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Pancreatic Neoplasms: HELP
Articles by Samir M. Hanash
Based on 10 articles published since 2010
(Why 10 articles?)
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Between 2010 and 2020, S. Hanash wrote the following 10 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Article Tumor Microbiome Diversity and Composition Influence Pancreatic Cancer Outcomes. 2019

Riquelme, Erick / Zhang, Yu / Zhang, Liangliang / Montiel, Maria / Zoltan, Michelle / Dong, Wenli / Quesada, Pompeyo / Sahin, Ismet / Chandra, Vidhi / San Lucas, Anthony / Scheet, Paul / Xu, Hanwen / Hanash, Samir M / Feng, Lei / Burks, Jared K / Do, Kim-Anh / Peterson, Christine B / Nejman, Deborah / Tzeng, Ching-Wei D / Kim, Michael P / Sears, Cynthia L / Ajami, Nadim / Petrosino, Joseph / Wood, Laura D / Maitra, Anirban / Straussman, Ravid / Katz, Matthew / White, James Robert / Jenq, Robert / Wargo, Jennifer / McAllister, Florencia. ·Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Center for Integrative Biology, Faculty of Science, Universidad Mayor, Santiago, Chile. · Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Engineering, Texas Southern University, Houston, TX, USA. · Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; McCombs Institute for the Early Detection and Treatment of Cancer, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. · Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Departments of Medicine, Oncology and Molecular Microbiology & Immunology, Johns Hopkins University School of Medicine and the Bloomberg School of Public Health, Baltimore, MD, USA. · Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA. · Department of Pathology and The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Sheikh Ahmed Pancreatic Cancer Research Center, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Resphera Biosciences, Baltimore, MD, USA. · Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Clinical Cancer Genetics Program, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: fmcallister@mdanderson.org. ·Cell · Pubmed #31398337.

ABSTRACT: Most patients diagnosed with resected pancreatic adenocarcinoma (PDAC) survive less than 5 years, but a minor subset survives longer. Here, we dissect the role of the tumor microbiota and the immune system in influencing long-term survival. Using 16S rRNA gene sequencing, we analyzed the tumor microbiome composition in PDAC patients with short-term survival (STS) and long-term survival (LTS). We found higher alpha-diversity in the tumor microbiome of LTS patients and identified an intra-tumoral microbiome signature (Pseudoxanthomonas-Streptomyces-Saccharopolyspora-Bacillus clausii) highly predictive of long-term survivorship in both discovery and validation cohorts. Through human-into-mice fecal microbiota transplantation (FMT) experiments from STS, LTS, or control donors, we were able to differentially modulate the tumor microbiome and affect tumor growth as well as tumor immune infiltration. Our study demonstrates that PDAC microbiome composition, which cross-talks to the gut microbiome, influences the host immune response and natural history of the disease.

2 Article Syndecan 1 is a critical mediator of macropinocytosis in pancreatic cancer. 2019

Yao, Wantong / Rose, Johnathon L / Wang, Wei / Seth, Sahil / Jiang, Hong / Taguchi, Ayumu / Liu, Jintan / Yan, Liang / Kapoor, Avnish / Hou, Pingping / Chen, Ziheng / Wang, Qiuyun / Nezi, Luigi / Xu, Zhaohui / Yao, Jun / Hu, Baoli / Pettazzoni, Piergiorgio F / Ho, I Lin / Feng, Ningping / Ramamoorthy, Vandhana / Jiang, Shan / Deng, Pingna / Ma, Grace J / Den, Peter / Tan, Zhi / Zhang, Shu Xing / Wang, Huamin / Wang, Y Alan / Deem, Angela K / Fleming, Jason B / Carugo, Alessandro / Heffernan, Timothy P / Maitra, Anirban / Viale, Andrea / Ying, Haoqiang / Hanash, Samir / DePinho, Ronald A / Draetta, Giulio F. ·Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Center for Co-Clinical Trials, University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. · Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, FL, USA. · Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA. gdraetta@mdanderson.org. · Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. gdraetta@mdanderson.org. ·Nature · Pubmed #30918400.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) remains recalcitrant to all forms of cancer treatment and carries a five-year survival rate of only 8%

