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Pancreatic Neoplasms: HELP
Articles by Daniel Öhlund
Based on 11 articles published since 2010
(Why 11 articles?)
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Between 2010 and 2020, D. Öhlund wrote the following 11 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Review Stromal biology and therapy in pancreatic cancer: ready for clinical translation? 2019

Neesse, Albrecht / Bauer, Christian Alexander / Öhlund, Daniel / Lauth, Matthias / Buchholz, Malte / Michl, Patrick / Tuveson, David A / Gress, Thomas M. ·Department of Gastroenterology and Gastrointestinal Oncology, University Medicine Goettingen, Goettingen, Germany. · Department of Gastroenterology, Endocrinology, Metabolism and Infectiology, University Hospital Marburg, UKGM, Philipps University Marburg, Marburg, Germany. · Department of Radiation Sciences, Umeå University, Umeå, Sweden. · Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden. · Department of Medicine, Philipps University, Center for Tumour and Immune Biology, Marburg, Germany. · Department of Internal Medicine I, Martin, Luther University Halle-Wittenberg, Halle, Germany. · Lustgarten Foundation Designated Pancreatic Cancer Research Lab at Cold Spring Harbor Laboratory, New York, USA. ·Gut · Pubmed #30177543.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) is notoriously aggressive and hard to treat. The tumour microenvironment (TME) in PDA is highly dynamic and has been found to promote tumour progression, metastasis niche formation and therapeutic resistance. Intensive research of recent years has revealed an incredible heterogeneity and complexity of the different components of the TME, including cancer-associated fibroblasts, immune cells, extracellular matrix components, tumour vessels and nerves. It has been hypothesised that paracrine interactions between neoplastic epithelial cells and TME compartments may result in either tumour-promoting or tumour-restraining consequences. A better preclinical understanding of such complex and dynamic network systems is required to develop more powerful treatment strategies for patients. Scientific activity and the number of compelling findings has virtually exploded during recent years. Here, we provide an update of the most recent findings in this area and discuss their translational and clinical implications for basic scientists and clinicians alike.

2 Article Novel prognostic markers within the CD44-stromal ligand network in pancreatic cancer. 2019

Franklin, Oskar / Billing, Ola / Öhlund, Daniel / Berglund, Anette / Herdenberg, Carl / Wang, Wanzhong / Hellman, Urban / Sund, Malin. ·Department of Surgical and Perioperative Sciences, Umeå University, Umeå, Sweden. · Department of Radiation Sciences, Umeå University, Umeå, Sweden. · Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden. · Department of Pathology/Cytology, Karolinska University Hospital, Stockholm, Sweden. · Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden. ·J Pathol Clin Res · Pubmed #30456933.

ABSTRACT: The dense stroma in pancreatic cancer tumours is rich in secreted extracellular matrix proteins and proteoglycans. Secreted hyaluronan, osteopontin and type IV collagen sustain oncogenic signalling by interactions with CD44s and its variant isoform CD44v6 on cancer cell membranes. Although well established in animal and in vitro models, this oncogenic CD44-stromal ligand network is less explored in human cancer. Here, we use a pancreatic cancer tissue microarray from 69 primary tumours and 37 metastatic lymph nodes and demonstrate that high tumour cell expression of CD44s and, surprisingly, low stromal deposition of osteopontin correlate with poor survival independent of established prognostic factors for pancreatic cancer. High stromal expression of hyaluronan was a universal trait of both primary tumours and metastatic lymph nodes. However, hyaluronan species of different molecular mass are known to function differently in pancreatic cancer biology and immunohistochemistry cannot distinguish between them. Using gas-phase electrophoretic molecular mobility analysis, we uncover a shift towards high molecular mass hyaluronan in pancreatic cancer tissue compared to normal pancreas and at a transcriptional level, we find that hyaluronan synthesising HAS2 correlates positively with CD44. The resulting prediction that high molecular mass hyaluronan would then correlate with poor survival in pancreatic cancer was confirmed in serum samples, where we demonstrate that hyaluronan >27 kDa measured before surgery is an independent predictor of postoperative survival. Our findings confirm the prognostic value of CD44 tissue expression and highlight osteopontin tissue expression and serum high molecular mass hyaluronan as novel prognostic markers in pancreatic cancer.

