Pick Topic
Review Topic
List Experts
Examine Expert
Save Expert
  Site Guide ··   
Pancreatic Neoplasms: HELP
Articles by Nabeel Bardeesy
Based on 41 articles published since 2010
(Why 41 articles?)
||||

Between 2010 and 2020, Nabeel Bardeesy wrote the following 41 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Review Pancreatic Cancer Metabolism: Breaking It Down to Build It Back Up. 2015

Perera, Rushika M / Bardeesy, Nabeel. ·Center for Cancer Research, Massachusetts General Hospital, Boston, Massachusetts. Center for Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts. Bardeesy.Nabeel@mgh.harvard.edu rushika.perera@ucsf.edu. ·Cancer Discov · Pubmed #26534901.

ABSTRACT: SIGNIFICANCE: Alterations in tumor cell and systemic metabolism are central to the biology of pancreatic cancer. Further investigation of these processes will provide important insights into how these tumors develop and grow, and suggest new approaches for its detection, prevention, and treatment.

2 Review Pancreatic adenocarcinoma. 2014

Ryan, David P / Hong, Theodore S / Bardeesy, Nabeel. ·From the Division of Hematology-Oncology, Department of Medicine (D.P.R., N.B.), and the Department of Radiation Oncology (T.S.H.), Massachusetts General Hospital, Boston. ·N Engl J Med · Pubmed #25207767.

ABSTRACT: -- No abstract --

3 Article Transcriptional control of subtype switching ensures adaptation and growth of pancreatic cancer. 2019

Adams, Christina R / Htwe, Htet Htwe / Marsh, Timothy / Wang, Aprilgate L / Montoya, Megan L / Subbaraj, Lakshmipriya / Tward, Aaron D / Bardeesy, Nabeel / Perera, Rushika M. ·Department of Anatomy, University of California, San Francisco, San Francisco, United States. · Department of Pathology, University of California, San Francisco, San Francisco, United States. · Department of Otolaryngology, University of California, San Francisco, San Francisco, United States. · Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, United States. · Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, United States. ·Elife · Pubmed #31134896.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) is a heterogeneous disease comprised of a basal-like subtype with mesenchymal gene signatures, undifferentiated histopathology and worse prognosis compared to the classical subtype. Despite their prognostic and therapeutic value, the key drivers that establish and control subtype identity remain unknown. Here, we demonstrate that PDA subtypes are not permanently encoded, and identify the GLI2 transcription factor as a master regulator of subtype inter-conversion. GLI2 is elevated in basal-like PDA lines and patient specimens, and forced GLI2 activation is sufficient to convert classical PDA cells to basal-like. Mechanistically, GLI2 upregulates expression of the pro-tumorigenic secreted protein, Osteopontin (OPN), which is especially critical for metastatic growth in vivo and adaptation to oncogenic KRAS ablation. Accordingly, elevated GLI2 and OPN levels predict shortened overall survival of PDA patients. Thus, the GLI2-OPN circuit is a driver of PDA cell plasticity that establishes and maintains an aggressive variant of this disease.

4 Article No Cell Left Unturned: Intraductal Papillary Mucinous Neoplasm Heterogeneity. 2019

Hernandez-Barco, Yasmin G / Bardeesy, Nabeel / Ting, David T. ·Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts. · Massachusetts General Hospital Division of Gastroenterology, Harvard Medical School, Boston, Massachusetts. · Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts. dting1@mgh.harvard.edu. ·Clin Cancer Res · Pubmed #30642914.

ABSTRACT: Intraductal papillary mucinous neoplasm (IPMN) is a pancreatic cancer precursor lesion with established genetic features, but the cellular ecosystem of these tumors remains to be fully characterized. This study utilizes single-cell RNA sequencing to describe the dynamic landscape of epithelial, immune, and stromal cells during IPMN progression to invasive cancer.

5 Article Mutant GNAS drives pancreatic tumourigenesis by inducing PKA-mediated SIK suppression and reprogramming lipid metabolism. 2018

Patra, Krushna C / Kato, Yasutaka / Mizukami, Yusuke / Widholz, Sebastian / Boukhali, Myriam / Revenco, Iulia / Grossman, Elizabeth A / Ji, Fei / Sadreyev, Ruslan I / Liss, Andrew S / Screaton, Robert A / Sakamoto, Kei / Ryan, David P / Mino-Kenudson, Mari / Castillo, Carlos Fernandez-Del / Nomura, Daniel K / Haas, Wilhelm / Bardeesy, Nabeel. ·Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. · Departments of Medicine, Harvard Medical School, Boston, MA, USA. · Institute of Biomedical Research, Sapporo Higashi Tokushukai Hospital, Sapporo, Hokkaido, Japan. · Asahikawa Medical University, Hokkaido, Japan. · Departments of Nutritional Sciences and Toxicology, Chemistry, and Molecular and Cell Biology, University of California, Berkeley, CA, USA. · Departments of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA. · Department of Genetics, Harvard Medical School, Boston, MA, USA. · Departments of Pathology, Massachusetts General Hospital, Boston, MA, USA. · Department of Pathology, Harvard Medical School, Boston, MA, USA. · Sunnybrook Research Institute, Toronto, Ontario, Canada. · Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada. · MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Scotland, UK. · Nestlé Institute of Health Sciences SA, Lausanne, Switzerland. · Departments of Surgery, Massachusetts General Hospital, Boston, MA, USA. · Department of Surgery, Harvard Medical School, Boston, MA, USA. · Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. Bardeesy.Nabeel@mgh.harvard.edu. · Departments of Medicine, Harvard Medical School, Boston, MA, USA. Bardeesy.Nabeel@mgh.harvard.edu. ·Nat Cell Biol · Pubmed #29941929.

