter J / Liddle, Christopher / Tuveson, David A / Downes, Michael / Evans, Ronald M. ·Gene Expression Laboratory, Salk Institute, La Jolla, CA 92037, USA. · Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. · Department of Medicine/Hematology and Oncology, University of California San Francisco, San Francisco, CA 94143, USA. · Cancer Research UK Cambridge Research Institute, The Li Ka Shing Centre, Robinson Way, Cambridge CB2 ORE, UK. · Center for Advanced Preclinical Research, NCI-Frederick, Frederick, MD 21702, USA. · Center for Advanced Preclinical Research, Leidos Biomed, Inc. Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA. · Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095, USA. · Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai Miyagi, 980-8574, Japan. · Pancreatic Research Group, Faculty of Medicine, South Western Sydney Clinical School, University of New South Wales, Sydney, NSW 2052, Australia. · Diabetes and Transcription Factors Group, Garvan Institute of Medical Research (GIMR), Sydney, NSW 2010, Australia; St Vincent's Clinical School, University of New South Wales, Sydney, NSW 2052, Australia. · Diabetes and Transcription Factors Group, Garvan Institute of Medical Research (GIMR), Sydney, NSW 2010, Australia; Faculty of Medicine, University of Sydney, Sydney, NSW 2052, Australia; Department of Diabetes and Endocrinology, Westmead Hospital, Sydney, NSW 2145, Australia. · Diabetes and Transcription Factors Group, Garvan Institute of Medical Research (GIMR), Sydney, NSW 2010, Australia; St Vincent's Clinical School, University of New South Wales, Sydney, NSW 2052, Australia; Faculty of Medicine, University of Sydney, Sydney, NSW 2052, Australia; Department of Diabetes and Endocrinology, Westmead Hospital, Sydney, NSW 2145, Australia. · Molecular and Cell Biology Laboratory, Salk Institute, La Jolla, CA 92037, USA. · Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA. · Abramson Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. · The Storr Liver Unit, Westmead Millennium Institute and University of Sydney, Westmead Hospital, Westmead, NSW 2145, Australia. · Gene Expression Laboratory, Salk Institute, La Jolla, CA 92037, USA. Electronic address: downes@salk.edu. · Gene Expression Laboratory, Salk Institute, La Jolla, CA 92037, USA; Howard Hughes Medical Institute, Salk Institute, La Jolla, CA 92037, USA. Electronic address: evans@salk.edu. ·Cell · Pubmed #25259922.

ABSTRACT: The poor clinical outcome in pancreatic ductal adenocarcinoma (PDA) is attributed to intrinsic chemoresistance and a growth-permissive tumor microenvironment. Conversion of quiescent to activated pancreatic stellate cells (PSCs) drives the severe stromal reaction that characterizes PDA. Here, we reveal that the vitamin D receptor (VDR) is expressed in stroma from human pancreatic tumors and that treatment with the VDR ligand calcipotriol markedly reduced markers of inflammation and fibrosis in pancreatitis and human tumor stroma. We show that VDR acts as a master transcriptional regulator of PSCs to reprise the quiescent state, resulting in induced stromal remodeling, increased intratumoral gemcitabine, reduced tumor volume, and a 57% increase in survival compared to chemotherapy alone. This work describes a molecular strategy through which transcriptional reprogramming of tumor stroma enables chemotherapeutic response and suggests vitamin D priming as an adjunct in PDA therapy. PAPERFLICK: