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ABSTRACT: Pancreatic cancer is the fourth leading cause of cancer death in our society, with a mortality that virtually parallels its incidence, a median survival of <12 months even with maximal therapy, and a 5-year survival rate of <5 %. The diversity of clinical outcomes and the molecular heterogeneity of histopathologically similar cancer types, incomplete knowledge of the genomic aberrations that drive carcinogenesis and the lack of therapeutics that specifically target most known genomic aberrations necessitates large-scale detailed analysis of cancer genomes to identify novel potential therapeutic strategies. As part of the International Cancer Genome Consortium (ICGC), the Australian Pancreatic Cancer Genome Initiative (APGI) used exomic sequencing and copy number analysis to define genomic aberrations that characterize a large, clinically focused, prospectively accrued cohort of patients with pancreatic cancer. The cohort consisted of early (clinical stages I and II) non-pre-treated patients with pancreatic ductal adenocarcinoma who underwent operative resection with curative intent. We devised approaches to adjust for low epithelial content in primary tumours and to define the genomic landscape of pancreatic cancer to identify novel candidate driver genes and mechanisms. We aim to develop stratified, molecular phenotype-guided therapeutic strategies using existing therapeutics that are either rescued, repurposed, in development, or are known to be effective in an undefined subgroup of PC patients. These are then tested in primary patient-derived xenografts and cell lines from the above deeply characterized cohort. In addition, we return information to treating clinicians that influences patient care and are launching a clinical trial called IMPaCT (Individualized Molecular Pancreatic Cancer Therapy). This umbrella design trial randomizes patients with metastatic disease to either standard first-line therapy with gemcitabine, or a molecular phenotype-guided approach using next-generation sequencing strategies to screen for actionable mutations defined through the ICGC effort.
Journal of hepato-biliary-pancreatic sciences. 05/2013;
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ABSTRACT: Large-scale cancer genome studies are unveiling significant complexity and heterogeneity even in histopathologically indistinguishable cancers. Differentiating 'driver' mutations that are functionally relevant from 'passenger' mutations is a major challenge in cancer genomics. While recurrent mutations in a gene provides supporting evidence of 'driver' status, novel computational methods and model systems are greatly improving our ability to identify genes important in carcinogenesis. Reimand and Bader have recently shown that driver gene discovery in discrete gene classes (in this case the kinome) is possible across multiple cancer types and has the potential to yield new druggable targets and clinically relevant leads.
Genome Medicine 02/2013; 5(2):19.
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David K Chang,
Nigel B Jamieson,
Amber L Johns,
Christopher J Scarlett,
Marina Pajic,
Angela Chou,
Mark Pinese,
Jeremy L Humphris,
Marc D Jones,
Christopher Toon, [......],
Karin A Oien,
Alan K Foulis,
Elizabeth A Musgrove,
Robert L Sutherland,
James G Kench,
C Ross Carter,
Anthony J Gill,
Aldo Scarpa,
Colin J McKay, Andrew V Biankin
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ABSTRACT: PURPOSEIndividuals with adenocarcinoma of the ampulla of Vater demonstrate a broad range of outcomes, presumably because these cancers may arise from any one of the three epithelia that converge at that location. This variability poses challenges for clinical decision making and the development of novel therapeutic strategies. PATIENTS AND METHODS
We assessed the potential clinical utility of histomolecular phenotypes defined using a combination of histopathology and protein expression (CDX2 and MUC1) in 208 patients from three independent cohorts who underwent surgical resection for adenocarcinoma of the ampulla of Vater. RESULTS: one, patients with histomolecular nonpancreaticobiliary (intestinal) carcinoma without LN metastases who had an excellent prognosis; two, those with histomolecular pancreaticobiliary carcinoma with LN metastases who had a poor outcome; and three, the remainder of patients (nonpancreaticobiliary, LN positive or pancreaticobiliary, LN negative) who had an intermediate outcome. CONCLUSION
Histopathologic and molecular criteria combine to define clinically relevant histomolecular phenotypes of adenocarcinoma of the ampulla of Vater and potentially represent distinct diseases with significant implications for current therapeutic strategies, the ability to interpret past clinical trials, and future trial design.
Journal of Clinical Oncology 02/2013; · 18.37 Impact Factor
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Elke Wauters,
Victor Javier Sanchez-Arevalo Lobo,
Andreia V Pinho,
Amanda Mawson,
Daniel Herranz,
Jianmin Wu,
Mark J Cowley,
Emily K Colvin,
Erna Ngawi Njicop,
Robert L Sutherland,
Tao Liu,
Manuel Serrano,
Luc Bouwens,
Fransisco X Real, Andrew V Biankin,
Ilse Rooman
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ABSTRACT: The exocrine pancreas can undergo acinar to ductal metaplasia (ADM), as in the case of pancreatitis where precursor lesions of pancreatic ductal adenocarcinoma (PDAC) can arise. The NAD+-dependent protein deacetylase Sirtuin-1 (Sirt1) has been implicated in carcinogenesis with dual roles depending on its subcellular localization. In this study, we examined the expression and the role of Sirt1 in different stages of pancreatic carcinogenesis, i.e. ADM models and established PDAC. In addition, we analysed the expression of KIAA1967, a key mediator of Sirt1 function, along with other potential Sirt1 downstream targets. Sirt1 was coexpressed with KIAA1967 in the nuclei of normal pancreatic acinar cells. In ADM, Sirt1 underwent a transient nuclear to cytoplasmic shuttling. Experiments where during ADM, we enforced repression of Sirt1 shuttling, inhibition of Sirt1 activity or modulation of its expression, all underscore that the temporary decrease of nuclear and increase of cytoplasmic Sirt1 stimulate ADM. Our results further underscore that important transcriptional regulators of acinar differentiation, i.e. pancreatic transcription factor-1a and ß-catenin can be deacetylated by Sirt1. Inhibition of Sirt1 is effective in suppression of ADM and in reducing cell viability in established PDAC tumors. KIAA1967 expression is differentially down regulated in PDAC and impacts on the sensitivity of PDAC cells to the Sirt1/2 inhibitor Tenovin-6. In PDAC, acetylation of ß-catenin is not affected, unlike p53, a well characterised Sirt1 regulated protein in tumor cells. Our results reveal that Sirt1 is an important regulator and potential therapeutic target in pancreatic carcinogenesis. Sirt1 is co-expressed with Dbc1 in nuclei of normal pancreatic acinar cells. In ADM, Sirt1 undergoes a transient nuclear to cytoplasmic shuttling. Experiments where during ADM, we enforced repression of Sirt1 shuttling, inhibition of Sirt1 activity or modulation of its expression, all underscore that the temporary decrease of nuclear and increase of cytoplasmic Sirt1 stimulate ADM. Our results further underscore that important regulators of acinar differentiation, i.e. the transcription factor Pancreatic transcription factor-1a and beta-catenin can be deacetylated by Sirt1. Inhibition of Sirt1 is effective in suppression of ADM and in reducing cell viability in established PDAC tumors. Dbc1 expression is differentially down regulated in PDAC and impacts on the sensitivity of PDAC cells to the Sirt1/2 inhibitor Tenovin-6. In PDAC, acetylation of beta-Catenin is not affected, unlike p53, a well characterised Sirt1 regulated protein in tumor cells. This is the first study to show that Sirt1 is an important regulator and potential therapeutic target throughout pancreatic carcinogenesis.
Cancer Research 01/2013; · 7.86 Impact Factor
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Andrew V Biankin,
Nicola Waddell,
Karin S Kassahn,
Marie-Claude Gingras,
Lakshmi B Muthuswamy,
Amber L Johns,
David K Miller,
Peter J Wilson,
Ann-Marie Patch,
Jianmin Wu, [......],
David A Largaespada,
Lodewyk F A Wessels,
Alistair G Rust,
Lincoln D Stein,
David A Tuveson,
Neal G Copeland,
Thomas J Hudson,
David A Wheeler,
John D McPherson,
Richard A Gibbs
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ABSTRACT: Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations. We define 16 significantly mutated genes, reaffirming known mutations (KRAS, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1), and uncover novel mutated genes including additional genes involved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM) and other mechanisms (ZIM2, MAP2K4, NALCN, SLC16A4 and MAGEA6). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signalling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. We also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis.
Nature 10/2012; · 36.28 Impact Factor
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Andrew V. Biankin,
Nicola Waddell,
Karin S. Kassahn,
Marie-Claude Gingras,
Lakshmi B. Muthuswamy,
Amber L. Johns,
David K. Miller,
Peter J. Wilson,
Ann-Marie Patch,
Jianmin Wu, [......],
Elizabeth A. Musgrove,
Aldo Scarpa,
James R. Eshleman,
Thomas J. Hudson,
Robert L. Sutherland,
David A. Wheeler,
John V. Pearson,
John D. McPherson,
Richard A. Gibbs,
Sean M. Grimmond
Nature 10/2012; advance online publication. · 36.28 Impact Factor
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Carole M Tactacan,
David K Chang,
Mark J Cowley,
Emily S Humphrey,
Jianmin Wu,
Anthony J Gill,
Angela Chou,
Katia Nones,
Sean M Grimmond,
Robert L Sutherland, Andrew V Biankin,
Roger J Daly
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ABSTRACT: BACKGROUND: The receptor tyrosine kinase RON exhibits increased expression during pancreatic cancer progression and promotes migration, invasion and gemcitabine resistance of pancreatic cancer cells in experimental models. However, the prognostic significance of RON expression in pancreatic cancer is unknown. METHODS: RON expression was characterized in several large cohorts, including a prospective study, totaling 492 pancreatic cancer patients and relationships with patient outcome and clinico-pathologic variables were assessed. RESULTS: RON expression was associated with outcome in a training set, but this was not recapitulated in the validation set, nor was there any association with therapeutic responsiveness in the validation set or the prospective study. CONCLUSIONS: Although RON is implicated in pancreatic cancer progression in experimental models, and may constitute a therapeutic target, RON expression is not associated with prognosis or therapeutic responsiveness in resected pancreatic cancer.
BMC Cancer 09/2012; 12(1):395. · 3.01 Impact Factor
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Sarah Song,
Katia Nones,
David Miller,
Ivon Harliwong,
Karin S Kassahn,
Mark Pinese,
Marina Pajic,
Anthony J Gill,
Amber L Johns,
Matthew Anderson, [......],
Qinying Xu,
Felicity Newell,
Mark J Cowley,
Jianmin Wu,
Peter Wilson,
Lynn Fink, Andrew V Biankin,
Nic Waddell,
Sean M Grimmond,
John V Pearson
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ABSTRACT: Tumour cellularity, the relative proportion of tumour and normal cells in a sample, affects the sensitivity of mutation detection, copy number analysis, cancer gene expression and methylation profiling. Tumour cellularity is traditionally estimated by pathological review of sectioned specimens; however this method is both subjective and prone to error due to heterogeneity within lesions and cellularity differences between the sample viewed during pathological review and tissue used for research purposes. In this paper we describe a statistical model to estimate tumour cellularity from SNP array profiles of paired tumour and normal samples using shifts in SNP allele frequency at regions of loss of heterozygosity (LOH) in the tumour. We also provide qpure, a software implementation of the method. Our experiments showed that there is a medium correlation 0.42 ([Formula: see text]-value = 0.0001) between tumor cellularity estimated by qpure and pathology review. Interestingly there is a high correlation 0.87 ([Formula: see text]-value [Formula: see text] 2.2e-16) between cellularity estimates by qpure and deep Ion Torrent sequencing of known somatic KRAS mutations; and a weaker correlation 0.32 ([Formula: see text]-value = 0.004) between IonTorrent sequencing and pathology review. This suggests that qpure may be a more accurate predictor of tumour cellularity than pathology review. qpure can be downloaded from https://sourceforge.net/projects/qpure/.
PLoS ONE 01/2012; 7(9):e45835. · 4.09 Impact Factor
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James J H Chong,
Vashe Chandrakanthan,
Munira Xaymardan,
Naisana S Asli,
Joan Li,
Ishtiaq Ahmed,
Corey Heffernan,
Mary K Menon,
Christopher J Scarlett,
Amirsalar Rashidianfar,
Christine Biben,
Hans Zoellner,
Emily K Colvin,
John E Pimanda, Andrew V Biankin,
Bin Zhou,
William T Pu,
Owen W J Prall,
Richard P Harvey
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ABSTRACT: Colony-forming units - fibroblast (CFU-Fs), analogous to those giving rise to bone marrow (BM) mesenchymal stem cells (MSCs), are present in many organs, although the relationship between BM and organ-specific CFU-Fs in homeostasis and tissue repair is unknown. Here we describe a population of adult cardiac-resident CFU-Fs (cCFU-Fs) that occupy a perivascular, adventitial niche and show broad trans-germ layer potency in vitro and in vivo. CRE lineage tracing and embryo analysis demonstrated a proepicardial origin for cCFU-Fs. Furthermore, in BM transplantation chimeras, we found no interchange between BM and cCFU-Fs after aging, myocardial infarction, or BM stem cell mobilization. BM and cardiac and aortic CFU-Fs had distinct CRE lineage signatures, indicating that they arise from different progenitor beds during development. These diverse origins for CFU-Fs suggest an underlying basis for differentiation biases seen in different CFU-F populations, and could also influence their capacity for participating in tissue repair.
Cell stem cell 12/2011; 9(6):527-40. · 23.56 Impact Factor
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ABSTRACT: The Protein Interaction Network Analysis (PINA) platform is a comprehensive web resource, which includes a database of unified protein-protein interaction data integrated from six manually curated public databases, and a set of built-in tools for network construction, filtering, analysis and visualization. The second version of PINA enhances its utility for studies of protein interactions at a network level, by including multiple collections of interaction modules identified by different clustering approaches from the whole network of protein interactions ('interactome') for six model organisms. All identified modules are fully annotated by enriched Gene Ontology terms, KEGG pathways, Pfam domains and the chemical and genetic perturbations collection from MSigDB. Moreover, a new tool is provided for module enrichment analysis in addition to simple query function. The interactome data are also available on the web site for further bioinformatics analysis. PINA is freely accessible at http://cbg.garvan.unsw.edu.au/pina/.
Nucleic Acids Research 11/2011; 40(Database issue):D862-5. · 8.03 Impact Factor
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ABSTRACT: Cancer arises as a consequence of mutations in genomes of cancer cells, which over time allow them to proliferate and spread to distant sites. Large-scale sequencing of cancer genomes is revealing an increasing number of potential driver mutations that may allow specific targeting of cancer genes, proteins, and pathways. Comprehensive views of cancer genomes are also revealing enormous heterogeneity of mutation profiles, even among tumours derived from the same organs and having similar pathological characteristics. There are now many examples where mutation profiles observed in tumours have been shown to correlate with clinical features of disease, drug response, and patient outcomes. When ignored, molecular heterogeneity can lead to failures in drug development, as drugs that may have efficacy in subgroups of patients with specific molecular phenotypes may show marginal response when tested in large groups of unselected patients. This article explores issues relevant to the clinical translation of sequence-based mutation profiles in the clinical development of targeted therapies and in the future management of cancer patients.
Human Genetics 06/2011; 130(1):79-91. · 5.07 Impact Factor
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Glenn M Marshall,
Pei Y Liu,
Samuele Gherardi,
Christopher J Scarlett,
Antonio Bedalov,
Ning Xu,
Nuncio Iraci,
Emanuele Valli,
Dora Ling,
Wayne Thomas,
Margo van Bekkum,
Eric Sekyere,
Kacper Jankowski,
Toby Trahair,
Karen L Mackenzie,
Michelle Haber,
Murray D Norris, Andrew V Biankin,
Giovanni Perini,
Tao Liu
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ABSTRACT: The N-Myc oncoprotein is a critical factor in neuroblastoma tumorigenesis which requires additional mechanisms converting a low-level to a high-level N-Myc expression. N-Myc protein is stabilized when phosphorylated at Serine 62 by phosphorylated ERK protein. Here we describe a novel positive feedback loop whereby N-Myc directly induced the transcription of the class III histone deacetylase SIRT1, which in turn increased N-Myc protein stability. SIRT1 binds to Myc Box I domain of N-Myc protein to form a novel transcriptional repressor complex at gene promoter of mitogen-activated protein kinase phosphatase 3 (MKP3), leading to transcriptional repression of MKP3, ERK protein phosphorylation, N-Myc protein phosphorylation at Serine 62, and N-Myc protein stabilization. Importantly, SIRT1 was up-regulated, MKP3 down-regulated, in pre-cancerous cells, and preventative treatment with the SIRT1 inhibitor Cambinol reduced tumorigenesis in TH-MYCN transgenic mice. Our data demonstrate the important roles of SIRT1 in N-Myc oncogenesis and SIRT1 inhibitors in the prevention and therapy of N-Myc-induced neuroblastoma.
PLoS Genetics 06/2011; 7(6):e1002135. · 8.69 Impact Factor
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ABSTRACT: Defining key driver mutations in cancer, the resulting aberrations in molecular mechanisms and the subsequent phenotype underpins the development and implementation of novel personalized medicine strategies. The literature is replete with biomarkers of prognosis and therapeutic responsiveness identified in single cohorts of patients that have not been independently validated and as a consequence, not developed. Integrating companion biomarker discovery with therapeutic development at the preclinical stage creates the opportunity to identify candidate biomarkers early, which would significantly facilitate both biomarker and therapeutic development. Advances in "-omic" technologies have led to large-scale efforts in characterizing and cataloguing the full range of aberrations in cancer. These include the International Cancer Genome Consortium and The Cancer Genome Atlas, which aim to comprehensively catalogue the range of genomic aberrations for large numbers of cancers for a progressively increasing range of cancer types and subtypes. The technical challenges associated with achieving these goals in some instances have required the generation of primary xenografts and cell lines. These extensively characterized model systems will provide an unprecedented resource for the discovery of biomarkers of therapeutic responsiveness for established therapies, and the development of companion biomarkers linked with preclinical novel therapeutic development in the future.
Human Genetics 04/2011; 130(1):93-101. · 5.07 Impact Factor
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ABSTRACT: Pancreatic cancer has a dismal prognosis and is the fourth most common cause of cancer related death in Western societies. In large part this is due to its typically late presentation, usually as locally advanced or metastatic disease. Identification of the non-invasive precursor lesions to pancreatic cancer raises the possibility of surgical treatment or chemoprevention at an early stage in the evolution of this disease, when more amenable to therapeutic interventions. Precursor lesions to pancreatic ductal adenocarcinoma, in particular pancreatic intraepithelial neoplasia (PanIN), have been recognised under a variety of synonyms for over 50 years. Over the past decade our understanding of the morphology, biological significance and molecular aberrations of these lesions has grown rapidly and there is now a widely accepted progression model integrating the accumulated morphological and molecular observations. Further progress is likely to be accelerated by improved mouse models of pancreatic cancer and by insight into the cancer genome gained by the International Cancer Genome Consortium (ICGC), in which an Australian consortium is leading the pancreatic cancer initiative. This review also outlines the morphological and molecular features of the other two precursors of pancreatic ductal adenocarcinoma, i.e., intraductal papillary mucinous neoplasms and mucinous cystic neoplasms.
Pathology 04/2011; 43(3):183-200. · 2.38 Impact Factor
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Rhonda A Kwong,
Christopher J Scarlett,
Larry H Kalish,
Ian E Cole,
James G Kench,
Eleanor Y M Sum,
Elizabeth A Musgrove,
Susan M Henshall,
Geoffrey J Lindeman, Andrew V Biankin,
Jane E Visvader,
Robert L Sutherland
Histopathology 02/2011; 58(3):477-80. · 3.08 Impact Factor
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Nam Q Nguyen,
Amber L Johns,
Anthony J Gill,
Nicole Ring,
David K Chang,
Annette Clarkson,
Neil D Merrett,
James G Kench,
Emily K Colvin,
Christopher J Scarlett, Andrew V Biankin
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ABSTRACT: Background and Aim: Clinicopathological data regarding pancreatic solid pseudopapillary tumors (SPT) in a multiethnic country are limited. The aim of the present study was to characterize pancreatic SPT in Australia.Methods: Clinicopathological features, treatment, immunohistochemical findings and outcome data of 34 patients (79% Caucasian, 12% Asian, 6% South Pacific Islander and 3% African) with pancreatic SPT were reviewed.Results: The most presenting complaint was abdominal pain. Median diameter of tumors was 60 mm (range: 20–220); predominantly located in the pancreatic tail (tail : body : head = 23:3:8). All tumors were resected and patients underwent surgery, including a liver resection for metastasis, all patients were alive after a median follow up of 70 months (IQR: 48–178). Two patients underwent repeated surgery for local recurrences with liver metastases after 8 and 18 months, which were successfully managed by surgical resection. Completeness of excision, perineural spread, vascular space invasion, mitotic rate and cellular atypia did not predict recurrence. In all cases, there was aberrant nuclear staining of beta-catenin and a loss of membranous expression of E-cadherin with aberrant nuclear localization of the cytoplasmic domain. Most pancreatic SPT were also strongly positive for CD10 (96%), progesterone receptor (79%), cytokeratin (28%), synapthophysin (26%) and chromogranin (15%).Conclusions: Pancreatic SPT occur in all races and are uniformly indolent. Given complete resection of a pancreatic SPT is usually curative and recurrences can be treated with re-operation, correct diagnosis is important.