ABSTRACT: G protein α

6 Article Altered exocrine function can drive adipose wasting in early pancreatic cancer. 2018

Danai, Laura V / Babic, Ana / Rosenthal, Michael H / Dennstedt, Emily A / Muir, Alexander / Lien, Evan C / Mayers, Jared R / Tai, Karen / Lau, Allison N / Jones-Sali, Paul / Prado, Carla M / Petersen, Gloria M / Takahashi, Naoki / Sugimoto, Motokazu / Yeh, Jen Jen / Lopez, Nicole / Bardeesy, Nabeel / Fernandez-Del Castillo, Carlos / Liss, Andrew S / Koong, Albert C / Bui, Justin / Yuan, Chen / Welch, Marisa W / Brais, Lauren K / Kulke, Matthew H / Dennis, Courtney / Clish, Clary B / Wolpin, Brian M / Vander Heiden, Matthew G. ·Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA. · Dana-Farber Cancer Institute, Boston, MA, USA. · Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada. · Mayo Clinic, Rochester, MN, USA. · Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. · University of California San Diego School of Medicine, La Jolla, CA, USA. · Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA. · MD Anderson, Department of Radiation Oncology, Houston, TX, USA. · Stanford Cancer Institute, Stanford, CA, USA. · David Geffen School of Medicine at University of California, Los Angeles, CA, USA. · Section of Hematology/Oncology, Boston University and Boston Medical Center, Boston, MA, USA. · Broad Institute of MIT and Harvard University, Cambridge, MA, USA. · Dana-Farber Cancer Institute, Boston, MA, USA. bwolpin@partners.org. · Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA. mvh@mit.edu. · Dana-Farber Cancer Institute, Boston, MA, USA. mvh@mit.edu. · Broad Institute of MIT and Harvard University, Cambridge, MA, USA. mvh@mit.edu. ·Nature · Pubmed #29925948.

ABSTRACT: Malignancy is accompanied by changes in the metabolism of both cells and the organism

7 Article Orthotopic and heterotopic murine models of pancreatic cancer and their different responses to FOLFIRINOX chemotherapy. 2018

Erstad, Derek J / Sojoodi, Mozhdeh / Taylor, Martin S / Ghoshal, Sarani / Razavi, Allen A / Graham-O'Regan, Katherine A / Bardeesy, Nabeel / Ferrone, Cristina R / Lanuti, Michael / Caravan, Peter / Tanabe, Kenneth K / Fuchs, Bryan C. ·Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, United States derstad@partners.org bfuchs@mgh.harvard.edu. · Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, United States. · Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, United States. · Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, United States. · Institute for Innovation in Imaging, Massachusetts General Hospital, Boston, MA 02114, United States. ·Dis Model Mech · Pubmed #29903803.

ABSTRACT: Syngeneic, immunocompetent allograft tumor models recapitulate important aspects of the tumor microenvironment and have short tumor latency with predictable growth kinetics, making them useful for trialing novel therapeutics. Here, we describe surgical techniques for orthotopic and heterotopic pancreatic ductal adenocarcinoma (PDAC) tumor implantation and characterize phenotypes based on implantation site.Mice (

8 Article STK38L kinase ablation promotes loss of cell viability in a subset of KRAS-dependent pancreatic cancer cell lines. 2017

Grant, Trevor J / Mehta, Anita K / Gupta, Anamika / Sharif, Ahmad A D / Arora, Kshitij S / Deshpande, Vikram / Ting, David T / Bardeesy, Nabeel / Ganem, Neil J / Hergovich, Alexander / Singh, Anurag. ·Department of Pharmacology and Experimental Therapeutics, Center for Cancer Research, Boston University Graduate School of Medicine, Boston, MA, USA. · University College London, Cancer Institute, London, United Kingdom. · Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA, USA. ·Oncotarget · Pubmed #29108249.

ABSTRACT: Pancreatic ductal adenocarcinomas (PDACs) are highly aggressive malignancies, associated with poor clinical prognosis and limited therapeutic options. Oncogenic

9 Article Tumor engraftment in patient-derived xenografts of pancreatic ductal adenocarcinoma is associated with adverse clinicopathological features and poor survival. 2017

Pergolini, Ilaria / Morales-Oyarvide, Vicente / Mino-Kenudson, Mari / Honselmann, Kim C / Rosenbaum, Matthew W / Nahar, Sabikun / Kem, Marina / Ferrone, Cristina R / Lillemoe, Keith D / Bardeesy, Nabeel / Ryan, David P / Thayer, Sarah P / Warshaw, Andrew L / Fernández-Del Castillo, Carlos / Liss, Andrew S. ·Department of Surgery and the Andrew L. Warshaw, MD Institute for Pancreatic Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States of America. · Department of Surgery, Universita' Politecnica delle Marche, Ancona, Italy. · Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States of America. · Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, United States of America. ·PLoS One · Pubmed #28854237.