3 Article Integrative Analysis of Novel Metabolic Subtypes in Pancreatic Cancer Fosters New Prognostic Biomarkers. 2019

Follia, Laura / Ferrero, Giulio / Mandili, Giorgia / Beccuti, Marco / Giordano, Daniele / Spadi, Rosella / Satolli, Maria Antonietta / Evangelista, Andrea / Katayama, Hiroyuki / Hong, Wang / Momin, Amin A / Capello, Michela / Hanash, Samir M / Novelli, Francesco / Cordero, Francesca. ·Center for Experimental Research and Medical Studies, Azienda Universitaria Ospedaliera Città della Salute e della Scienza di Torino, Turin, Italy. · Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy. · Department of Computer Sciences, University of Turin, Turin, Italy. · Centro Oncologico Ematologico Subalpino, Azienda Universitaria Ospedaliera Città della Salute e della Scienza di Torino, Turin, Italy. · Servizio di Epidemiologia dei Tumori, Azienda Universitaria Ospedaliera Città della Salute e della Scienza di Torino, Turin, Italy. · Department of Clinical Cancer Prevention Research, MD Anderson Cancer Center, Houston, TX, United States. · Molecular Biotechnology Center, University of Turin, Turin, Italy. ·Front Oncol · Pubmed #30873387.

ABSTRACT:

4 Article Exosomes harbor B cell targets in pancreatic adenocarcinoma and exert decoy function against complement-mediated cytotoxicity. 2019

Capello, Michela / Vykoukal, Jody V / Katayama, Hiroyuki / Bantis, Leonidas E / Wang, Hong / Kundnani, Deepali L / Aguilar-Bonavides, Clemente / Aguilar, Mitzi / Tripathi, Satyendra C / Dhillon, Dilsher S / Momin, Amin A / Peters, Haley / Katz, Matthew H / Alvarez, Hector / Bernard, Vincent / Ferri-Borgogno, Sammy / Brand, Randall / Adler, Douglas G / Firpo, Matthew A / Mulvihill, Sean J / Molldrem, Jeffrey J / Feng, Ziding / Taguchi, Ayumu / Maitra, Anirban / Hanash, Samir M. ·Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. · The McCombs Institute for the Early Detection and Treatment of Cancer, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. · Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. · Department of Biostatistics, University of Kansas Medical Center, Kansas City, KS, 66160, USA. · Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. · Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. · Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. · Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, PA, 15232, USA. · Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, 84132, USA. · Department of Surgery, University of Utah School of Medicine, Salt Lake City, UT, 84132, USA. · Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. · Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. shanash@mdanderson.org. · The McCombs Institute for the Early Detection and Treatment of Cancer, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. shanash@mdanderson.org. · Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. shanash@mdanderson.org. ·Nat Commun · Pubmed #30651550.

ABSTRACT: Although B cell response is frequently found in cancer, there is little evidence that it alters tumor development or progression. The process through which tumor-associated antigens trigger humoral response is not well delineated. We investigate the repertoire of antigens associated with humoral immune response in pancreatic ductal adenocarcinoma (PDAC) using in-depth proteomic profiling of immunoglobulin-bound proteins from PDAC patient plasmas and identify tumor antigens that induce antibody response together with exosome hallmark proteins. Additional profiling of PDAC cell-derived exosomes reveals significant overlap in their protein content with immunoglobulin-bound proteins in PDAC plasmas, and significant autoantibody reactivity is observed between PDAC cell-derived exosomes and patient plasmas compared to healthy controls. Importantly, PDAC-derived exosomes induce a dose-dependent inhibition of PDAC serum-mediated complement-dependent cytotoxicity towards cancer cells. In summary, we provide evidence that exosomes display a large repertoire of tumor antigens that induce autoantibodies and exert a decoy function against complement-mediated cytotoxicity.

5 Article Surfaceome profiling enables isolation of cancer-specific exosomal cargo in liquid biopsies from pancreatic cancer patients. 2018

Castillo, J / Bernard, V / San Lucas, F A / Allenson, K / Capello, M / Kim, D U / Gascoyne, P / Mulu, F C / Stephens, B M / Huang, J / Wang, H / Momin, A A / Jacamo, R O / Katz, M / Wolff, R / Javle, M / Varadhachary, G / Wistuba, I I / Hanash, S / Maitra, A / Alvarez, H. ·Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, USA. · The University of Texas MD Anderson Cancer UTHealth Graduate School of Biomedical Sciences, Houston, USA. · Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, USA. · Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA. · Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, USA. · ContinuumDx, Houston, USA. · McCombs Institute for the Early Detection and Treatment of Cancer, The University of Texas MD Anderson Cancer Center, Houston, USA. · Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, USA. · Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA. · Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, USA. · Department of Sheikh Ahmed Pancreatic Cancer Research Center, The University of Texas MD Anderson Cancer Center, Houston, USA. ·Ann Oncol · Pubmed #29045505.

ABSTRACT: Background: Detection of circulating tumor DNA can be limited due to their relative scarcity in circulation, particularly while patients are actively undergoing therapy. Exosomes provide a vehicle through which cancer-specific material can be enriched from the compendium of circulating non-neoplastic tissue-derived nucleic acids. We carried out a comprehensive profiling of the pancreatic ductal adenocarcinoma (PDAC) exosomal 'surfaceome' in order to identify surface proteins that will render liquid biopsies amenable to cancer-derived exosome enrichment for downstream molecular profiling. Patients and methods: Surface exosomal proteins were profiled in 13 human PDAC and 2 non-neoplastic cell lines by liquid chromatography-mass spectrometry. A total of 173 prospectively collected blood samples from 103 PDAC patients underwent exosome isolation. Droplet digital PCR was used on 74 patients (136 total exosome samples) to determine baseline KRAS mutation call rates while patients were on therapy. PDAC-specific exosome capture was then carried out on additional 29 patients (37 samples) using an antibody cocktail directed against selected proteins, followed by droplet digital PCR analysis. Exosomal DNA in a PDAC patient resistant to therapy were profiled using a molecular barcoded, targeted sequencing panel to determine the utility of enriched nucleic acid material for comprehensive molecular analysis. Results: Proteomic analysis of the exosome 'surfaceome' revealed multiple PDAC-specific biomarker candidates: CLDN4, EPCAM, CD151, LGALS3BP, HIST2H2BE, and HIST2H2BF. KRAS mutations in total exosomes were detected in 44.1% of patients undergoing active therapy compared with 73.0% following exosome capture using the selected biomarkers. Enrichment of exosomal cargo was amenable to molecular profiling, elucidating a putative mechanism of resistance to PARP inhibitor therapy in a patient harboring a BRCA2 mutation. Conclusion: Exosomes provide unique opportunities in the context of liquid biopsies for enrichment of tumor-specific material in circulation. We present a comprehensive surfaceome characterization of PDAC exosomes which allows for capture and molecular profiling of tumor-derived DNA.

6 Article Combined circulating tumor DNA and protein biomarker-based liquid biopsy for the earlier detection of pancreatic cancers. 2017

Cohen, Joshua D / Javed, Ammar A / Thoburn, Christopher / Wong, Fay / Tie, Jeanne / Gibbs, Peter / Schmidt, C Max / Yip-Schneider, Michele T / Allen, Peter J / Schattner, Mark / Brand, Randall E / Singhi, Aatur D / Petersen, Gloria M / Hong, Seung-Mo / Kim, Song Cheol / Falconi, Massimo / Doglioni, Claudio / Weiss, Matthew J / Ahuja, Nita / He, Jin / Makary, Martin A / Maitra, Anirban / Hanash, Samir M / Dal Molin, Marco / Wang, Yuxuan / Li, Lu / Ptak, Janine / Dobbyn, Lisa / Schaefer, Joy / Silliman, Natalie / Popoli, Maria / Goggins, Michael G / Hruban, Ralph H / Wolfgang, Christopher L / Klein, Alison P / Tomasetti, Cristian / Papadopoulos, Nickolas / Kinzler, Kenneth W / Vogelstein, Bert / Lennon, Anne Marie. ·The Ludwig Center, The Johns Hopkins Medical Institutions, Baltimore, MD 21287. · Howard Hughes Medical Institute, The Johns Hopkins Medical Institutions, Baltimore, MD 21287. · Sidney Kimmel Cancer Center at Johns Hopkins, The Johns Hopkins Medical Institutions, Baltimore, MD 21287. · The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD 21287. · Department of Biomedical Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. · Department of Surgery, The Johns Hopkins Medical Institutions, Baltimore, MD 21287. · Division of Systems Biology and Personalized Medicine, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3021, Australia. · Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC 3010, Australia. · Department of Medical Oncology, Western Health, Melbourne, VIC 3021, Australia. · Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202. · Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202. · Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10065. · Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065. · Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15260. · Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15260. · Department of Epidemiology, Mayo Clinic, Rochester, MN 55902. · Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea. · Department of Hepatobiliary and Pancreas Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea. · Division of Pancreatic Surgery, Department of Surgery, San Raffaele Scientific Institute Research Hospital, 20132 Milan, Italy. · Department of Pathology, San Raffaele Scientific Institute Research Hospital, 20132 Milan, Italy. · The Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. · Department of Biostatistics, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205. · Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, MD 21287. · Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD 21287. · Department of Epidemiology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205. · Division of Biostatistics and Bioinformatics, Department of Oncology, The Johns Hopkins Medical Institutions, Baltimore, MD 21287. · The Ludwig Center, The Johns Hopkins Medical Institutions, Baltimore, MD 21287; bertvog@gmail.com amlennon@jhmi.edu. · The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD 21287; bertvog@gmail.com amlennon@jhmi.edu. ·Proc Natl Acad Sci U S A · Pubmed #28874546.

ABSTRACT: The earlier diagnosis of cancer is one of the keys to reducing cancer deaths in the future. Here we describe our efforts to develop a noninvasive blood test for the detection of pancreatic ductal adenocarcinoma. We combined blood tests for

7 Article Sequential Validation of Blood-Based Protein Biomarker Candidates for Early-Stage Pancreatic Cancer. 2017

Capello, Michela / Bantis, Leonidas E / Scelo, Ghislaine / Zhao, Yang / Li, Peng / Dhillon, Dilsher S / Patel, Nikul J / Kundnani, Deepali L / Wang, Hong / Abbruzzese, James L / Maitra, Anirban / Tempero, Margaret A / Brand, Randall / Firpo, Matthew A / Mulvihill, Sean J / Katz, Matthew H / Brennan, Paul / Feng, Ziding / Taguchi, Ayumu / Hanash, Samir M. ·Departments of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · International Agency for Research on Cancer (IARC) Lyon, France. · Division of Medical Oncology, Duke University, Durham, NC, USA. · Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Pancreas Center, University of California San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA · Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, PA, USA. · Department of Surgery, University of Utah School of Medicine, Salt Lake City, UT, USA. · Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. ·J Natl Cancer Inst · Pubmed #28376157.

ABSTRACT: Background: CA19-9, which is currently in clinical use as a pancreatic ductal adenocarcinoma (PDAC) biomarker, has limited performance in detecting early-stage disease. We and others have identified protein biomarker candidates that have the potential to complement CA19-9. We have carried out sequential validations starting with 17 protein biomarker candidates to determine which markers and marker combination would improve detection of early-stage disease compared with CA19-9 alone. Methods: Candidate biomarkers were subjected to enzyme-linked immunosorbent assay based sequential validation using independent multiple sample cohorts consisting of PDAC cases (n = 187), benign pancreatic disease (n = 93), and healthy controls (n = 169). A biomarker panel for early-stage PDAC was developed based on a logistic regression model. All statistical tests for the results presented below were one-sided. Results: Six out of the 17 biomarker candidates and CA19-9 were validated in a sample set consisting of 75 PDAC patients, 27 healthy subjects, and 19 chronic pancreatitis patients. A second independent set of 73 early-stage PDAC patients, 60 healthy subjects, and 74 benign pancreatic disease patients (combined validation set) yielded a model that consisted of TIMP1, LRG1, and CA19-9. Additional blinded testing of the model was done using an independent set of plasma samples from 39 resectable PDAC patients and 82 matched healthy subjects (test set). The model yielded areas under the curve (AUCs) of 0.949 (95% confidence interval [CI] = 0.917 to 0.981) and 0.887 (95% CI = 0.817 to 0.957) with sensitivities of 0.849 and 0.667 at 95% specificity in discriminating early-stage PDAC vs healthy subjects in the combined validation and test sets, respectively. The performance of the biomarker panel was statistically significantly improved compared with CA19-9 alone (P < .001, combined validation set; P = .008, test set). Conclusion: The addition of TIMP1 and LRG1 immunoassays to CA19-9 statistically significantly improves the detection of early-stage PDAC.

8 Article High prevalence of mutant KRAS in circulating exosome-derived DNA from early-stage pancreatic cancer patients. 2017

Allenson, K / Castillo, J / San Lucas, F A / Scelo, G / Kim, D U / Bernard, V / Davis, G / Kumar, T / Katz, M / Overman, M J / Foretova, L / Fabianova, E / Holcatova, I / Janout, V / Meric-Bernstam, F / Gascoyne, P / Wistuba, I / Varadhachary, G / Brennan, P / Hanash, S / Li, D / Maitra, A / Alvarez, H. ·Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA. · Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, USA. · Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, USA. · Sheikh Ahmed Pancreatic Cancer Research Center, The University of Texas MD Anderson Cancer Center, Houston, USA. · Genetic Epidemiology Group International Agency for Research on Cancer, Lyon, France. · Department of GI Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA. · Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic. · Regional Authority of Public Health in Banska Bystrica, Banska Bystrica, Slovakia. · Institute of Public Health and Preventive Medicine, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic. · Department of Preventive Medicine, Palacky University of Medicine, Olomouc, Czech Republic. · Department of Epidemiology and Public Health, Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic. · Department of Investigational Cancer Therapeutics and the Institute for Personalized Cancer Therapy, Houston, USA. · Section of Experimental Pathology, University of Texas M.D. Anderson Cancer Center, Houston, USA · Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, USA. ·Ann Oncol · Pubmed #28104621.

ABSTRACT: Background: Exosomes arise from viable cancer cells and may reflect a different biology than circulating cell-free DNA (cfDNA) shed from dying tissues. We compare exosome-derived DNA (exoDNA) to cfDNA in liquid biopsies of patients with pancreatic ductal adenocarcinoma (PDAC). Patients and methods: Patient samples were obtained between 2003 and 2010, with clinically annotated follow up to 2015. Droplet digital PCR was performed on exoDNA and cfDNA for sensitive detection of KRAS mutants at codons 12/13. A cumulative series of 263 individuals were studied, including a discovery cohort of 142 individuals: 68 PDAC patients of all stages; 20 PDAC patients initially staged with localized disease, with blood drawn after resection for curative intent; and 54 age-matched healthy controls. A validation cohort of 121 individuals (39 cancer patients and 82 healthy controls) was studied to validate KRAS detection rates in early-stage PDAC patients. Primary outcome was circulating KRAS status as detected by droplet digital PCR. Secondary outcomes were disease-free and overall survival. Results: KRAS mutations in exoDNA, were identified in 7.4%, 66.7%, 80%, and 85% of age-matched controls, localized, locally advanced, and metastatic PDAC patients, respectively. Comparatively, mutant KRAS cfDNA was detected in 14.8%, 45.5%, 30.8%, and 57.9% of these individuals. Higher exoKRAS MAFs were associated with decreased disease-free survival in patients with localized disease. In the validation cohort, mutant KRAS exoDNA was detected in 43.6% of early-stage PDAC patients and 20% of healthy controls. Conclusions: Exosomes are a distinct source of tumor DNA that may be complementary to other liquid biopsy DNA sources. A higher percentage of patients with localized PDAC exhibited detectable KRAS mutations in exoDNA than previously reported for cfDNA. A substantial minority of healthy samples demonstrated mutant KRAS in circulation, dictating careful consideration and application of liquid biopsy findings, which may limit its utility as a broad cancer-screening method.

9 Article Prognostic and Functional Significance of MAP4K5 in Pancreatic Cancer. 2016

Wang, Oliver H / Azizian, Nancy / Guo, Ming / Capello, Michela / Deng, Defeng / Zang, Fenglin / Fry, Jason / Katz, Matthew H / Fleming, Jason B / Lee, Jeffrey E / Wolff, Robert A / Hanash, Samir / Wang, Huamin / Maitra, Anirban. ·Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America. · Department of Clinical Cancer Prevention, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America. · Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America. · Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America. · Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America. · Department of Translational Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America. ·PLoS One · Pubmed #27023625.

