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Pancreatic Neoplasms: HELP
Articles by Debabrata Mukhopadhyay
Based on 19 articles published since 2009
(Why 19 articles?)
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Between 2009 and 2019, Debabrata Mukhopadhyay wrote the following 19 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Review New insights into pancreatic cancer-induced paraneoplastic diabetes. 2013

Sah, Raghuwansh P / Nagpal, Sajan Jiv Singh / Mukhopadhyay, Debabrata / Chari, Suresh T. ·Department of Internal Medicine, Mayo Clinic, 200 First Street South West, Rochester, MN 55905, USA. ·Nat Rev Gastroenterol Hepatol · Pubmed #23528347.

ABSTRACT: Up to 85% of patients with pancreatic cancer have diabetes or hyperglycaemia, which frequently manifests as early as 2-3 years before a diagnosis of pancreatic cancer. Conversely, patients with new-onset diabetes have a 5-8-fold increased risk of being diagnosed with pancreatic cancer within 1-3 years of developing diabetes. Emerging evidence now indicates that pancreatic cancer causes diabetes. As in type 2 diabetes, β-cell dysfunction and peripheral insulin resistance are seen in pancreatic cancer-induced diabetes. However, unlike in patients with type 2 diabetes, glucose control worsens in patients with pancreatic cancer in the face of ongoing, often profound, weight loss. Diabetes and weight loss, which precede cachexia onset by several months, are paraneoplastic phenomena induced by pancreatic cancer. Although the pathogenesis of these pancreatic cancer-induced metabolic alterations is only beginning to be understood, these are likely mechanisms to promote the survival and growth of pancreatic cancer in a hostile and highly desmoplastic microenvironment. Interestingly, these metabolic changes could enable early diagnosis of pancreatic cancer, if they can be distinguished from the ones that occur in patients with type 2 diabetes. One such possible biomarker is adrenomedullin, which is a potential mediator of β-cell dysfunction in pancreatic cancer-induced diabetes.

2 Review Fabrication of gold nanoparticles for targeted therapy in pancreatic cancer. 2010

Patra, Chitta Ranjan / Bhattacharya, Resham / Mukhopadhyay, Debabrata / Mukherjee, Priyabrata. ·Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA. ·Adv Drug Deliv Rev · Pubmed #19914317.

ABSTRACT: The targeted delivery of a drug should result in enhanced therapeutic efficacy with low to minimal side effects. This is a widely accepted concept, but limited in application due to lack of available technologies and process of validation. Biomedical nanotechnology can play an important role in this respect. Biomedical nanotechnology is a burgeoning field with myriads of opportunities and possibilities for advancing medical science and disease treatment. Cancer nanotechnology (1-100 nm size range) is expected to change the very foundations of cancer treatment, diagnosis and detection. Nanomaterials, especially gold nanoparticles (AuNPs) have unique physico-chemical properties, such as ultra small size, large surface area to mass ratio, and high surface reactivity, presence of surface plasmon resonance (SPR) bands, biocompatibility and ease of surface functionalization. In this review, we will discuss how the unique physico-chemical properties of gold nanoparticles may be utilized for targeted drug delivery in pancreatic cancer leading to increased efficacy of traditional chemotherapeutics.

3 Article Phases of Metabolic and Soft Tissue Changes in Months Preceding a Diagnosis of Pancreatic Ductal Adenocarcinoma. 2019

Sah, Raghuwansh P / Sharma, Ayush / Nagpal, Sajan / Patlolla, Sri Harsha / Sharma, Anil / Kandlakunta, Harika / Anani, Vincent / Angom, Ramcharan Singh / Kamboj, Amrit K / Ahmed, Nazir / Mohapatra, Sonmoon / Vivekanandhan, Sneha / Philbrick, Kenneth A / Weston, Alexander / Takahashi, Naoki / Kirkland, James / Javeed, Naureen / Matveyenko, Aleksey / Levy, Michael J / Mukhopadhyay, Debabrata / Chari, Suresh T. ·Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota. · Department of Biochemistry and Molecular Biology, Mayo Clinic, Jacksonville, Florida. · Department of Radiology Informatics, Mayo Clinic, Rochester, Minnesota. · Division of Radiology, Mayo Clinic, Rochester, Minnesota. · Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, Minnesota. · Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota. · Department of Biochemistry and Molecular Biology, Mayo Clinic, Jacksonville, Florida. Electronic address: Mukhopadhyay.debabrata@mayo.edu. · Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota. Electronic address: Chari.suresh@mayo.edu. ·Gastroenterology · Pubmed #30677401.

ABSTRACT: BACKGROUND & AIMS: Identifying metabolic abnormalities that occur before pancreatic ductal adenocarcinoma (PDAC) diagnosis could increase chances for early detection. We collected data on changes in metabolic parameters (glucose, serum lipids, triglycerides; total, low-density, and high-density cholesterol; and total body weight) and soft tissues (abdominal subcutaneous fat [SAT], adipose tissue, visceral adipose tissue [VAT], and muscle) from patients 5 years before the received a diagnosis of PDAC. METHODS: We collected data from 219 patients with a diagnosis of PDAC (patients) and 657 healthy individuals (controls) from the Rochester Epidemiology Project, from 2000 through 2015. We compared metabolic profiles of patients with those of age- and sex-matched controls, constructing temporal profiles of fasting blood glucose, serum lipids including triglycerides, cholesterol profiles, and body weight and temperature for 60 months before the diagnosis of PDAC (index date). To construct the temporal profile of soft tissue changes, we collected computed tomography scans from 68 patients, comparing baseline (>18 months before diagnosis) areas of SAT, VAT, and muscle at L2/L3 vertebra with those of later scans until time of diagnosis. SAT and VAT, isolated from healthy individuals, were exposed to exosomes isolated from PDAC cell lines and analyzed by RNA sequencing. SAT was collected from KRAS RESULTS: There were no significant differences in metabolic or soft tissue features of patients vs controls until 30 months before PDAC diagnosis. In the 30 to 18 months before PDAC diagnosis (phase 1, hyperglycemia), a significant proportion of patients developed hyperglycemia, compared with controls, without soft tissue changes. In the 18 to 6 months before PDAC diagnosis (phase 2, pre-cachexia), patients had significant increases in hyperglycemia and decreases in serum lipids, body weight, and SAT, with preserved VAT and muscle. In the 6 to 0 months before PDAC diagnosis (phase 3, cachexia), a significant proportion of patients had hyperglycemia compared with controls, and patients had significant reductions in all serum lipids, SAT, VAT, and muscle. We believe the patients had browning of SAT, based on increases in body temperature, starting 18 months before PDAC diagnosis. We observed expression of uncoupling protein 1 (UCP1) in SAT exposed to PDAC exosomes, SAT from mice with PDACs, and SAT from all 5 patients but only 1 of 4 controls. CONCLUSIONS: We identified 3 phases of metabolic and soft tissue changes that precede a diagnosis of PDAC. Loss of SAT starts 18 months before PDAC identification, and is likely due to browning. Overexpression of UCP1 in SAT might be a biomarker of early-stage PDAC, but further studies are needed.

4 Article Mixed poly(vinyl pyrrolidone)-based drug-loaded nanomicelles shows enhanced efficacy against pancreatic cancer cell lines. 2017

Veeren, Anisha / Bhaw-Luximon, Archana / Mukhopadhyay, Debabrata / Jhurry, Dhanjay. ·Centre for Biomedical and Biomaterials Research (CBBR), University of Mauritius, MSIRI Building, Réduit, Mauritius. · Department of Biochemistry/Molecular Biology, Mayo Clinic, Jacksonville, FL 32224, USA. · Centre for Biomedical and Biomaterials Research (CBBR), University of Mauritius, MSIRI Building, Réduit, Mauritius. Electronic address: dhanjay.jhurry@gmail.com. ·Eur J Pharm Sci · Pubmed #28323118.

ABSTRACT: We report in this paper on the enhanced efficacy of a physical mixture of two single anti-cancer loaded nanomicelles against PANC-1 and BxPC-3. Poly(vinyl pyrrolidone-b-polycaprolactone) (PVP-b-PCL) and poly(vinyl pyrrolidone-b-poly(dioxanone-co-methyl dioxanone)) (PVP-b-P(DX-co-MeDX)) were synthesized and successfully loaded with various anti-cancer drugs - gemcitabine (GEM), doxorubicin.HCl (DOX.HCl), doxorubicin.NH

5 Article Genomic analyses identify molecular subtypes of pancreatic cancer. 2016

Bailey, Peter / Chang, David K / Nones, Katia / Johns, Amber L / Patch, Ann-Marie / Gingras, Marie-Claude / Miller, David K / Christ, Angelika N / Bruxner, Tim J C / Quinn, Michael C / Nourse, Craig / Murtaugh, L Charles / Harliwong, Ivon / Idrisoglu, Senel / Manning, Suzanne / Nourbakhsh, Ehsan / Wani, Shivangi / Fink, Lynn / Holmes, Oliver / Chin, Venessa / Anderson, Matthew J / Kazakoff, Stephen / Leonard, Conrad / Newell, Felicity / Waddell, Nick / Wood, Scott / Xu, Qinying / Wilson, Peter J / Cloonan, Nicole / Kassahn, Karin S / Taylor, Darrin / Quek, Kelly / Robertson, Alan / Pantano, Lorena / Mincarelli, Laura / Sanchez, Luis N / Evers, Lisa / Wu, Jianmin / Pinese, Mark / Cowley, Mark J / Jones, Marc D / Colvin, Emily K / Nagrial, Adnan M / Humphrey, Emily S / Chantrill, Lorraine A / Mawson, Amanda / Humphris, Jeremy / Chou, Angela / Pajic, Marina / Scarlett, Christopher J / Pinho, Andreia V / Giry-Laterriere, Marc / Rooman, Ilse / Samra, Jaswinder S / Kench, James G / Lovell, Jessica A / Merrett, Neil D / Toon, Christopher W / Epari, Krishna / Nguyen, Nam Q / Barbour, Andrew / Zeps, Nikolajs / Moran-Jones, Kim / Jamieson, Nigel B / Graham, Janet S / Duthie, Fraser / Oien, Karin / Hair, Jane / Grützmann, Robert / Maitra, Anirban / Iacobuzio-Donahue, Christine A / Wolfgang, Christopher L / Morgan, Richard A / Lawlor, Rita T / Corbo, Vincenzo / Bassi, Claudio / Rusev, Borislav / Capelli, Paola / Salvia, Roberto / Tortora, Giampaolo / Mukhopadhyay, Debabrata / Petersen, Gloria M / Anonymous91128 / Munzy, Donna M / Fisher, William E / Karim, Saadia A / Eshleman, James R / Hruban, Ralph H / Pilarsky, Christian / Morton, Jennifer P / Sansom, Owen J / Scarpa, Aldo / Musgrove, Elizabeth A / Bailey, Ulla-Maja Hagbo / Hofmann, Oliver / Sutherland, Robert L / Wheeler, David A / Gill, Anthony J / Gibbs, Richard A / Pearson, John V / Waddell, Nicola / Biankin, Andrew V / Grimmond, Sean M. ·Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK. · The Kinghorn Cancer Centre, 370 Victoria St, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia. · Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, New South Wales 2200, Australia. · South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, New South Wales 2170, Australia. · QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia. · Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA. · Michael DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas 77030, USA. · Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA. · Department of Human Genetics, University of Utah, Salt Lake City, Utah 84112, USA. · Genetic and Molecular Pathology, SA Pathology, Adelaide, South Australia 5000, Australia. · School of Biological Sciences, The University of Adelaide, Adelaide, South Australia 5000, Australia. · Harvard Chan Bioinformatics Core, Harvard T. H. Chan School of Public Health, Boston, Massachusetts 02115, USA. · Macarthur Cancer Therapy Centre, Campbelltown Hospital, New South Wales 2560, Australia. · Department of Pathology. SydPath, St Vincent's Hospital, Sydney, NSW 2010, Australia. · St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, New South Wales 2052, Australia. · School of Environmental &Life Sciences, University of Newcastle, Ourimbah, New South Wales 2258, Australia. · Department of Surgery, Royal North Shore Hospital, St Leonards, Sydney, New South Wales 2065, Australia. · University of Sydney, Sydney, New South Wales 2006, Australia. · Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown New South Wales 2050, Australia. · School of Medicine, University of Western Sydney, Penrith, New South Wales 2175, Australia. · Fiona Stanley Hospital, Robin Warren Drive, Murdoch, Western Australia 6150, Australia. · Department of Gastroenterology, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia 5000, Australia. · Department of Surgery, Princess Alexandra Hospital, Ipswich Rd, Woollongabba, Queensland 4102, Australia. · School of Surgery M507, University of Western Australia, 35 Stirling Hwy, Nedlands 6009, Australia and St John of God Pathology, 12 Salvado Rd, Subiaco, Western Australia 6008, Australia. · Academic Unit of Surgery, School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow Royal Infirmary, Glasgow G4 OSF, UK. · West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow G31 2ER, UK. · Department of Medical Oncology, Beatson West of Scotland Cancer Centre, 1053 Great Western Road, Glasgow G12 0YN, UK. · Department of Pathology, Southern General Hospital, Greater Glasgow &Clyde NHS, Glasgow G51 4TF, UK. · GGC Bio-repository, Pathology Department, Southern General Hospital, 1345 Govan Road, Glasgow G51 4TY, UK. · Department of Surgery, TU Dresden, Fetscherstr. 74, 01307 Dresden, Germany. · Departments of Pathology and Translational Molecular Pathology, UT MD Anderson Cancer Center, Houston Texas 77030, USA. · The David M. Rubenstein Pancreatic Cancer Research Center and Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA. · Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA. · ARC-Net Applied Research on Cancer Centre, University and Hospital Trust of Verona, Verona 37134, Italy. · Department of Pathology and Diagnostics, University of Verona, Verona 37134, Italy. · Department of Surgery, Pancreas Institute, University and Hospital Trust of Verona, Verona 37134, Italy. · Department of Medical Oncology, Comprehensive Cancer Centre, University and Hospital Trust of Verona, Verona 37134, Italy. · Mayo Clinic, Rochester, Minnesota 55905, USA. · Elkins Pancreas Center, Baylor College of Medicine, One Baylor Plaza, MS226, Houston, Texas 77030-3411, USA. · Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK. · Institute for Cancer Science, University of Glasgow, Glasgow G12 8QQ, UK. · University of Melbourne, Parkville, Victoria 3010, Australia. ·Nature · Pubmed #26909576.

ABSTRACT: Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-β, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63∆N transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.

6 Article Pathogenesis of pancreatic cancer exosome-induced lipolysis in adipose tissue. 2016

Sagar, Gunisha / Sah, Raghuwansh P / Javeed, Naureen / Dutta, Shamit K / Smyrk, Thomas C / Lau, Julie S / Giorgadze, Nino / Tchkonia, Tamar / Kirkland, James L / Chari, Suresh T / Mukhopadhyay, Debabrata. ·Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA. · Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA. · Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA. · Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, Minnesota, USA. ·Gut · Pubmed #26061593.

ABSTRACT: BACKGROUND AND OBJECTIVES: New-onset diabetes and concomitant weight loss occurring several months before the clinical presentation of pancreatic cancer (PC) appear to be paraneoplastic phenomena caused by tumour-secreted products. Our recent findings have shown exosomal adrenomedullin (AM) is important in development of diabetes in PC. Adipose tissue lipolysis might explain early onset weight loss in PC. We hypothesise that lipolysis-inducing cargo is carried in exosomes shed by PC and is responsible for the paraneoplastic effects. Therefore, in this study we investigate if exosomes secreted by PC induce lipolysis in adipocytes and explore the role of AM in PC-exosomes as the mediator of this lipolysis. DESIGN: Exosomes from patient-derived cell lines and from plasma of patients with PC and non-PC controls were isolated and characterised. Differentiated murine (3T3-L1) and human adipocytes were exposed to these exosomes to study lipolysis. Glycerol assay and western blotting were used to study lipolysis. Duolink Assay was used to study AM and adrenomedullin receptor (ADMR) interaction in adipocytes treated with exosomes. RESULTS: In murine and human adipocytes, we found that both AM and PC-exosomes promoted lipolysis, which was abrogated by ADMR blockade. AM interacted with its receptor on the adipocytes, activated p38 and extracellular signal-regulated (ERK1/2) mitogen-activated protein kinases and promoted lipolysis by phosphorylating hormone-sensitive lipase. PKH67-labelled PC-exosomes were readily internalised into adipocytes and involved both caveolin and macropinocytosis as possible mechanisms for endocytosis. CONCLUSIONS: PC-secreted exosomes induce lipolysis in subcutaneous adipose tissue; exosomal AM is a candidate mediator of this effect.

7 Article Metformin suppresses pancreatic tumor growth with inhibition of NFκB/STAT3 inflammatory signaling. 2015

Tan, Xiang-Lin / Bhattacharyya, Kalyan K / Dutta, Shamit K / Bamlet, William R / Rabe, Kari G / Wang, Enfeng / Smyrk, Thomas C / Oberg, Ann L / Petersen, Gloria M / Mukhopadhyay, Debabrata. ·From the *Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, MN; †Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick; ‡Department of Epidemiology, School of Public Health, Rutgers, The State University of New Jersey, Piscataway, NJ; and §Department of Biochemistry and Molecular Biology, ∥Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, and ¶Division of Anatomic Pathology, Mayo Clinic, Rochester, MN. ·Pancreas · Pubmed #25875801.

ABSTRACT: OBJECTIVES: To further elucidate the anticancer mechanisms of metformin against pancreatic cancer, we evaluated the inhibitory effects of metformin on pancreatic tumorigenesis in a genetically engineered mouse model and investigated its possible anti-inflammatory and antiangiogenesis effects. METHODS: Six-week-old LSL-Kras;Trp53 mice (10 per group) were administered once daily intraperitoneally with saline (control) for 1 week or metformin (125 mg/kg) for 1 week (Met_1wk) or 3 weeks (Met_3wk) before tumor initiation. All mice continued with their respective injections for 6 weeks after tumor initiation. Molecular changes were evaluated through quantitative polymerase chain reaction, immunohistochemistry, and Western blotting. RESULTS: At euthanasia, pancreatic tumor volume in the Met_1wk (median, 181.8 mm) and Met_3wk (median, 137.9 mm) groups was significantly lower than those in the control group (median, 481.1 mm; P = 0.001 and 0.0009, respectively). No significant difference was observed between the Met_1wk and Met_3wk groups (P = 0.51). These results were further confirmed using tumor weight and tumor burden measurements. Furthermore, metformin treatment decreased the phosphorylation of nuclear factor κB and signal transducer and activator of transcription 3 as well as the expression of specificity protein 1 transcription factor and several nuclear factor κB-regulated genes. CONCLUSIONS: Metformin may inhibit pancreatic tumorigenesis by modulating multiple molecular targets in inflammatory pathways.

8 Article The heparan sulfate mimetic PG545 interferes with Wnt/β-catenin signaling and significantly suppresses pancreatic tumorigenesis alone and in combination with gemcitabine. 2015

Jung, Deok-Beom / Yun, Miyong / Kim, Eun-Ok / Kim, Jaekwang / Kim, Bonglee / Jung, Ji Hoon / Wang, Enfeng / Mukhopadhyay, Debabrata / Hammond, Edward / Dredge, Keith / Shridhar, Viji / Kim, Sung-Hoon. ·College of Korean Medicine, Kyung Hee University, Seoul, South Korea. · Korean Medicine Clinical Trial Center, Kyung Hee University, Seoul, South Korea. · Department of Biochemistry and Molecular Biology, MN, USA. · Progen Pharmaceuticals Ltd, Brisbane, Queensland, Australia. · Experimental Pathology, Mayo Clinic College of Medicine, Rochester, MN, USA. ·Oncotarget · Pubmed #25669977.

ABSTRACT: The heparan sulfate mimetic PG545 has been shown to exert anti-angiogenic and anti-metastatic activity in vitro and in vivo cancer models. Although much of this activity has been attributed to inhibition of heparanase and heparan sulfate-binding growth factors, it was hypothesized that PG545 may additionally disrupt Wnt signaling, an important pathway underlying the malignancy of pancreatic cancer. We show that PG545, by directly interacting with Wnt3a and Wnt7a, inhibits Wnt/β-catenin signaling leading to inhibition of proliferation in pancreatic tumor cell lines. Additionally, we demonstrate for the first time that the combination of PG545 with gemcitabine has strong synergistic effects on viability, motility and apoptosis induction in several pancreatic cell lines. In an orthotopic xenograft mouse model, combination of PG545 with gemcitabine efficiently inhibited tumor growth and metastasis compared to single treatment alone. Also, PG545 treatment alone decreased the levels of β-catenin and its downstream targets, cyclin D1, MMP-7 and VEGF which is consistent with our in vitro data. Collectively, our findings suggest that PG545 exerts anti-tumor activity by disrupting Wnt/β-catenin signaling and combination with gemcitabine should be considered as a novel therapeutic strategy for pancreatic cancer treatment.

9 Article Pancreatic Cancer-Derived Exosomes Cause Paraneoplastic β-cell Dysfunction. 2015

Javeed, Naureen / Sagar, Gunisha / Dutta, Shamit K / Smyrk, Thomas C / Lau, Julie S / Bhattacharya, Santanu / Truty, Mark / Petersen, Gloria M / Kaufman, Randal J / Chari, Suresh T / Mukhopadhyay, Debabrata. ·Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota. · Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota. · Department of Surgery, Mayo Clinic, Rochester, Minnesota. · Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota. · Degenerative Disease Research Program, Sanford Burnham Medical Research Institute, La Jolla, California. · Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota. mukhopadhyay.debabrata@mayo.edu chari.suresh@mayo.edu. · Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota. mukhopadhyay.debabrata@mayo.edu chari.suresh@mayo.edu. ·Clin Cancer Res · Pubmed #25355928.

ABSTRACT: PURPOSE: Pancreatic cancer frequently causes diabetes. We recently proposed adrenomedullin as a candidate mediator of pancreatic β-cell dysfunction in pancreatic cancer. How pancreatic cancer-derived adrenomedullin reaches β cells remote from the cancer to induce β-cell dysfunction is unknown. We tested a novel hypothesis that pancreatic cancer sheds adrenomedullin-containing exosomes into circulation, which are transported to β cells and impair insulin secretion. EXPERIMENTAL METHODS: We characterized exosomes from conditioned media of pancreatic cancer cell lines (n = 5) and portal/peripheral venous blood of patients with pancreatic cancer (n = 20). Western blot analysis showed the presence of adrenomedullin in pancreatic cancer-exosomes. We determined the effect of adrenomedullin-containing pancreatic cancer exosomes on insulin secretion from INS-1 β cells and human islets, and demonstrated the mechanism of exosome internalization into β cells. We studied the interaction between β-cell adrenomedullin receptors and adrenomedullin present in pancreatic cancer-exosomes. In addition, the effect of adrenomedullin on endoplasmic reticulum (ER) stress response genes and reactive oxygen/nitrogen species generation in β cells was shown. RESULTS: Exosomes were found to be the predominant extracellular vesicles secreted by pancreatic cancer into culture media and patient plasma. Pancreatic cancer-exosomes contained adrenomedullin and CA19-9, readily entered β cells through caveolin-mediated endocytosis or macropinocytosis, and inhibited insulin secretion. Adrenomedullin in pancreatic cancer exosomes interacted with its receptor on β cells. Adrenomedullin receptor blockade abrogated the inhibitory effect of exosomes on insulin secretion. β cells exposed to adrenomedullin or pancreatic cancer exosomes showed upregulation of ER stress genes and increased reactive oxygen/nitrogen species. CONCLUSIONS: Pancreatic cancer causes paraneoplastic β-cell dysfunction by shedding adrenomedullin(+)/CA19-9(+) exosomes into circulation that inhibit insulin secretion, likely through adrenomedullin-induced ER stress and failure of the unfolded protein response.

10 Article GAIP interacting protein C-terminus regulates autophagy and exosome biogenesis of pancreatic cancer through metabolic pathways. 2014

Bhattacharya, Santanu / Pal, Krishnendu / Sharma, Anil K / Dutta, Shamit K / Lau, Julie S / Yan, Irene K / Wang, Enfeng / Elkhanany, Ahmed / Alkharfy, Khalid M / Sanyal, Arunik / Patel, Tushar C / Chari, Suresh T / Spaller, Mark R / Mukhopadhyay, Debabrata. ·Department Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, United States of America. · Departments of Transplantation and Cancer Biology, Mayo Clinic, Jacksonville, Florida, United States of America. · Department Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, United States of America; Department of Pharmacy, King Saud University, Riyadh, Saudi Arabia. · Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, United States of America. · Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, and Norris Cotton Cancer Center, Lebanon, New Hampshire, United States of America. ·PLoS One · Pubmed #25469510.

ABSTRACT: GAIP interacting protein C terminus (GIPC) is known to play an important role in a variety of physiological and disease states. In the present study, we have identified a novel role for GIPC as a master regulator of autophagy and the exocytotic pathways in cancer. We show that depletion of GIPC-induced autophagy in pancreatic cancer cells, as evident from the upregulation of the autophagy marker LC3II. We further report that GIPC regulates cellular trafficking pathways by modulating the secretion, biogenesis, and molecular composition of exosomes. We also identified the involvement of GIPC on metabolic stress pathways regulating autophagy and microvesicular shedding, and observed that GIPC status determines the loading of cellular cargo in the exosome. Furthermore, we have shown the overexpression of the drug resistance gene ABCG2 in exosomes from GIPC-depleted pancreatic cancer cells. We also demonstrated that depletion of GIPC from cancer cells sensitized them to gemcitabine treatment, an avenue that can be explored as a potential therapeutic strategy to overcome drug resistance in cancer.

11 Article Inhibition of endoglin-GIPC interaction inhibits pancreatic cancer cell growth. 2014

Pal, Krishnendu / Pletnev, Alexandre A / Dutta, Shamit K / Wang, Enfeng / Zhao, Ruizhi / Baral, Aradhita / Yadav, Vinod Kumar / Aggarwal, Suruchi / Krishnaswamy, Soundararajan / Alkharfy, Khalid M / Chowdhury, Shantanu / Spaller, Mark R / Mukhopadhyay, Debabrata. ·Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota. · Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth and Norris Cotton Cancer Center, Lebanon, New Hampshire. · Proteomics and Structural Biology Unit, Institute of Genomics and Integrative Biology, Council for Scientific and Industrial Research, New Delhi, India. · G.N.R. Knowledge Center for Genome Informatics, Institute of Genomics and Integrative Biology, Council for Scientific and Industrial Research, New Delhi, India. · Department of Biochemistry, King Saud University, Riyadh, Saudi Arabia. · Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota. Department of Pharmacy, King Saud University, Riyadh, Saudi Arabia. · Proteomics and Structural Biology Unit, Institute of Genomics and Integrative Biology, Council for Scientific and Industrial Research, New Delhi, India. G.N.R. Knowledge Center for Genome Informatics, Institute of Genomics and Integrative Biology, Council for Scientific and Industrial Research, New Delhi, India. · Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota. mukhopadhyay.debabrata@mayo.edu. ·Mol Cancer Ther · Pubmed #25125675.

ABSTRACT: Endoglin, a 180-kDa disulfide-linked homodimeric transmembrane receptor protein mostly expressed in tumor-associated endothelial cells, is an endogenous binding partner of GAIP-interacting protein, C terminus (GIPC). Endoglin functions as a coreceptor of TβRII that binds TGFβ and is important for vascular development, and consequently has become a compelling target for antiangiogenic therapies. A few recent studies in gastrointestinal stromal tumor (GIST), breast cancer, and ovarian cancer, however, suggest that endoglin is upregulated in tumor cells and is associated with poor prognosis. These findings indicate a broader role of endoglin in tumor biology, beyond angiogenic effects. The goal of our current study is to evaluate the effects of targeting endoglin in pancreatic cancer both in vitro and in vivo. We analyzed the antiproliferative effect of both RNAi-based and peptide ligand-based inhibition of endoglin in pancreatic cancer cell lines, the latter yielding a GIPC PDZ domain-targeting lipopeptide with notable antiproliferative activity. We further demonstrated that endoglin inhibition induced a differentiation phenotype in the pancreatic cancer cells and sensitized them against conventional chemotherapeutic drug gemcitabine. Most importantly, we have demonstrated the antitumor effect of both RNAi-based and competitive inhibitor-based blocking of endoglin in pancreatic cancer xenograft models in vivo. To our knowledge, this is the first report exploring the effect of targeting endoglin in pancreatic cancer cells.

12 Article Identification of a new class of MDM2 inhibitor that inhibits growth of orthotopic pancreatic tumors in mice. 2014

Wang, Wei / Qin, Jiang-Jiang / Voruganti, Sukesh / Wang, Ming-Hai / Sharma, Horrick / Patil, Shivaputra / Zhou, Jianwei / Wang, Hui / Mukhopadhyay, Debabrata / Buolamwini, John K / Zhang, Ruiwen. ·Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas; Cancer Biology Center, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas. · Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas. · Cancer Biology Center, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas; Department of Biomedical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas. · Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee. · Department of Molecular Cell Biology and Toxicology, Cancer Center, School of Public Health, Nanjing Medical University, Nanjing, China. · Key Laboratory of Food Safety Research Center, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China. · Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota. · Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee. Electronic address: jbuolamwini@uthsc.edu. · Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas; Cancer Biology Center, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas. Electronic address: ruiwen.zhang@ttuhsc.edu. ·Gastroenterology · Pubmed #25016295.

ABSTRACT: BACKGROUND & AIMS: The oncogene MDM2, which encodes an E3 ubiquitin ligase, is overexpressed in pancreatic cancers and is therefore a therapeutic target. Current inhibitors of MDM2 target the interaction between MDM2 and P53; these would have no effect on cancer cells that do not express full-length P53, including many pancreatic cancer cells. We searched for a compound that specifically inhibits MDM2 itself. METHODS: We performed a virtual screen and structure-based design to identify specific inhibitors of MDM2. We tested the activities of compounds identified on viability, proliferation, and protein levels of HPAC, Panc-1, AsPC-1, and Mia-Paca-2 pancreatic cancer cell lines. We tested whether intraperitoneal injections of one of the compounds identified affected growth of xenograft tumors from Panc-1 cells, or orthotopic tumors from Panc-1 and AsPC-1 cells (injected into pancreata), in nude mice. RESULTS: We identified a compound, called SP141, which bound directly to MDM2, promoting its auto-ubiquitination and degradation by the proteasome. The compound reduced levels of MDM2 in pancreatic cancer cell lines, as well as their proliferation, with 50% inhibitory concentrations <0.5 μM (0.38-0.50 μM). Increasing concentrations of SP141 induced increasing levels of apoptosis and G2-M-phase arrest of pancreatic cancer cell lines, whether or not they expressed functional P53. Injection of nude mice with SP141 (40 mg/kg/d) inhibited growth of xenograft tumors (by 75% compared with control mice), and led to regression of orthotopic tumors. CONCLUSIONS: In a screen for specific inhibitors of MDM2, we identified a compound called SP141 that reduces levels of MDM2 in pancreatic cancer cell lines, as well as their proliferation and ability to form tumors in nude mice. SP141 is a new class of MDM2 inhibitor that promotes MDM2 auto-ubiquitination and degradation. It might be further developed as a therapeutic agent for pancreatic cancer.

13 Article Neuropilin-2 promotes extravasation and metastasis by interacting with endothelial α5 integrin. 2013

Cao, Ying / Hoeppner, Luke H / Bach, Steven / E, Guangqi / Guo, Yan / Wang, Enfeng / Wu, Jianmin / Cowley, Mark J / Chang, David K / Waddell, Nicola / Grimmond, Sean M / Biankin, Andrew V / Daly, Roger J / Zhang, Xiaohui / Mukhopadhyay, Debabrata. ·Department of Biochemistry and Molecular Biology, College of Medicine, Mayo Clinic, Rochester, MN 55905. · Bioengineering Program & Department of Mechanical Engineering and Mechanics, Lehigh University, Bethlehem, PA 18015. · The Kinghorn Cancer Centre, Cancer Research Division, Garvan Institute of Medical Research, 370 Victoria St, Darlinghurst, Sydney, NSW 2010, Australia. · Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, NSW 2200, Australia. · South Western Sydney Clinical School, Faculty of Medicine, University of NSW, Liverpool NSW 2170, Australia. · Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD 4072, Australia. ·Cancer Res · Pubmed #23689123.

ABSTRACT: Metastasis, the leading cause of cancer death, requires tumor cell intravasation, migration through the bloodstream, arrest within capillaries, and extravasation to invade distant tissues. Few mechanistic details have been reported thus far regarding the extravasation process or re-entry of circulating tumor cells at metastatic sites. Here, we show that neuropilin-2 (NRP-2), a multifunctional nonkinase receptor for semaphorins, vascular endothelial growth factor (VEGF), and other growth factors, expressed on cancer cells interacts with α5 integrin on endothelial cells to mediate vascular extravasation and metastasis in zebrafish and murine xenograft models of clear cell renal cell carcinoma (RCC) and pancreatic adenocarcinoma. In tissue from patients with RCC, NRP-2 expression is positively correlated with tumor grade and is highest in metastatic tumors. In a prospectively acquired cohort of patients with pancreatic cancer, high NRP-2 expression cosegregated with poor prognosis. Through biochemical approaches as well as Atomic Force Microscopy (AFM), we describe a unique mechanism through which NRP-2 expressed on cancer cells interacts with α5 integrin on endothelial cells to mediate vascular adhesion and extravasation. Taken together, our studies reveal a clinically significant role of NRP-2 in cancer cell extravasation and promotion of metastasis.

14 Article Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. 2012

Biankin, Andrew V / Waddell, Nicola / Kassahn, Karin S / Gingras, Marie-Claude / Muthuswamy, Lakshmi B / Johns, Amber L / Miller, David K / Wilson, Peter J / Patch, Ann-Marie / Wu, Jianmin / Chang, David K / Cowley, Mark J / Gardiner, Brooke B / Song, Sarah / Harliwong, Ivon / Idrisoglu, Senel / Nourse, Craig / Nourbakhsh, Ehsan / Manning, Suzanne / Wani, Shivangi / Gongora, Milena / Pajic, Marina / Scarlett, Christopher J / Gill, Anthony J / Pinho, Andreia V / Rooman, Ilse / Anderson, Matthew / Holmes, Oliver / Leonard, Conrad / Taylor, Darrin / Wood, Scott / Xu, Qinying / Nones, Katia / Fink, J Lynn / Christ, Angelika / Bruxner, Tim / Cloonan, Nicole / Kolle, Gabriel / Newell, Felicity / Pinese, Mark / Mead, R Scott / Humphris, Jeremy L / Kaplan, Warren / Jones, Marc D / Colvin, Emily K / Nagrial, Adnan M / Humphrey, Emily S / Chou, Angela / Chin, Venessa T / Chantrill, Lorraine A / Mawson, Amanda / Samra, Jaswinder S / Kench, James G / Lovell, Jessica A / Daly, Roger J / Merrett, Neil D / Toon, Christopher / Epari, Krishna / Nguyen, Nam Q / Barbour, Andrew / Zeps, Nikolajs / Anonymous1421514 / Kakkar, Nipun / Zhao, Fengmei / Wu, Yuan Qing / Wang, Min / Muzny, Donna M / Fisher, William E / Brunicardi, F Charles / Hodges, Sally E / Reid, Jeffrey G / Drummond, Jennifer / Chang, Kyle / Han, Yi / Lewis, Lora R / Dinh, Huyen / Buhay, Christian J / Beck, Timothy / Timms, Lee / Sam, Michelle / Begley, Kimberly / Brown, Andrew / Pai, Deepa / Panchal, Ami / Buchner, Nicholas / De Borja, Richard / Denroche, Robert E / Yung, Christina K / Serra, Stefano / Onetto, Nicole / Mukhopadhyay, Debabrata / Tsao, Ming-Sound / Shaw, Patricia A / Petersen, Gloria M / Gallinger, Steven / Hruban, Ralph H / Maitra, Anirban / Iacobuzio-Donahue, Christine A / Schulick, Richard D / Wolfgang, Christopher L / Morgan, Richard A / Lawlor, Rita T / Capelli, Paola / Corbo, Vincenzo / Scardoni, Maria / Tortora, Giampaolo / Tempero, Margaret A / Mann, Karen M / Jenkins, Nancy A / Perez-Mancera, Pedro A / Adams, David J / Largaespada, David A / Wessels, Lodewyk F A / Rust, Alistair G / Stein, Lincoln D / Tuveson, David A / Copeland, Neal G / Musgrove, Elizabeth A / Scarpa, Aldo / Eshleman, James R / Hudson, Thomas J / Sutherland, Robert L / Wheeler, David A / Pearson, John V / McPherson, John D / Gibbs, Richard A / Grimmond, Sean M. ·The Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst, Sydney, New South Wales 2010, Australia. ·Nature · Pubmed #23103869.

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.

15 Article Adrenomedullin is up-regulated in patients with pancreatic cancer and causes insulin resistance in β cells and mice. 2012

Aggarwal, Gaurav / Ramachandran, Vijaya / Javeed, Naureen / Arumugam, Thiruvengadam / Dutta, Shamit / Klee, George G / Klee, Eric W / Smyrk, Thomas C / Bamlet, William / Han, Jing Jing / Rumie Vittar, Natalia B / de Andrade, Mariza / Mukhopadhyay, Debabrata / Petersen, Gloria M / Fernandez-Zapico, Martin E / Logsdon, Craig D / Chari, Suresh T. ·Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA. ·Gastroenterology · Pubmed #22960655.

ABSTRACT: BACKGROUND & AIMS: New-onset diabetes in patients with pancreatic cancer is likely to be a paraneoplastic phenomenon caused by tumor-secreted products. We aimed to identify the diabetogenic secretory product(s) of pancreatic cancer. METHODS: Using microarray analysis, we identified adrenomedullin as a potential mediator of diabetes in patients with pancreatic cancer. Adrenomedullin was up-regulated in pancreatic cancer cell lines, in which supernatants reduced insulin signaling in beta cell lines. We performed quantitative reverse-transcriptase polymerase chain reaction and immunohistochemistry on human pancreatic cancer and healthy pancreatic tissues (controls) to determine expression of adrenomedullin messenger RNA and protein, respectively. We studied the effects of adrenomedullin on insulin secretion by beta cell lines and whole islets from mice and on glucose tolerance in pancreatic xenografts in mice. We measured plasma levels of adrenomedullin in patients with pancreatic cancer, patients with type 2 diabetes mellitus, and individuals with normal fasting glucose levels (controls). RESULTS: Levels of adrenomedullin messenger RNA and protein were increased in human pancreatic cancer samples compared with controls. Adrenomedullin and conditioned media from pancreatic cell lines inhibited glucose-stimulated insulin secretion from beta cell lines and islets isolated from mice; the effects of conditioned media from pancreatic cancer cells were reduced by small hairpin RNA-mediated knockdown of adrenomedullin. Conversely, overexpression of adrenomedullin in mice with pancreatic cancer led to glucose intolerance. Mean plasma levels of adrenomedullin (femtomoles per liter) were higher in patients with pancreatic cancer compared with patients with diabetes or controls. Levels of adrenomedullin were higher in patients with pancreatic cancer who developed diabetes compared those who did not. CONCLUSIONS: Adrenomedullin is up-regulated in patients with pancreatic cancer and causes insulin resistance in β cells and mice.

16 Article Designing nanoconjugates to effectively target pancreatic cancer cells in vitro and in vivo. 2011

Khan, Jameel Ahmad / Kudgus, Rachel A / Szabolcs, Annamaria / Dutta, Shamit / Wang, Enfeng / Cao, Sheng / Curran, Geoffry L / Shah, Vijay / Curley, Steven / Mukhopadhyay, Debabrata / Robertson, J David / Bhattacharya, Resham / Mukherjee, Priyabrata. ·Department of Biochemistry and Molecular Biology, College of Medicine, Mayo Clinic, Rochester, Minnesota, United States of America. ·PLoS One · Pubmed #21738572.

ABSTRACT: BACKGROUND: Pancreatic cancer is the fourth leading cause of cancer related deaths in America. Monoclonal antibodies are a viable treatment option for inhibiting cancer growth. Tumor specific drug delivery could be achieved utilizing these monoclonal antibodies as targeting agents. This type of designer therapeutic is evolving and with the use of gold nanoparticles it is a promising approach to selectively deliver chemotherapeutics to malignant cells. Gold nanoparticles (GNPs) are showing extreme promise in current medicinal research. GNPs have been shown to non-invasively kill tumor cells by hyperthermia using radiofrequency. They have also been implemented as early detection agents due to their unique X-ray contrast properties; success was revealed with clear delineation of blood capillaries in a preclinical model by CT (computer tomography). The fundamental parameters for intelligent design of nanoconjugates are on the forefront. The goal of this study is to define the necessary design parameters to successfully target pancreatic cancer cells. METHODOLOGY/PRINCIPAL FINDINGS: The nanoconjugates described in this study were characterized with various physico-chemical techniques. We demonstrate that the number of cetuximab molecules (targeting agent) on a GNP, the hydrodynamic size of the nanoconjugates, available reactive surface area and the ability of the nanoconjugates to sequester EGFR (epidermal growth factor receptor), all play critical roles in effectively targeting tumor cells in vitro and in vivo in an orthotopic model of pancreatic cancer. CONCLUSION: Our results suggest the specific targeting of tumor cells depends on a number of crucial components 1) targeting agent to nanoparticle ratio 2) availability of reactive surface area on the nanoparticle 3) ability of the nanoconjugate to bind the target and 4) hydrodynamic diameter of the nanoconjugate. We believe this study will help define the design parameters for formulating better strategies for specifically targeting tumors with nanoparticle conjugates.

17 Article Pancreatic stellate cell models for transcriptional studies of desmoplasia-associated genes. 2010

Mathison, Angela / Liebl, Ann / Bharucha, Jinai / Mukhopadhyay, Debabrata / Lomberk, Gwen / Shah, Vijay / Urrutia, Raul. ·Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minn, USA. ·Pancreatology · Pubmed #20847583.

ABSTRACT: BACKGROUND: Pancreatic stellate cells are emerging as key players in pathophysiopathological processes underlying the development of pancreatic disease, including pancreatitis and cancer. The cells are scarce in the pancreas making their isolation time and resource use consuming. METHODS: Therefore, with the ultimate goal of facilitating mechanistic studies, here we report the isolation, characterization, and immortalization of stellate cell lines from rat and mouse origin. RESULTS: These cell lines display morphological and molecular markers as well as non-tumorigenic characteristics similar to the frequently used hepatic counterparts. In addition, we have tested their robustness as a model for transcriptional regulatory studies. We find that these cells respond well to TGFβ signaling by triggering a distinct cascade of gene expression, some genes overlap with the TGFβ response of LX2 cells. These cells express several key chromatin proteins and epigenetic regulators involved in the regulation of gene expression, including co-repressors such as Sin3A (short-term repression), HP1 (long-term repression), as well as CBP/p300 (activation). Furthermore, these cells are well suited for Gal4-based transcriptional activation and repression assays. CONCLUSIONS: The cell model reported here may therefore help fuel investigations in the field of signaling, transcription, and perhaps other studies on similarly exciting cellular processes. and IAP.

18 Article Targeting GIPC/synectin in pancreatic cancer inhibits tumor growth. 2009

Muders, Michael H / Vohra, Pawan K / Dutta, Shamit K / Wang, Enfeng / Ikeda, Yasuhiro / Wang, Ling / Udugamasooriya, D Gomika / Memic, Adnan / Rupasinghe, Chamila N / Baretton, Gustavo B / Aust, Daniela E / Langer, Silke / Datta, Kaustubh / Simons, Michael / Spaller, Mark R / Mukhopadhyay, Debabrata. ·Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota 55905, USA. ·Clin Cancer Res · Pubmed #19509165.

ABSTRACT: PURPOSE: Various studies have shown the importance of the GAIP interacting protein, COOH-terminus (GIPC, also known as Synectin) as a central adaptor molecule in different signaling pathways and as an important mediator of receptor stability. GIPC/Synectin is associated with different growth-promoting receptors such as insulin-like growth factor receptor I (IGF-IR) and integrins. These interactions were mediated through its PDZ domain. GIPC/Synectin has been shown to be overexpressed in pancreatic and breast cancer. The goal of this study was to show the importance of GIPC/Synectin in pancreatic cancer growth and to evaluate a possible therapeutic strategy by using a GIPC-PDZ domain inhibitor. Furthermore, the effect of targeting GIPC on the IGF-I receptor as one of its associated receptors was tested. EXPERIMENTAL DESIGN: The in vivo effects of GIPC/Synectin knockdown were studied after lentiviral transduction of luciferase-expressing pancreatic cancer cells with short hairpin RNA against GIPC/Synectin. Additionally, a GIPC-PDZ--targeting peptide was designed. This peptide was tested for its influence on pancreatic cancer growth in vitro and in vivo. RESULTS: Knockdown of GIPC/Synectin led to a significant inhibition of pancreatic adenocarcinoma growth in an orthotopic mouse model. Additionally, a cell-permeable GIPC-PDZ inhibitor was able to block tumor growth significantly without showing toxicity in a mouse model. Targeting GIPC was accompanied by a significant reduction in IGF-IR expression in pancreatic cancer cells. CONCLUSIONS: Our findings show that targeting GIPC/Synectin and its PDZ domain inhibits pancreatic carcinoma growth and is a potential strategy for therapeutic intervention of pancreatic cancer.

19 Article Insulin receptor substrate-2 mediated insulin-like growth factor-I receptor overexpression in pancreatic adenocarcinoma through protein kinase Cdelta. 2009

Kwon, Junhye / Stephan, Susann / Mukhopadhyay, Ananya / Muders, Michael H / Dutta, Shamit K / Lau, Julie S / Mukhopadhyay, Debabrata. ·Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA. ·Cancer Res · Pubmed #19190347.

ABSTRACT: Pancreatic adenocarcinoma (PCA) is an almost invariably fatal disease. Recently, it has been shown by several groups as well as ours that insulin-like growth factor-I receptor (IGF-IR) overexpression is related to higher proliferation, survival, angiogenesis, and highly invasive pancreatic tumors. Several studies have been carried out to understand the pathways that lead to growth factor-mediated signaling, but the molecular mechanism of receptor overexpression remains mostly unknown. Treatment with neutralizing antibodies or a specific kinase inhibitor against IGF-IR could block the receptor expression in PCA cells. Furthermore, we also showed that insulin receptor substrate (IRS)-2, but not IRS-1, is involved in regulation of IGF-IR expression, which is most likely not transcriptional control. By blocking mammalian target of rapamycin (mTOR) pathway with rapamycin as well as other biochemical analysis, we defined a unique regulation of IGF-IR expression mediated by protein kinase Cdelta (PKCdelta) and mTOR pathway. Moreover, we showed that the down-regulation of IGF-IR expression due to IRS-2 small interfering RNA can be compensated by overexpression of dominant-active mutant of PKCdelta, suggesting that PKCdelta is downstream of IGF-IR/IRS-2 axis. Overall, these findings suggest a novel regulatory role of IRS-2 on the expression of IGF-IR through PKCdelta and mTOR in pancreatic cancer cells.