3 Article CA19-9 and apolipoprotein-A2 isoforms as detection markers for pancreatic cancer: a prospective evaluation. 2019

Honda, Kazufumi / Katzke, Verena A / Hüsing, Anika / Okaya, Shinobu / Shoji, Hirokazu / Onidani, Kaoru / Olsen, Anja / Tjønneland, Anne / Overvad, Kim / Weiderpass, Elisabete / Vineis, Paolo / Muller, David / Tsilidis, Kostas / Palli, Domenico / Pala, Valeria / Tumino, Rosario / Naccarati, Alessio / Panico, Salvatore / Aleksandrova, Krasimira / Boeing, Heiner / Bueno-de-Mesquita, H Bas / Peeters, Petra H / Trichopoulou, Antonia / Lagiou, Pagona / Khaw, Kay-Tee / Wareham, Nick / Travis, Ruth C / Merino, Susana / Duell, Eric J / Rodríguez-Barranco, Miguel / Chirlaque, María Dolores / Barricarte, Aurelio / Rebours, Vinciane / Boutron-Ruault, Marie-Chiristine / Romana Mancini, Francesca / Brennan, Paul / Scelo, Ghislaine / Manjer, Jonas / Sund, Malin / Öhlund, Daniel / Canzian, Federico / Kaaks, Rudolf. ·Department of Biomarker for Early Detection of Cancer, National Cancer Center Research Institute, Tokyo, Japan. · Japan Agency for Medical Research and Development (AMED) CREST, Tokyo, Japan. · Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. · Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, Tokyo, Japan. · Diet, Genes and Environment, Danish Cancer Society Research Center, Copenhagen, Denmark. · Department of Public Health, Section for Epidemiology, Aarhus University, Aarhus, Denmark. · Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, Tromsø, Norway. · Department of Research, Cancer Registry of Norway, Institute of Population-Based Cancer Research, Oslo, Norway. · Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. · Genetic Epidemiology Group, Folkhälsan Research Center, Helsinki, Finland. · Department of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, London, United Kingdom. · Department of Hygiene and Epidemiology, School of Medicine, University of Ioannina, Ioannina, Greece. · Cancer Risk Factors and Life-Style Epidemiology Unit, Cancer Research and Prevention Institute - ISPO, Florence, Italy. · Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy. · Cancer Registry and Histopathology Unit, "Civic - M.P. Arezzo" Hospital, Ragusa, Italy. · Department of Molecular and Genetic Epidemiology, IIGM - Italian Institute for Genomic Medicine, Torino, Italy. · Dipartimento di Medicina Clinica e Chirurgia, Federico II University, Naples, Italy. · Department of Epidemiology, German Institute of Human Nutrition, Potsdam-Rehbruecke (DIfE), Nuthetal, Germany. · Department of Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands. · Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, The Netherlands. · Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia. · Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, The Netherlands. · MRC-PHE Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College, London, United Kingdom. · Unit of Nutritional Epidemiology and Nutrition in Public Health, Department of Hygiene, Epidemiology and Medical Statistics, National and Kapodistrian University of Athens, School of Medicine, WHO Collaborating Center for Nutrition and Health. · Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts. · Cancer Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom. · MRC Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom. · Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom. · Public Health Directorate, Asturias, Spain, Acknowledgment of funds: Regional Government of Asturias. · PanC4 Consortium, Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO-IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain. · Escuela Andaluza de Salud Pública. Instituto de Investigación Biosanitaria ibs.GRANADA, Hospitales Universitarios de Granada/Universidad de Granada, Granada, Spain. · CIBER Epidemiology and Public Health CIBERESP, Madrid, Spain. · Department of Epidemiology, Murcia Regional Health Council, CIBER Epidemiología y Salud Pública (CIBERESP), Spain, Ronda de Levante, Murcia, Spain. · Navarra Public Health Institute, Pamplona, Spain. · IdiSNA, Navarra Institute for Health Research, Pamplona, Spain. · Pancreatology Unit, Beaujon Hospital, Clichy, France. · INSERM - UMR 1149, University Paris 7, Paris, France. · CESP, INSERM U1018, Univ. Paris-Sud, UVSQ, Université Paris-Saclay, Villejuif, France. · Lifestyle, Genes and Health: Integrative Trans-Generational Epidemiology, Gustave Roussy, Villejuif, France. · Section of Genetics, International Agency for Research on Cancer (IARC), World Health Organization, Lyon, France. · Department of Surgery, Skåne University Hospital, Lund University, Lund, Sweden. · Department of Surgical and Preoperative Sciences, Umeå University, Umeå, Sweden. · Department of Radiation Sciences and Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden. · Genomic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. ·Int J Cancer · Pubmed #30259989.

ABSTRACT: Recently, we identified unique processing patterns of apolipoprotein A2 (ApoA2) in patients with pancreatic cancer. Our study provides a first prospective evaluation of an ApoA2 isoform ("ApoA2-ATQ/AT"), alone and in combination with carbohydrate antigen 19-9 (CA19-9), as an early detection biomarker for pancreatic cancer. We performed ELISA measurements of CA19-9 and ApoA2-ATQ/AT in 156 patients with pancreatic cancer and 217 matched controls within the European EPIC cohort, using plasma samples collected up to 60 months prior to diagnosis. The detection discrimination statistics were calculated for risk scores by strata of lag-time. For CA19-9, in univariate marker analyses, C-statistics to distinguish future pancreatic cancer patients from cancer-free individuals were 0.80 for plasma taken ≤6 months before diagnosis, and 0.71 for >6-18 months; for ApoA2-ATQ/AT, C-statistics were 0.62, and 0.65, respectively. Joint models based on ApoA2-ATQ/AT plus CA19-9 significantly improved discrimination within >6-18 months (C = 0.74 vs. 0.71 for CA19-9 alone, p = 0.022) and ≤ 18 months (C = 0.75 vs. 0.74, p = 0.022). At 98% specificity, and for lag times of ≤6, >6-18 or ≤ 18 months, sensitivities were 57%, 36% and 43% for CA19-9 combined with ApoA2-ATQ/AT, respectively, vs. 50%, 29% and 36% for CA19-9 alone. Compared to CA19-9 alone, the combination of CA19-9 and ApoA2-ATQ/AT may improve detection of pancreatic cancer up to 18 months prior to diagnosis under usual care, and may provide a useful first measure for pancreatic cancer detection prior to imaging.

4 Article VEGF receptor-2/neuropilin 1 trans-complex formation between endothelial and tumor cells is an independent predictor of pancreatic cancer survival. 2018

Morin, Eric / Sjöberg, Elin / Tjomsland, Vegard / Testini, Chiara / Lindskog, Cecilia / Franklin, Oskar / Sund, Malin / Öhlund, Daniel / Kiflemariam, Sara / Sjöblom, Tobias / Claesson-Welsh, Lena. ·Uppsala University, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Science for Life Laboratory, Uppsala, Sweden. · University of Oslo, Department of Hepato-pancreato-biliary Surgery, Oslo University Hospital, Institute of Clinical Medicine, Oslo, Norway. · Umeå University, Department of Surgery and Perioperative Sciences, Umeå, Sweden. · Umeå University, Department of Radiation Sciences, Umeå, Sweden. · Umeå University, Wallenberg Centre for Molecular Medicine, Umeå, Sweden. ·J Pathol · Pubmed #30027561.

ABSTRACT: Unstable and dysfunctional tumor vasculature promotes cancer progression and spread. Signal transduction by the pro-angiogenic vascular endothelial growth factor (VEGF) receptor-2 (VEGFR2) is modulated by VEGFA-dependent complex formation with neuropilin 1 (NRP1). NRP1 expressed on tumor cells can form VEGFR2/NRP1 trans-complexes between tumor cells and endothelial cells which arrests VEGFR2 on the endothelial surface, thus interfering with productive VEGFR2 signaling. In mouse fibrosarcoma, VEGFR2/NRP1 trans-complexes correlated with reduced tumor vessel branching and reduced tumor cell proliferation. Pancreatic ductal adenocarcinoma (PDAC) strongly expressed NRP1 on both tumor cells and endothelial cells, in contrast to other common cancer forms. Using proximity ligation assay, VEGFR2/NRP1 trans-complexes were identified in human PDAC tumor tissue, and its presence was associated with reduced tumor vessel branching, reduced tumor cell proliferation, and improved patient survival after adjusting for other known survival predictors. We conclude that VEGFR2/NRP1 trans-complex formation is an independent predictor of PDAC patient survival. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

