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Division of Gastrointestinal and Liver Pathology


Email rhruban@jhmi.edu
Phone (410) 955-9132

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Pancreatic Cancer


Ralph H. Hruban, M.D.

Baxley Professor in Pathology;
Director, Department of Pathology;
Pathologist-in-Chief, Johns Hopkins Hospital;
Director, Division of Gastrointestinal and Liver Pathology;
Deputy Director for Fund and Program Development;
Primary Appointment in Pathology; Secondary Appointment in Oncology


My research is focused on pancreatic cancer. I collaborate extensively with Drs. Christine Iacobuzio-Donahue, Michael Goggins, Scott Kern, Anirban Maitra, and Bert Vogelstein in their studies of the molecular genetics of pancreatic carcinoma. I am particularly interested in the precursors of invasive pancreatic cancer and in the genetic basis for the clustering of pancreatic cancer in some families.

Publications
Blackford A, Parmigiani G, Kensler TW, Wolfgang CL, Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Eshleman JR, Goggins M, Jaffee EM, Iacobuzio-Donahue CA, Maitra A, Klein AP, Cameron JL, Olino K, Schulick R, Winter J, Vogelstein B, Velculescu VE, Kinzler KW, Hruban RH. Genetic Mutations Associated With Cigarette Smoking in Pancreatic Cancer. Cancer Res. 69:3681-8, 2009.

Shi C, Klein AP, Goggins M, Maitra A, Canto M, Ali S, Schulick R, Palmisano E, Hruban RH. Increased prevalence of precursor lesions in familial pancreatic cancer patients. Clin Cancer Res. 15:7737-43, 2009.

Jiao Y, Shi C, Edil BH, de Wilde RF, Klimstra DS, Maitra A, Schulick RD, Tang LH, Wolfgang CL, Choti MA, Velculescu VE, Diaz LA, Vogelstein B, Kinzler KW*, Hruban RH*, Papadopoulos N*. DAXX/ATRX, MEN1 and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science. 331:1199-203, 2011

Matthaei H, Hong SM, Mayo SC, dal Molin M, Olino K, Venkat R, Goggins M, Herman JM, Edil BH, Wolfgang CL, Cameron JL, Schulick RD, Maitra A, Hruban RH. Presence of pancreatic intraepithelial neoplasia in the pancreatic transaction margin does not influence outcome in patients with R0 resected pancreatic cancer. Ann Surg Oncol. 18:3493-9, 2011.

Hong SM, Goggins M, Wolfgang CL, Schulick RD, Edil BH, Cameron JL, Handri-Luca A, Herman JM, Hruban RH. Vascular invasion in infiltrating ductal adenocarcinoma of the pancreas can mimic pancreatic intraepithelial neoplasia: a histopathologic study of 209 cases. Am J Surg Pathol. 36:235-41, 2012.

Wu J, Jiao Y, dal Molin M, Maitra A, de Wilde RF, Wood LD, Eshleman JR, Goggins MG, Wolfgang CL, Canto MI, Schulick RD, Edil BH, Choti MA, Adsay V, Kimstra DS, Offerhaus GJ, Klein AP, Kopelovich L, Carter H, Karchin R, Allen PJ, Schmidt CM, Naito Y, Diaz LA, Kinzler KW, Papadopoulos N, Hruban RH*, Vogelstein B*. Whole-exome sequencing of neoplastic cysts of the pancreas reveals recurrent mutations in components of ubiquitin-dependent pathways. Proc Natl Acad Sci. 108:21188-93, 2011.

Roberts NJ, Jiao Y, Yu J, Kopelovich L, Petersen GM, Bondy ML, Gallinger S, Schwartz AG, Syngal S, Cote ML, Axilbund J, Schulick R, Ali SZ, Eshleman JR, Velculescu VE, Goggins M, Vogelstein B, Papadopoulos N, Hruban RH*, Kinzler KW*, Klein AP*. ATM mutations in patients with hereditary pancreatic cancer. Cancer Discovery. 2:41-6, 2012.

*=co-senior authors




Email rander54@jhmi.edu
Phone (410) 955-3511

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Publications

Liver Cancer

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Robert A. Anders, M.D., Ph.D.

Primary Appointment in Pathology


My laboratory's interests focus on the basic processes that lead to liver cell death and division. We approach these questions through the use of both experimental models and examination of human tissues. We are specifically interested in how the Hippo pathway controls the livers response to injury and malignant transformation. We have uncovered this pathway as a key mediator of hepatocyte and cholangiocyte biology.

Publications
Please visit Publications web link on left



Email jboitnot@jhmi.edu
Phone (410) 955-8377
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John K. Boitnott, M.D.

Primary Appointment in Pathology
Former Pathologist-in-Chief, Johns Hopkins Hospital


My principal area of interest is liver disease with an associated interest in disease of the biliary tract and pancreas. Most of my work involves collaborative clinico-pathologic studies. Areas in which there are now particularly good opportunities for such studies at Johns Hopkins include: liver transplants, bone marrow transplants, hepatic neoplasms, Budd-Chiari syndrome, sclerosing cholangitis, bile duct carcinomas and pancreatic carcinomas.

Publications
Diehl AM, Boitnott JK, Herlong HF, Potter JJ, Van Duyn MA, Chandler E,Mezey E. Effect of parenteral amino acid supplementation in alcoholichepatitis. Hepatology 5:57-63, 1989.

Christensen WN, Boitnott JK, Kuhajda FP. Immunoperoxidase staining as adiagnostic aid for hepatocellular carcinoma. Mod Pathol 2:8-12, 1989.

Allison DC, Bose KK, Hruban RH, Piantadosi S, Dooley WC, Boitnott JK,Cameron JL. Pancreatic cancer cell DNA content correlates with long-termsurvival after pancreaticoduodenectomy. Ann Surg 214:648-656, 1991.

Ayuse T, Brienza N, Revelly JP, Boitnott JK, Robotham JL. The role ofnitric oxide in the porcine liver circulation under normal and endotoxemic conditions. J Appl Physiol 78:1319-1329, 1995.




Email tcornis3@jhmi.edu
Phone (410) 955-5963

Related Websites
Oncology Tissue Services Lab

All Publications
(Google Scholar)


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Toby C. Cornish, M.D., Ph.D.

Primary Appointment in Pathology
Associate Director, Division of Pathology Informatics
Co-director for Image Analysis, Oncology Tissue Services Lab


My research interests include include pancreatic and other cancers of the GI tract as well as medical gastrointestinal disease. My informatics interests include histologic image analysis, the application of digital pathology in education and clinical practice, and the development of mobile applications for pathology education. I have developed or co-developed a number of packages for biomarker quantitation on whole slide images (WSI) including TMAJ/FrIDA, PIP, and HPASubC. I am also the co-author of three apps for the iPad: The Atlas of Pancreatic Pathology (winner of the 2012 Dr. Frank H. Netter Award for Special Contributions to Medical Education), The Johns Hopkins Atlas of Pancreatic Cytopathology, and the iCarebook for Pancreatic Cancer.

Publications

Cornish TC and Halushka MK. Color Deconvolution for the Analysis of Tissue Microarrays. Anal Quant Cytol and Histol. 2009; 31:304-312.

Kim B, Barker JB, Hruban RH, Sandone C, and Cornish TC. The Johns Hopkins Atlas of Pancreatic Pathology: Developing an Interactive Atlas and Teaching Algorithm for the Apple iPad. J Biocommun, 2012; 38(1):4-10.

Cornish TC, Swapp RE, Kaplan KJ. Whole-slide Imaging: Routine Pathologic Diagnosis. Adv Anat Pathol. 2012 May;19(3):152-9.

Cornish TC, McClintock DS. Medicolegal and regulatory aspects of whole slide imaging-based telepathology. Diagnostic Histopathol. 2014 Dec;20(12):475-481.

Shi C, Gonzalez RS, Zhao Z, Koyama T, Cornish TC, Hande KR, Walker R, Sandler M, Berlin J, Liu EH. Liver metastases of small intestine neuroendocrine tumors: ki-67 heterogeneity and world health organization grade discordance with primary tumors. Amer. J. Clin. Pathol. 2015: 143(3):398-404.

Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, Skora AD, Luber BS, Azad NS, Laheru D, Biedrzycki B, Donehower RC, Zaheer A, Fisher GA, Crocenzi TS, Lee JJ, Duffy SM, Goldberg RM, de A, Koshiji M, Bhaijee F, Huebner T, Hruban RH, Wood LD, Cuka N, Pardoll DM, Papadopoulos N, Kinzler KW, Zhou S, Cornish TC, Taube JM, Anders RA, Eshleman JR, Vogelstein B, Diaz LA. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med. 2015. In press.

Cornish TC, Chakravarti A, Kapoor A, Halushka MK. HPASubC: a suite of tools for user subclassification of Human Protein Atlas tissue images. J. Pathol. Inform. 2015. In press.




Email jeshlem@jhmi.edu
Phone (410) 955-3511
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James R. Eshleman, M.D., Ph.D.

Primary Appointment in Pathology; Secondary Appointment in Oncology
Member, Graduate Program in Pathobiology; Member, Graduate Program in Cellular and Molecular Medicine; Associate Director, Molecular Diagnostics Laboratory


Pancreatic cancer is the 10th leading cause of new cancers in the US, but the 3rd most common in cancer deaths. The 5-year survival of pancreatic cancer is currently less than 5%. Critical to improving these statistics is a full and detailed understanding of the gene mutations in pancreatic cancer, and familial predispositions. Towards this end, we recently performed full exomic sequencing for 24 pancreatic cancers and reported a new familial predisposition gene. Other ways to impact on this disease are early detection, molecular subclassification, and novel therapeutics.

My research laboratory is also involved in translational research in molecular diagnostics and basic science research on novel therapeutics. We have recently reported a novel method for point mutation detection, and are currently incorporating this strategy for early detection of pancreas cancer in collaboration with Drs. Michael Goggins Chris Gocke and Ralph Hruban.

I also have a significant interest in nucleic acid based novel therapeutics. Recently, we have developed a novel strategy to select against specific cell populations using "anti-gene padlocks." Anti-gene padlocks are oligonucleotides capable of reacting and intertwining with DNA followed by end-to-end ligation. We have demonstrated their activity in bacterial cells, where once bound and ligated, the padlock is inextricably attached. If the target is present in a bacterial cell's chromosome, the cell is killed. Experiments are currently underway to determine the critical features of anti-gene locks, the mechanism of cell death and whether this novel therapeutic can be used to target human cells in a similar fashion.

I also have special interests in Molecular Pathology.

Publications

Shi C, Eshleman SH, Jones D, Fukushima N, Hua L, Parker AR, Yeo CJ, Hruban RH, Goggins MG, and Eshleman JR. LigAmp for Sensitive Detection of Single Nucleotide Differences. Nature Methods, 1: 141-147, November, 2004.

Shi C, Parker AR, Hua L, Morrell CN, Lee SC, Bandaru W, Wu TC and Eshleman JR. Anti-gene padlocks kill bacterial cells based on their genotype. Submitted.

Shi C, Fukushima N, Abe T, Bian Y, Hua L, Wendelburg BJ, Yeo CJ, Hruban RH, Goggins MG, and Eshleman JR. Sensitive and quantitative detection of KRAS2 gene mutations in pancreatic duct juice differentiates patients with pancreatic cancer from chronic pancreatitis, potential for early detection. Cancer Biol Ther, 3/2008; 7:260-7.

Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Kamiyama H, Jimeno A, Hong SM, Fu B, Lin MT, Calhoun ES, Kamiyama M, Walter K, Nikolskaya T, Nikolsky Y, Hartigan J, Smith DR, Hidalgo M, Leach SD, Klein AP, Jaffee EM, Goggins M, Maitra A, Iacobuzio-Donahue C, Eshleman JR, Kern SE, Hruban RH, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, and Kinzler KW. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science. 9/2008; 321:1801-6.

Shi C, Hong SM, Lim P, Kamiyama H, Khan M, Anders RA, Goggins M, Hruban RH, and Eshleman JR. KRAS2 mutations in human pancreatic acinar-ductal metaplastic lesions are limited to those with PanIN: Implications for the human pancreatic cancer cell of origin. Mol Cancer Res, 2/2009; 7:230-6 [NIHMS #89589].

Jones S, Hruban RH, Kamiyama M, Borges M, Zhang X, Parsons DW, Cheng-Ho Lin J, Palmisano E, Brune K, Jaffee EM, Iacobuzio-Donahue CA, Maitra A, Parmigini G, Kern SE, Velculescu VE, Kinzler KW, Vogelstein B, Eshleman JR, Goggins M, and Klein AP. Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. Science. 4/2009; 324:217.

Shi C, Chandrasekharan A, Thuluvath PJ, Karikari C, Argani P, Goggins M, Maitra A, and Eshleman JR. Ultrasensitive detection of KRAS2 mutations in bile and serum from patients with biliary tract carcinoma using LigAmp technology. J Molec Diagnostics. In Press.




Email mgoggins@jhmi.edu
Phone (410) 955-3511

Related Websites
PC Early Detection Lab

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Michael G. Goggins, M.D.

Primary Appointment in Pathology; Secondary Appointments in Medicine, Oncology
Member, Graduate Program in Pathobiology


My research is focused on pancreatic cancer. The main focus of my research is improving the early detection of pancreatic cancer. Much of the early detection research is directed towards the Cancer of the Pancreas Screening studies which are evaluating the utility of screening individuals with an increased risk of developing pancreatic cancer based on their inherited risk. The focus of the CAPS studies is evaluating diagnostic tests that could improve the development of pancreatic cancer and pancreatic cancer precursor lesions. The search for diagnostic tests involves the characterizing the molecular differences between pancreatic cancers and their precursor lesions and normal pancreas. Improving the early detection of pancreatic cancer requires a more comprehensive assessment of pancreatic cancer risk. I work with other members of the pancreatic cancer team at Hopkins to better understand the genetic and environmental risk factors and comorbidities that contribute to pancreatic cancer risk.

Publications
Yu J, Blackford A, Dal Molin M, Wolfgang C, Goggins M. Time to progression of pancreatic ductal adenocarcinoma from low-to-high tumour stages. Gut 2015;epub Jan31. PMC4520782

Eshleman JR, Norris AL, Sadakari Y, Debeljak M, Borges M, Harrington C, Lin E, Brant A, Barkley T, Almario JA, Topazian M, Farrell J, Syngal S, Lee JH, Yu J, Hruban RH, Kanda M, Canto MI, Goggins M. KRAS and GNAS Mutations in Pancreatic Juice Collected From the Duodenum of Patients at High Risk for Neoplasia Undergoing Endoscopic Ultrasound. Clin Gastroenterol Hepatol 2015;13:963-9. PMC4404180.

Sadakari Y, Kanda M, Maitani K, Borges M, Canto MI, Goggins M. Mutant KRAS and GNAS DNA Concentrations in Secretin-Stimulated Pancreatic Fluid Collected from the Pancreatic Duct and the Duodenal Lumen. Clin Transl Gastroenterol 2014;in press. PMCID in process

Vincent A, Hong SM, Hu C, Omura N, Young A, Kim H, Yu J, Knight S, Ayars M, Griffith M, Van Seuningen I, Maitra A, Goggins M. Epigenetic silencing of EYA2 in pancreatic adenocarcinomas promotes tumor growth. Oncotarget 2014; 5:2575-2587. PMC4058028

Kim H, Saka B, Knight S, Borges M, Childs E, Klein AP, Wolfgang CL, Herman JM, Adsay V, Hruban RH, Goggins M. Having pancreatic cancer with tumoral loss of ATM and normal TP53 protein expression is associated with a poorer prognosis. Clin Cancer Res 2014;20: 1865-72 PMC3975663

Li A, Yu J, Kim H, Wolfgang CL, Canto MI, Hruban RH, Goggins M. MicroRNA array analysis finds elevated serum miR-1290 accurately distinguishes patients with low-stage pancreatic cancer from healthy and disease controls. Clin Cancer Res 2013;19:3600-3610 PMC3707520

Kanda M, Sadakari Y, Borges M, Topazian M, Farrell J, Syngal S, Lee J, Kamel I, Lennon AM, Knight S, Fujiwara S, Hruban RH, Canto MI, Goggins M. Mutant TP53 in Duodenal Samples of Pancreatic Juice from Patients with Pancreatic Cancer or High-Grade Dysplasia. Clin Gastroenterol Hepatol 2012:11:719-30 PMC3600161

Yu J, Li A, Hong SM, Hruban R, Goggins, M. MicroRNA Alterations of Pancreatic Intraepithelial Neoplasms (PanINs). Clin Cancer Res 2012; 8(4):981-92 PMC3288338

Amato E, Molin MD, Mafficini A, Yu J, Malleo G, Rusev B, Fassan M, Antonello D, Sadakari Y, Castelli P, Zamboni G, Maitra A, Salvia R, Hruban RH, Bassi C, Capelli P, Lawlor RT, Goggins M, Scarpa A. Targeted next-generation sequencing of cancer genes dissects the molecular profiles of intraductal papillary neoplasms of the pancreas. J Pathol 2014;233:217-227. PMC4057302

Kanda M, Matthaei H, Wu J, Hong SM, Yu J, Borges M, Hruban RH, Maitra A, Kinzler K, Vogelstein B, Goggins M. Presence of Somatic Mutations in Most Early-Stage Pancreatic Intraepithelial Neoplasia. Gastroenterology 2012;142:730-733.e9. Epub 2012 Jan 5. PMC3321090

Jones S, Hruban RH, Kamiyama M, Borges M, Zhang X, Parsons DW, Lin JC, Palmisano E, Brune K, Jaffee EM, Iacobuzio-Donahue CA, Maitra A, Parmigiani G, Kern SE, Velculescu VE, Kinzler KW, Vogelstein B, Eshleman JR*, Goggins M*, Klein AP*. Exomic Sequencing Identifies PALB2 as a Pancreatic Cancer Susceptibility Gene. Science 2009; 324:217.: PMC2684332 *senior authors.

Canto MI, Hruban RH, Fishman EK, Kamel IR, Schulick R, Zhang Z, Topazian M, Takahashi N, Fletcher J, Petersen G, Klein AP, Axilbund J, Griffin C, Syngal S, Saltzman JR, Mortele KJ, Lee J, Tamm E, Vikram R, Bhosale P, Margolis D, Farrell J, Goggins M. Frequent detection of pancreatic lesions in asymptomatic high-risk individuals. Gastroenterology 2012;142:796-804. PMC3321068

Kanda M, Knight S, Topazian M, Syngal S, Farrell JJ, Lee J, Kamel I, Lennon AM, Borges M, Young A, Fujiwara S, Seike J, Eshleman J, Hruban RH, Canto MI, Goggins M. Mutant GNAS detected in duodenal collections of secretin-stimulated pancreatic juice indicates the presence or emergence of pancreatic cysts. Gut 2013;62:1024-33 PMC3893110

Hong SM, Vincent A, Kanda M, Leclerc J, Omura N, Borges M, Klein AP, Canto M, Hruban RH, Goggins M. Genome-wide somatic copy number alterations in low-Grade PanINs and IPMNs from individuals with a family history of Pancreatic Cancer. Clin Cancer Res 2012;18:4303-12.

Hong SM, Omura N, Vincent A, Li A, Knight S, Yu J, Hruban RH, Goggins M. Genome-wide CpG island profiling of intraductal papillary mucinous neoplasms of the pancreas. Clin Cancer Res 2012;18:700-12. PMC3271174

Vincent A, Omura N, Hong SM, Jaffe A, Eshleman J, Goggins M. Genome-Wide Analysis of Promoter Methylation Associated with Gene Expression Profile in Pancreatic Adenocarcinoma. Clin Cancer Res 2011;17:4341-54 PMC3131423

Goggins M. Markers of Pancreatic Cancer: Working Toward Early Detection. Clin Cancer Res 2011;17:635-7. PMC3079322

Hong SM, Heaphy CM, Shi C, Eo SH, Cho H, Meeker AK, Eshleman JR, Hruban RH, Goggins M. Telomeres are shortened in acinar-to-ductal metaplasia lesions associated with pancreatic intraepithelial neoplasia but not in isolated acinar-to-ductal metaplasias. Mod Pathol 2011;24:256-66. PMC3166222

Hong SM, Li A, Olino K, Wolfgang CL, Herman JM, Schulick RD, Iacobuzio-Donahue C, Hruban RH, Goggins M. Loss of E-Cadherin Expression and Outcome among Patients with Resectable Pancreatic Adenocarcinomas. Mod Pathol 2011; 24(9):1237-47. PMC3155013

Li A, Omura N, Hong SM, Vincent A, Walter K, Griffith M, Borges M, Goggins M. Pancreatic cancers epigenetically silence SIP1, hypomethylate and overexpress miR-200a/-200b, in association with elevated circulating miR-200a and miR-200b levels. Cancer Research 2010; 70(13):5226-37 PMC3130565

Walter K, Omura N, Hong SM, Griffith M, Vincent A, Borges M, Goggins M. Overexpression of Smoothened activates the Sonic Hedgehog signaling pathway in pancreatic cancer associated fibroblasts. Clin Cancer Res. 2010; 16:1781-9. PMCID: PMC2846609

Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Kamiyama H, Jimeno A, Hong SM, Fu B, Lin MT, Calhoun ES, Kamiyama M, Walter K, Nikolskaya T, Nikolsky Y, Hartigan J, Smith DR, Hidalgo M, Leach SD, Klein AP, Jaffee EM, Goggins M, Maitra A, Iacobuzio-Donahue C, Eshleman JR, Kern SE, Hruban RH, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 2008;321(5897):1801-6. PMID: 18772397




Email skern1@jhmi.edu
Phone (410) 614-3314
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Scott E. Kern, M.D.

Primary Appointment in Oncology; Secondary Appointment in Pathology
Member, Graduate Program in Human Genetics and Molecular Biology; Member, Graduate Program in Pathobiology


I am a cancer geneticist and gastrointestinal pathologist interested in clonal genetic changes in neoplasia. This has included genetic alterations in colorectal and pancreatic carcinoma, their association with pathological characteristics and prognosis, cloning of the DCC and DPC4 genes, localization of the BRCA2 gene, identifying the causes of familial pancreatic cancer, the DNA-binding characteristics of p53 and DPC4, the functional basis of cancer biomarkers, and the principles of genotype-specific anticancer therapy.

Publications

Kern SE, Kinzler KW, Bruskin A, Jarosz D, Friedman P, Prives C, Vogelstein B.Identification of p53 as a sequence-specific DNA-binding protein. Science 252:1708-11, 1991.

Hahn SA, Schutte M, Hoque ATMS, Moskaluk CA, da Costa LT, Rozenblum E,Weinstein CL, Fischer A, Yeo CJ, Hruban RH, Kern SE. DPC4, a candidate tumor-suppressor gene at human chromosome 18q21.1. Science 271:350-353,1996.

Brody JR, Calhoun ES, Gallmeier E, and Kern SE. Ultra-fast, high-resolution agarose electrophoresis of DNA and RNA using low-molarity conductive media. BioTechniques 2004; 37:598-602.

Hucl T, Rago C, Gorospe M, Kern SE. A syngeneic variance library for functional annotation of human genetic variation: Application to BRCA2 exon 27. Cancer Res 2008; 68:5023-30

Ren RY, Patel K, Paun BC, Kern SE. Structural analysis of the cancer-specific mesothelin promoter/enhancer sequences. JBC 2011; 286:11960-9.




Email annele@jhmi.edu
Phone (410) 955-9297

Related Websites
Article Press Release

Le Cancer Metabolism Research Laboratory

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Anne Le, M.D., M.Sc.

Primary Appointment in Pathology


My research is primarily focused on cancer metabolism, specifically studying the key enzymes of glycolysis and glutaminolysis: lactate dehydrogenase A and glutaminase. My research has shown that the inhibition of these enzymes induced oxidative stress thereby inhibiting tumor progression, demonstrating that targeting these metabolic processes can be used in the near future as a feasible cancer therapy. Using a Metabolomics approach, my laboratory is defining the factors that predict the sensitivity of pancreatic cancers to current chemotherapies and also to our novel small drug-like molecules. Our goal is to characterize and enable targeted selection of patients based upon predicted metabolic response. Furthermore in this pursuit, we have developed an innovative dual fluorescent protein reporter, termed HypoxCR, which can simultaneously detect cells that are hypoxic and/or cycling to study the effects of the tumor's microenvironment on the sensitivity to metabolic inhibitors.

Publications
Le A, Lane NA, Hamaker M, Bose S, Barbi J, Tsukamoto T, Rojas CJ, Slusher BS, Zhang H, Zimmerman LJ, Liebler DC, Slebos R, Lorkiewicz P, Higashi RM, Fan WMT and Dang CV. Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in human B lymphocytes. (Co-corresponding author). Cell Metab. 2012 Jan 4;15(1):110-21.

Le A, Cooper CR, Gouw AM, Dinavahi R, Maitra A, Deck LM, Royer RE, Vander Jagt DL, Semenza GL, Dang CV. Inhibition of Lactate Dehydrogenase A Induces Oxidative Stress and Inhibits Tumor Progression. Proc Natl Acad Sci U S A. 2010 Feb 2; 107(5):2037-42.

Yustein J, Liu Y, Gao P, Jie C, Le A, Vuica-Ross M, Chng W, Eberhart C, Bergsagel L, Dang CV. Induction of ectopic Myc target gene, JAG2, augments hypoxic growth and tumorigenesis in a human B cell model. Proc Natl Acad Sci U S A. 2010 Feb 23;107(8):3534-9.

Dang CV, Le A, Gao P. MYC-induced cancer cell energy metabolism and therapeutic opportunities. Clin Cancer Res. 2009 Nov 1; 15(21):6479-83.

Le A, Zielinski R, He C, Crow MT, Biswal S, Tuder RM, Becker PM. Pulmonary epithelial neuropilin-1 deletion enhances development of cigarette smoke-induced emphysema. Am J Respir Crit Care Med. 2009 Sep 1; 180(5):396-406 (Cover image).




Email emontgom@jhmi.edu
Phone (410) 614-2308

Related Websites
Barrett's Esophagus Web

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Elizabeth A. Montgomery, M.D.

Primary Appointment in Pathology


My research efforts are clinicopathologic studies of well-characterized and novel entities encountered in surgical pathology using both conventional light microscopy and newer techniques. Specific interests include several topics in gastrointestinal pathology, especially Barrett esophagus. I look forward to additional clinicopathological work using newer technology. I also have a strong interest in soft tissue pathology and recent studies have been of telomeres in translocation-associated sarcomas compared to chromosome unstable types.

Publications
Montgomery E, Bronner M, Goldblum J, Greenson J, Haber M, Hart J, Lamps L, Lauwers G, Lazenby A, Lewin D, Robert M, Toledano A, Shyr Y, Washington K. Diagnostic reproducibility of dysplasia in Barrett esophagus (BE): Are affirmation. Human Pathology 2001; 32: 368-78.

Montgomery E, Goldblum J, Greenson JK, et al. Dysplasia as a predictive marker for invasive carcinoma in Barrett's esophagus; A follow-up study basedon 138 cases from a diagnostic variability study. Human Pathology 2001; 32:379-388.

Montgomery E, Wilentz R, Argani P, Hruban RH, Fisher C, Kern SE, Lengauer C. Analysis of Anaphase Figures in Routine Histologic Sections Distinguishes Chromosomally Unstable From Chromosomally Stable Malignancies. Cancer Biology and Therapy 2003;3:248-52

Montgomery E, Argani P, Hicks JL, DeMarzo AM and Meeker AK. In situ analysis of telomere lengths in translocation associated and non-translocation associated sarcomas. Am J Pathol 2004; 164: 1523-1529.

Hansel DE, Dhara S, Huang RC, Ashfaq R, Deasel M, Shimada Y, Bernstein HS, Harmon J, Brock M, Forastiere A, Washington MK, Maitra A, Montgomery E. CDC2/CDK1 Expression in Esophageal Adenocarcinoma and Precursor Lesions Serves as a Diagnostic and Cancer Progression Marker and Potential Novel Drug Target. Am J Surg Pathol. In press [2005].




Email velculescu@jhmi.edu
Phone (410) 955-7033
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Victor Velculescu, M.D., Ph.D.

Primary Appointment in Oncology; Secondary Appointment in Pathology;
Co-Director, Cancer Biology Program


Cancer Genomics

It is now widely accepted that cancer is a disease mediated by alterations in specific genes. The last decade has witnessed a dramatic increase in our understanding of the genomic characteristics of human cancer. In my laboratory we began these studies through a systematic analysis of gene families in human cancer, identifying PIK3CA as one of the most commonly mutated cancer genes. We extended these approaches with colleagues at JHU and other institutions to perform the first analyses of cancer genomes in breast, colorectal, pancreas, brain and other cancers. These efforts revealed the genomic landscape of human cancers, identifying new therapeutic targets such as mutant IDH genes in brain cancers and dysregulation of chromatin remodeling as a major mechanism of tumorigenesis. These analyses were spurred through novel genomic approaches we developed, including SAGE, Digital Karyotyping, and high throughput sequencing methods.

Despite the progress that has been made, much remains to be discovered in understanding the dynamic changes that occur in cancer genomes during therapy, resistance and progression, and using this information for early detection and intervention. My group currently focuses on identifying genetic alterations in cancer affecting sensitivity and resistance to targeted therapies, and connecting such changes to key clinical characteristics and novel therapeutic approaches. We have recently developed methods that allow non-invasive characterization of cancer, including the PARE method that provided the first whole genome analysis of tumor DNA in the circulation of cancer patients. These analyses provide a window into real-time genomic analyses of cancer patients and provide new avenues for personalized diagnostic and therapeutic intervention.

Publications

Wang TL, Maierhofer C, Speicher MR, Lengauer C, Vogelstein B, Kinzler KW, Velculescu VE. Digital karyotyping. PNAS 99:16156-16161, 2002

Bardelli A, Parsons DW, Silliman N, Ptak J, Szabo S, Saha S, Markowitz S, Willson JK, Parmigiani G, Kinzler KW, Vogelstein B, Velculescu VE. Mutational analysis of the tyrosine kinome. Science 300:949, 2003

Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, Yan H, Gazdar A, Powell SM, Riggins GJ, Willson JK, Markowitz S, Kinzler KW, Vogelstein B, Velculescu VE. High Frequency of Mutations of the PIK3CA Gene in Human Cancers. Science, 304(5670): 554, 2004.

Samuels Y, Diaz LA Jr, Schmidt-Kittler O, Cummins JM, Delong L, Cheong I, Rago C, Huso DL, Lengauer C, Kinzler KW, Vogelstein B, Velculescu VE. Mutant PIK3CA promotes cell growth and invasion of human cancer cells. Cancer Cell 2005;7:561-73.

Sjoblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber T, Mandelker D, Leary RJ, Ptak J, Silliman N, Szabo S, Buckhaults P, Farrell C, Meeh P, Markowitz SD, Willis J, Dawson D, Willson JK, Gazdar AF, Hartigan J, Wu L, Liu C, Parmigiani G, Park BH, Bachman KE, Papadopoulos N, Vogelstein B, Kinzler KW, Velculescu VE. The Consensus Coding Sequences of Human Breast and Colorectal Cancers. Science. 314(5797):268-74, 2006.

Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu IM, Gallia GL, Olivi A, McLendon R, Rasheed BA, Keir S, Nikolskaya T, Nikolsky Y, Busam DA, Tekleab H, Diaz LA Jr, Hartigan J, Smith DR, Strausberg RL, Marie SK, Shinjo SM, Yan H, Riggins GJ, Bigner DD, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW. An integrated genomic analysis of human glioblastoma multiforme. Science. 321(5897):1807-12, 2008. PMCID: PMC2820389

Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Kamiyama H, Jimeno A, Hong SM, FuB, Lin MT, Calhoun ES, Kamiyama M, Walter K, Nikolskaya T, Nikolsky Y, Hartigan J, Smith DR, Hidalgo M, Leach SD, Klein AP, Jaffee EM, Goggins M, Maitra A, Iacobuzio-Donahue C, Eshleman JR, Kern SE, Hruban RH, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science. 321(5897):1801-6, 2008. PMCID: PMC2848990.

Leary RJ, Kinde I, Diehl F, Schmidt K, Clouser C, Duncan C, Antipova A, Lee C, McKernan K, de la Vega, F, Kinzler KW, Vogelstein B, Diaz LA Jr, Velculescu VE. Development of Personalized Tumor Biomarkers Using Massively Parallel Sequencing. Science TM, 2: 20ra14, 2010. PMCID: PMC2858564.

Parsons DW, Li M, Zhang X, Jones S, Leary RJ, Lin JC, Boca SM, Carter H, Samayoa J, Bettegowda C, Gallia GL, Jallo GI, Binder ZA, Nikolsky Y, Hartigan J, Smith DR, Gerhard DS, Fults DW, VandenBerg S, Berger MS, Marie SK, Shinjo SM, Clara C, Phillips PC, Minturn JE, Biegel JA, Judkins AR, Resnick AC, Storm PB, Curran T, He Y, Rasheed BA, Friedman HS, Keir ST, McLendon R, Northcott PA, Taylor MD, Burger PC, Riggins GJ, Karchin R, Parmigiani G, Bigner DD, Yan H, Papadopoulos N, Vogelstein B, Kinzler KW, Velculescu VE. The genetic landscape of the childhood cancer medulloblastoma. Science 331: 435-439, 2010. PMCID: PMC3110744.

Sausen M, Leary RJ, Jones S, Wu J, Reynolds CP, Liu X, Blackford A, Parmigiani G, Diaz LA Jr, Papadopoulos N, Vogelstein B, Kinzler KW, Velculescu VE, Hogarty MD. Integrated genomic analyses identify ARID1A and ARID1B alterations in the childhood cancer neuroblastoma. Nature Genetics. 45: 12-17, 2012. PMCID: PMC3557959.

Leary RJ, Sausen M, Kinde I, Papadopoulos N, Carpten JD, Craig D, O'Shaughnessy J, Kinzler KW, Parmigiani G, Vogelstein B, Diaz LA Jr, Velculescu VE. Detection of chromosomal alterations in the circulation of cancer patients with whole-genome sequencing. Science TM. 4:162ra154, 2012. PMCID: PMC3641759.

Haber DA, Velculescu VE. Blood-Based Analyses of Cancer: Circulating Tumor Cells and Circulating Tumor DNA. Cancer Discovery. 2014 Jun;4(6):650-61. PubMed PMID: 24801577.

Publications for Victor Velculescu through PubMed




Email lvoltag1@jhmi.edu
Phone (410) 955-3580
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Lysandra Voltaggio, M.D.

Primary Appointment in Pathology


My research interests focus primarily on clinicopathologic studies of inflammatory and infectious disorders of the gastrointestinal tract. I am specifically interested in identifying histologic patterns of inflammation using light microscopy that can help pathologists identify both common and rare entities affecting the gastrointestinal tract.

Publications
Voltaggio, L., Montgomery, E.A. Gastric Mesenchymal Lesions Other Than Gastrointestinal Stromal Tumor. Diagnostic Histopathology. 2014. June; 20(6): 228-238

Voltaggio, L., Montgomery, E.A., Ali, M.A., Singhi, A.D. Arnold, C. Sex, Lies, and Gastrointestinal Tract Biopsies: A Review of Selected Sexually Transmitted Proctocolitides. Advances in Anatomic Pathology. 2014. March; 21(2): 83-93.

Arnold, C.A., Montgomery, E.A., Voltaggio, L. Syphilitic and Lymphogranuloma Venereum (LGV) Proctocolitis: Clues to a Frequently Missed Diagnosis. Am J Surg Pathol. 2013 Jan;37(1):38-46.

Ali, A., Lam-Himlin, D., Voltaggio, L. Eosinophilic Esophagitis Clinical, Endoscopic, and Histopathologic Review. Gastrointestinal Endoscopy. 2012 Dec;76(6):1224-37.

Voltaggio L., Murray R., Lasota J., Miettinen M. Gastric Shwannoma: A Clinicopathologic Study of 51 Cases and Review of the Literature. Human Pathology. 2011 Nov 30. Epub ahead of print.




Email ldwood@jhmi.edu
Phone (410) 955-3511
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Laura Wood, M.D., Ph.D.

Primary Appointment in Pathology


My laboratory focuses on genomic and morphological characterization of pancreatic and liver neoplasms. Decades of cancer research have shown that cancer is a genetic disease caused by somatic mutations in oncogenes and tumor suppressor genes. With rapid advances in sequencing and bioinformatics technology, whole exome or even whole genome sequencing studies of tumors can now be routinely performed. However, the next key step is utilizing these technologies to address specific clinically relevant questions about cancer genomes. My laboratory focuses on two such clinically relevant issues: (1) the transition from non-invasive precursor lesions to invasive cancer and (2) intratumoral heterogeneity. We investigate these questions with cutting-edge genomic approaches, including genetic analyses of single cells. In addition, in collaboration with Dr. Denis Wirtz in the School of Engineering, we also perform high-throughput phenotyping analyses of human tumors. The goal of these studies is to characterize the phenotypic determinants of invasion and heterogeneity as well as correlate tumor genotype and phenotype on the single cell level.

Publications
Sjöblom T*, Jones S*, Wood LD*, Parsons DW*, Lin J, Barber TD, Mandelker D, Leary RJ, Ptak J, Silliman N, Szabo S, Buckhaults P, Farrell C, Meeh P, Markowitz SD, Willis J, Dawson D, Willson JK, Gazdar AF, Hartigan J, Wu L, Liu C, Parmigiani G, Park BH, Bachman KE, Papadopoulos N, Vogelstein B, Kinzler KW, Velculescu VE. The consensus coding sequences of human breast and colorectal cancers. Science. 2006 Oct 13; 314(5797):268-74.

Wood LD*, Parsons DW*, Jones S*, Lin J*, Sjöblom T*, Leary RJ, Shen D, Boca SM, Barber T, Ptak J, Silliman N, Szabo S, Dezso Z, Ustyanksky V, Nikolskaya T, Nikolsky Y, Karchin R, Wilson PA, Kaminker JS, Zhang Z, Croshaw R, Willis J, Dawson D, Shipitsin M, Willson JKV, Sukumar S, Polyak K, Park BH, Pethiyagoda CL, Pant PVK, Ballinger DG, Sparks AB, Hartigan J, Smith DR, Suh E, Papadopoulos N, Buckhaults P, Markowitz SD, Parmigiani G, Kinzler KW, Velculescu VE, Vogelstein B. The genomic landscapes of human breast and colorectal cancers. Science. 2007 Nov 16; 318(5853):1108-13.

Li M, Zhao H, Zhang X, Wood LD, Anders RA, Choti MA, Pawlik TM, Daniel HD, Kannangai R, Offerhaus GJ, Velculescu VE, Wang L, Zhou S, Vogelstein B, Hruban RH, Papadopoulos N, Cai J, Torbenson MS, Kinzler KW. Inactivating mutations of the chromatin remodeling gene ARID2 in hepatocellular carcinoma. Nat Genet. 2011 Aug 7; 43(9):828-9.

Wu J, Jiao Y, Dal Molin M, Maitra A, de Wilde RF, Wood LD, Eshleman JR, Goggins MG, Wolfgang CL, Canto MI, Schulick RD, Edil BH, Choti MA, Adsay V, Klimstra DS, Offerhaus GJ, Klein AP, Kopelovich L, Carter H, Karchin R, Allen PJ, Schmidt CM, Naito Y, Diaz LA Jr, Kinzler KW, Papadopoulos N, Hruban RH, Vogelstein B. Whole-exome sequencing of neoplastic cysts of the pancreas reveals recurrent mutations in components of ubiquitin-dependent pathways. Proc Natl Acad Sci USA. 2011 Dec 27; 108(52):21188-93.

Wood LD, Heaphy CM, Daniel HJ, Naini BV, Lassman CR, Arroyo MR, Kamel IR, Cosgrove D, Boitnott J, Meeker AK, Torbenson M. Chromophobe hepatocellular carcinoma with abrupt anaplasia: a proposal for a new subtype of hepatocellular carcinoma with unique morphologic and molecular features. Mod Pathol. 2013 May. Epub ahead of print.



 


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