ABSTRACT: OBJECTIVES: MAP4K5 plays an important role in regulating a range of cellular responses and is involved in Wnt signaling in hematopoietic cells. However, its functions in human malignancies have not been studied. The major objectives of this study are to examine the expression, functions and clinical significance of MAP4K5 in pancreatic ductal adenocarcinoma (PDAC). MATERIALS AND METHODS: The expression levels of MAP4K5, E-cadherin, vimentin, and carboxylesterase 2 (CES2) were examined by immunohistochemistry in 105 PDAC and matched non-neoplastic pancreas samples from our institution. The RNA sequencing data of 112 PDAC patients were downloaded from the TCGA data portal. Immunoblotting and RNA sequencing analysis were used to examine the expression of MAP4K5 and E-cadherin in pancreatic cancer cell lines. The effect of knockdown MAP4K5 using siRNA on the expression of CDH1 and vimentin were examined by Real-time RT-PCR in Panc-1 and AsPC-1 cells. Statistical analyses were performed using IBM SPSS Statistics. RESULTS: MAP4K5 protein is expressed at high levels specifically in the pancreatic ductal cells of 100% non-neoplastic pancreas samples, but is decreased or lost in 77.1% (81/105) of PDAC samples. MAP4K5-low correlated with the loss of E-cadherin (P = 0.001) and reduced CES2 expression (P = 0.002) in our patient populations. The expression levels of MAP4K5 mRNA directly correlated with the expression levels of CDH1 mRNA (R = 0.2490, P = 0.008) in the second cohort of 112 PDAC patients from The Cancer Genome Atlas (TCGA) RNA-seq dataset. Similar correlations between the expression of MAP4K5 and E-cadherin were observed both at protein and mRNA levels in multiple pancreatic cancer cell lines. Knockdown MAP4K5 led to decreased CDH1 mRNA expression in Panc-1 and AsPC-1 cells. MAP4K5-low correlated significantly with reduced overall survival and was an independent prognosticator in patients with stage II PDAC. CONCLUSIONS: MAP4K5 expression is decreased or lost in majority of PDACs. The strong associations between low MAP4K5 expression and loss of E-cadherin, reduced CES2 expression and decreased overall survival may suggest an important role of MAP4K5 in epithelial-to-mesenchymal transition, chemotherapy resistance and tumor progression in pancreatic cancer. Targeting impaired MAP4K5 signaling may represent a new therapeutic strategy for pancreatic cancer.

10 Article Carboxylesterase 2 as a Determinant of Response to Irinotecan and Neoadjuvant FOLFIRINOX Therapy in Pancreatic Ductal Adenocarcinoma. 2015

Capello, Michela / Lee, Minhee / Wang, Hong / Babel, Ingrid / Katz, Matthew H / Fleming, Jason B / Maitra, Anirban / Wang, Huamin / Tian, Weihua / Taguchi, Ayumu / Hanash, Samir M. ·: Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX (MC, HW, SMH) · Fred Hutchinson Cancer Research Center, Seattle, WA (ML, IB) · Departments of Surgical Oncology (MHK, JBF), Pathology (AM, HW, WT), and Translational Molecular Pathology (AM, HW, AT, SMH), The University of Texas MD Anderson Cancer Center, Houston, TX. ·J Natl Cancer Inst · Pubmed #26025324.

ABSTRACT: BACKGROUND: Serine hydrolases (SHs) are among the largest classes of enzymes in humans and play crucial role in many pathophysiological processes of cancer. We have undertaken a comprehensive proteomic analysis to assess the differential expression and cellular localization of SHs, which uncovered distinctive expression of Carboxylesterase 2 (CES2), the most efficient carboxyl esterase in activating the prodrug irinotecan into SN-38, in pancreatic ductal adenocarcinoma (PDAC). We therefore assessed the extent of heterogeneity in CES2 expression in PDAC and its potential relevance to irinotecan based therapy. METHODS: CES2 expression in PDAC and paired nontumor tissues was evaluated by immunohistochemistry. CES2 activity was assessed by monitoring the hydrolysis of the substrate p-NPA and correlated with irinotecan IC50 values by means of Pearson's correlation. Kaplan-Meier and Cox regression analyses were applied to assess the association between overall survival and CES2 expression in patients who underwent neoadjuvant FOLFIRINOX treatment. All statistical tests were two-sided. RESULTS: Statistically significant overexpression of CES2, both at the mRNA and protein levels, was observed in PDAC compared with paired nontumor tissue (P < .001), with 48 of 118 (40.7%) tumors exhibiting high CES2 expression. CES2 activity in 11 PDAC cell lines was inversely correlated with irinotecan IC50 values (R = -0.68, P = .02). High CES2 expression in tumor tissue was associated with longer overall survival in resectable and borderline resectable patients who underwent neoadjuvant FOLFIRINOX treatment (hazard ratio = 0.14, 95% confidence interval = 0.04 to 0.51, P = .02). CONCLUSION: Our findings suggest that CES2 expression and activity, by mediating the intratumoral activation of irinotecan, is a contributor to FOLFIRINOX sensitivity in pancreatic cancer and CES2 assessment may define a subset of patients likely to respond to irinotecan based therapy.