5 Article Plasma Micro-RNA Alterations Appear Late in Pancreatic Cancer. 2018

Franklin, Oskar / Jonsson, Pär / Billing, Ola / Lundberg, Erik / Öhlund, Daniel / Nyström, Hanna / Lundin, Christina / Antti, Henrik / Sund, Malin. ·Department of Surgical and Perioperative Sciences, Umeå University, Sweden. · Department of Chemistry, Umeå University, Sweden. ·Ann Surg · Pubmed #28425921.

ABSTRACT: OBJECTIVES: The aim of this research was to study whether plasma microRNAs (miRNA) can be used for early detection of pancreatic cancer (PC) by analyzing prediagnostic plasma samples collected before a PC diagnosis. BACKGROUND: PC has a poor prognosis due to late presenting symptoms and early metastasis. Circulating miRNAs are altered in PC at diagnosis but have not been evaluated in a prediagnostic setting. METHODS: We first performed an initial screen using a panel of 372 miRNAs in a retrospective case-control cohort that included early-stage PC patients and healthy controls. Significantly altered miRNAs at diagnosis were then measured in an early detection case-control cohort wherein plasma samples in the cases are collected before a PC diagnosis. Carbohydrate antigen 19-9 (Ca 19-9) levels were measured in all samples for comparison. RESULTS: Our initial screen, including 23 stage I-II PC cases and 22 controls, revealed 15 candidate miRNAs that were differentially expressed in plasma samples at PC diagnosis. We combined all 15 miRNAs into a multivariate statistical model, which outperformed Ca 19-9 in receiver-operating characteristics analysis. However, none of the candidate miRNAs, individually or in combination, were significantly altered in prediagnostic plasma samples from 67 future PC patients compared with 132 matched controls. In comparison, Ca 19-9 levels were significantly higher in the cases at <5 years before diagnosis. CONCLUSION: Plasma miRNAs are altered in PC patients at diagnosis, but the candidate miRNAs found in this study appear late in the course of the disease and cannot be used for early detection of the disease.

6 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.

7 Article NRF2 Promotes Tumor Maintenance by Modulating mRNA Translation in Pancreatic Cancer. 2016

Chio, Iok In Christine / Jafarnejad, Seyed Mehdi / Ponz-Sarvise, Mariano / Park, Youngkyu / Rivera, Keith / Palm, Wilhelm / Wilson, John / Sangar, Vineet / Hao, Yuan / Öhlund, Daniel / Wright, Kevin / Filippini, Dea / Lee, Eun Jung / Da Silva, Brandon / Schoepfer, Christina / Wilkinson, John Erby / Buscaglia, Jonathan M / DeNicola, Gina M / Tiriac, Herve / Hammell, Molly / Crawford, Howard C / Schmidt, Edward E / Thompson, Craig B / Pappin, Darryl J / Sonenberg, Nahum / Tuveson, David A. ·Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724, USA. · Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada. · Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. · Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. · Institute of Systems Biology, 401 Terry Avenue N, Seattle, WA 98109, USA. · Departments of Molecular & Integrative Physiology and Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA. · Division of Gastroenterology, Department of Medicine, Stony Brook University School of Medicine, Stony Brook, NY 11794, USA. · Meyer Cancer Center, Weill Cornell Medical College, New York, NY 10021, USA. · Department of Microbiology and Immunology, Montana State University, Bozeman, MT 59718, USA. · Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724, USA. Electronic address: dtuveson@cshl.edu. ·Cell · Pubmed #27477511.

ABSTRACT: Pancreatic cancer is a deadly malignancy that lacks effective therapeutics. We previously reported that oncogenic Kras induced the redox master regulator Nfe2l2/Nrf2 to stimulate pancreatic and lung cancer initiation. Here, we show that NRF2 is necessary to maintain pancreatic cancer proliferation by regulating mRNA translation. Specifically, loss of NRF2 led to defects in autocrine epidermal growth factor receptor (EGFR) signaling and oxidation of specific translational regulatory proteins, resulting in impaired cap-dependent and cap-independent mRNA translation in pancreatic cancer cells. Combined targeting of the EGFR effector AKT and the glutathione antioxidant pathway mimicked Nrf2 ablation to potently inhibit pancreatic cancer ex vivo and in vivo, representing a promising synthetic lethal strategy for treating the disease.

8 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.

9 Article Combining conventional and stroma-derived tumour markers in pancreatic ductal adenocarcinoma. 2015

Franklin, Oskar / Öhlund, Daniel / Lundin, Christina / Öman, Mikael / Naredi, Peter / Wang, Wanzhong / Sund, Malin. ·Department of Surgical and Perioperative Sciences, Umeå, Sweden. · Department of Pathology, Umeå University, Umeå, Sweden. ·Cancer Biomark · Pubmed #25524936.

ABSTRACT: BACKGROUND: A lack of disease-specific symptoms and good tumour markers makes early detection and diagnosis of pancreatic ductal adenocarcinoma (PDAC) challenging. OBJECTIVE: To analyse the tissue expression and circulating levels of four stroma-derived substances (type IV collagen, endostatin/type XVIII collagen, osteopontin and tenascin C) and four conventional tumour markers (CA 19-9, TPS, CEA and Ca 125) in a PDAC cohort. METHODS: Tissue expression of markers in normal pancreas and PDAC tissue was analysed with immunofluorescence. Plasma concentrations of markers were measured before and after surgery. Patients with non-malignant disorders served as controls. RESULTS: The conventional and stromal substances were expressed in the cancer cell compartment and the stroma, respectively. Although most patients had increased levels of many markers before surgery, 2/12 (17%) of patients had normal levels of Ca 19-9 at this stage. High preoperative endostatin/type XVIII collagen, and postoperative type IV collagen was associated with short survival. Neither the pre- nor postoperative levels of TPS, Ca 125 or CA 19-9 were associated to survival. CONCLUSIONS: PDAC is characterized by an abundant stroma. These initial observations indicate that the stroma can be a source of PDAC tumour markers that are found in different compartments of the cancer, thus reflecting different aspects of tumour biology.

10 Article Type IV collagen stimulates pancreatic cancer cell proliferation, migration, and inhibits apoptosis through an autocrine loop. 2013

Öhlund, Daniel / Franklin, Oskar / Lundberg, Erik / Lundin, Christina / Sund, Malin. ·Department of Surgical and Perioperative Sciences, Umeå University, Umeå, Sweden. ·BMC Cancer · Pubmed #23530721.

ABSTRACT: BACKGROUND: Pancreatic cancer shows a highly aggressive and infiltrative growth pattern and is characterized by an abundant tumor stroma known to interact with the cancer cells, and to influence tumor growth and drug resistance. Cancer cells actively take part in the production of extracellular matrix proteins, which then become deposited into the tumor stroma. Type IV collagen, an important component of the basement membrane, is highly expressed by pancreatic cancer cells both in vivo and in vitro. In this study, the cellular effects of type IV collagen produced by the cancer cells were characterized. METHODS: The expression of type IV collagen and its integrin receptors were examined in vivo in human pancreatic cancer tissue. The cellular effects of type IV collagen were studied in pancreatic cancer cell lines by reducing type IV collagen expression through RNA interference and by functional receptor blocking of integrins and their binding-sites on the type IV collagen molecule. RESULTS: We show that type IV collagen is expressed close to the cancer cells in vivo, forming basement membrane like structures on the cancer cell surface that colocalize with the integrin receptors. Furthermore, the interaction between type IV collagen produced by the cancer cell, and integrins on the surface of the cancer cells, are important for continuous cancer cell growth, maintenance of a migratory phenotype, and for avoiding apoptosis. CONCLUSION: We show that type IV collagen provides essential cell survival signals to the pancreatic cancer cells through an autocrine loop.

11 Minor Building up the tension between the epithelial and stromal compartment in pancreatic ductal adenocarcinoma. 2016

Biffi, G / Öhlund, D / Tuveson, D. ·The Cancer Centre at Cold Spring Harbor Laboratory (CSHL), New York, NY, USA. ·Cell Death Differ · Pubmed #27285108.

ABSTRACT: -- No abstract --