Journal of Gastroenterology and Hepatology 01/2011; 26(2):267 - 274. · 2.87 Impact Factor
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Christopher J Scarlett,
Emily K Colvin,
Mark Pinese,
David K Chang,
Adrienne L Morey,
Elizabeth A Musgrove,
Marina Pajic,
Minoti Apte,
Susan M Henshall,
Robert L Sutherland,
James G Kench, Andrew V Biankin
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ABSTRACT: Chronic pancreatitis and pancreatic cancer are characterised by extensive stellate cell mediated fibrosis, and current therapeutic development includes targeting pancreatic cancer stroma and tumor-host interactions. Recent evidence has suggested that circulating bone marrow derived stem cells (BMDC) contribute to solid organs. We aimed to define the role of circulating haematopoietic cells in the normal and diseased pancreas.
Whole bone marrow was harvested from male β-actin-EGFP donor mice and transplanted into irradiated female recipient C57/BL6 mice. Chronic pancreatitis was induced with repeat injections of caerulein, while carcinogenesis was induced with an intrapancreatic injection of dimethylbenzanthracene (DMBA). Phenotype of engrafted donor-derived cells within the pancreas was assessed by immunohistochemistry, immunofluorescence and in situ hybridisation.
GFP positive cells were visible in the exocrine pancreatic epithelia from 3 months post transplantation. These exhibited acinar morphology and were positive for amylase and peanut agglutinin. Mice administered caerulein developed chronic pancreatitis while DMBA mice exhibited precursor lesions and pancreatic cancer. No acinar cells were identified to be donor-derived upon cessation of cerulein treatment, however rare occurrences of bone marrow-derived acinar cells were observed during pancreatic regeneration. Increased recruitment of BMDC was observed within the desmoplastic stroma, contributing to the activated pancreatic stellate cell (PaSC) population in both diseases. Expression of stellate cell markers CELSR3, PBX1 and GFAP was observed in BMD cancer-associated PaSCs, however cancer-associated, but not pancreatitis-associated BMD PaSCs, expressed the cancer PaSC specific marker CELSR3.
This study demonstrates that BMDC can incorporate into the pancreas and adopt the differentiated state of the exocrine compartment. BMDC that contribute to the activated PaSC population in chronic pancreatitis and pancreatic cancer have different phenotypes, and may play important roles in these diseases. Further, bone marrow transplantation may provide a useful model for the study of tumor-host interactions in cancer and pancreatitis.
PLoS ONE 01/2011; 6(10):e26088. · 4.09 Impact Factor
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Emily K Colvin,
Johana M Susanto,
James G Kench,
Vivienna N Ong,
Amanda Mawson,
Mark Pinese,
David K Chang,
Ilse Rooman,
Sandra A O'Toole,
Davendra Segara,
Elizabeth A Musgrove,
Robert L Sutherland,
Minoti V Apte,
Christopher J Scarlett, Andrew V Biankin
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ABSTRACT: Activation of embryonic signaling pathways quiescent in the adult pancreas is a feature of pancreatic cancer (PC). These discoveries have led to the development of novel inhibitors of pathways such as Notch and Hedgehog signaling that are currently in early phase clinical trials in the treatment of several cancer types. Retinoid signaling is also essential for pancreatic development, and retinoid therapy is used successfully in other malignancies such as leukemia, but little is known concerning retinoid signaling in PC.
We investigated the role of retinoid signaling in vitro and in vivo in normal pancreas, pancreatic injury, regeneration and cancer. Retinoid signaling is active in occasional cells in the adult pancreas but is markedly augmented throughout the parenchyma during injury and regeneration. Both chemically induced and genetically engineered mouse models of PC exhibit a lack of retinoid signaling activity compared to normal pancreas. As a consequence, we investigated Cellular Retinoid Binding Protein 1 (CRBP1), a key regulator of retinoid signaling known to play a role in breast cancer development, as a potential therapeutic target. Loss, or significant downregulation of CRBP1 was present in 70% of human PC, and was evident in the very earliest precursor lesions (PanIN-1A). However, in vitro gain and loss of function studies and CRBP1 knockout mice suggested that loss of CRBP1 expression alone was not sufficient to induce carcinogenesis or to alter PC sensitivity to retinoid based therapies.
In conclusion, retinoid signalling appears to play a role in pancreatic regeneration and carcinogenesis, but unlike breast cancer, it is not mediated directly by CRBP1.
PLoS ONE 01/2011; 6(12):e29075. · 4.09 Impact Factor
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Falko Hochgräfe,
Luxi Zhang,
Sandra A O'Toole,
Brigid C Browne,
Mark Pinese,
Ana Porta Cubas,
Gillian M Lehrbach,
David R Croucher,
Danny Rickwood,
Alice Boulghourjian,
Robert Shearer,
Radhika Nair,
Alexander Swarbrick,
Dana Faratian,
Peter Mullen,
David J Harrison, Andrew V Biankin,
Robert L Sutherland,
Mark J Raftery,
Roger J Daly
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ABSTRACT: To identify therapeutic targets and prognostic markers for basal breast cancers, breast cancer cell lines were subjected to mass spectrometry-based profiling of protein tyrosine phosphorylation events. This revealed that luminal and basal breast cancer cells exhibit distinct tyrosine phosphorylation signatures that depend on pathway activation as well as protein expression. Basal breast cancer cells are characterized by elevated tyrosine phosphorylation of Met, Lyn, EphA2, epidermal growth factor receptor (EGFR), and FAK, and Src family kinase (SFK) substrates such as p130Cas. SFKs exert a prominent role in these cells, phosphorylating key regulators of adhesion and migration and promoting tyrosine phosphorylation of the receptor tyrosine kinases EGFR and Met. Consistent with these observations, SFK inhibition attenuated cellular proliferation, survival, and motility. Basal breast cancer cell lines exhibited differential responsiveness to small molecule inhibitors of EGFR and Met that correlated with the degree of target phosphorylation, and reflecting kinase coactivation, inhibiting two types of activated network kinase (e.g., EGFR and SFKs) was more effective than single agent approaches. FAK signaling enhanced both proliferation and invasion, and Lyn was identified as a proinvasive component of the network that is associated with a basal phenotype and poor prognosis in patients with breast cancer. These studies highlight multiple kinases and substrates for further evaluation as therapeutic targets and biomarkers. However, they also indicate that patient stratification based on expression/activation of drug targets, coupled with use of multi-kinase inhibitors or combination therapies, may be required for effective treatment of this breast cancer subgroup.
Cancer Research 11/2010; 70(22):9391-401. · 7.86 Impact Factor
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Zhihong Xu,
Alain Vonlaufen,
Phoebe A Phillips,
Eva Fiala-Beer,
Xuguo Zhang,
Lu Yang, Andrew V Biankin,
David Goldstein,
Romano C Pirola,
Jeremy S Wilson,
Minoti V Apte
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ABSTRACT: Pancreatic stellate cells (PSCs) produce the stromal reaction in pancreatic cancer (PC), and their interaction with cancer cells facilitates cancer progression. This study investigated the role of human PSCs (hPSCs) in the metastatic process and tumor angiogenesis using both in vivo (orthotopic model) and in vitro (cultured PSC and PC cells) approaches. A sex mismatch study (injection of male hPSCs plus female PC cells into the pancreas of female mice) was conducted to determine whether hPSCs accompany cancer cells to metastatic sites. Metastatic nodules were examined by fluorescent in situ hybridization for the presence of the Y chromosome. Angiogenesis was assessed by i) immunostaining tumors for CD31, an endothelial cell marker; and ii) quantifying human microvascular endothelial cell (HMEC-1) tube formation in vitro on exposure to conditioned media from hPSCs. Transendothelial migration was assessed in vitro by examining the movement of fluorescently labeled hPSCs through an endothelial cell monolayer. Human PSCs i) were found in multiple metastatic sites in each mouse injected with male hPSCs plus female PC cells; ii) increased CD31 expression in primary tumors from mice injected with MiaPaCa-2 and hPSCs and stimulated tube formation by HMEC-1 in vitro; and iii) exhibited transendothelial migration that was stimulated by cancer cells. Human PSCs accompany cancer cells to metastatic sites, stimulate angiogenesis, and are able to intravasate/extravasate to and from blood vessels.
American Journal Of Pathology 10/2010; 177(5):2585-96. · 4.89 Impact Factor