ABSTRACT: Patient-derived xenograft (PDX) tumors are powerful tools to study cancer biology. However, the ability of PDX tumors to model the biological and histological diversity of pancreatic ductal adenocarcinoma (PDAC) is not well known. In this study, we subcutaneously implanted 133 primary and metastatic PDAC tumors into immunodeficient mice. Fifty-seven tumors were successfully engrafted and even after extensive passaging, the histology of poorly-, moderately-, and well-differentiated tumors was maintained in the PDX models. Moreover, the fibroblast and collagen contents in the stroma of patient tumors were recapitulated in the corresponding PDX models. Analysis of the clinicopathological features of patients revealed xenograft tumor engraftment was associated with lymphovascular invasion (P = 0.001) and worse recurrence-free (median, 7 vs. 16 months, log-rank P = 0.047) and overall survival (median, 13 vs. 21 months, log-rank P = 0.038). Among successful engraftments, median time of growth required for reimplantation into new mice was 151 days. Reflective of the inherent biological diversity between PDX tumors with rapid (<151 days) and slow growth, differences in their growth were maintained during extensive passaging. Rapid growth was additionally associated with lymph node metastasis (P = 0.022). The association of lymphovascular invasion and lymph node metastasis with PDX formation and rapid growth may reflect an underlying biological mechanism that allows these tumors to adapt and grow in a new environment. While the ability of PDX tumors to mimic the cellular and non-cellular features of the parental tumor stroma provides a valuable model to study the interaction of PDAC cells with the tumor microenvironment, the association of successful engraftment with adverse clinicopathological features suggests PDX models over represent more aggressive forms of this disease.

10 Article The Presence of Interleukin-13 at Pancreatic ADM/PanIN Lesions Alters Macrophage Populations and Mediates Pancreatic Tumorigenesis. 2017

Liou, Geou-Yarh / Bastea, Ligia / Fleming, Alicia / Döppler, Heike / Edenfield, Brandy H / Dawson, David W / Zhang, Lizhi / Bardeesy, Nabeel / Storz, Peter. ·Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA. · Department of Pathology & Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA. · Department of Laboratory Medicine & Pathology, Mayo Clinic, Rochester, MN 55905, USA. · Center for Cancer Research, Massachusetts General Hospital, Department of Medicine, Harvard Medical School, Boston, 02115 MA, USA. · Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA. Electronic address: storz.peter@mayo.edu. ·Cell Rep · Pubmed #28514653.

ABSTRACT: The contributions of the innate immune system to the development of pancreatic cancer are still ill defined. Inflammatory macrophages can initiate metaplasia of pancreatic acinar cells to a duct-like phenotype (acinar-to-ductal metaplasia [ADM]), which then gives rise to pancreatic intraepithelial neoplasia (PanIN) when oncogenic KRas is present. However, it remains unclear when and how this inflammatory macrophage population is replaced by tumor-promoting macrophages. Here, we demonstrate the presence of interleukin-13 (IL-13), which can convert inflammatory into Ym1+ alternatively activated macrophages, at ADM/PanIN lesions. We further show that Ym1+ macrophages release factors, such as IL-1ra and CCL2, to drive pancreatic fibrogenesis and tumorigenesis. Treatment of mice expressing oncogenic KRas under an acinar cell-specific promoter with a neutralizing antibody for IL-13 significantly decreased the accumulation of alternatively activated macrophages at these lesions, resulting in decreased fibrosis and lesion growth.

11 Article Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH-Mutant Molecular Profiles. 2017

Farshidfar, Farshad / Zheng, Siyuan / Gingras, Marie-Claude / Newton, Yulia / Shih, Juliann / Robertson, A Gordon / Hinoue, Toshinori / Hoadley, Katherine A / Gibb, Ewan A / Roszik, Jason / Covington, Kyle R / Wu, Chia-Chin / Shinbrot, Eve / Stransky, Nicolas / Hegde, Apurva / Yang, Ju Dong / Reznik, Ed / Sadeghi, Sara / Pedamallu, Chandra Sekhar / Ojesina, Akinyemi I / Hess, Julian M / Auman, J Todd / Rhie, Suhn K / Bowlby, Reanne / Borad, Mitesh J / Anonymous5350899 / Zhu, Andrew X / Stuart, Josh M / Sander, Chris / Akbani, Rehan / Cherniack, Andrew D / Deshpande, Vikram / Mounajjed, Taofic / Foo, Wai Chin / Torbenson, Michael S / Kleiner, David E / Laird, Peter W / Wheeler, David A / McRee, Autumn J / Bathe, Oliver F / Andersen, Jesper B / Bardeesy, Nabeel / Roberts, Lewis R / Kwong, Lawrence N. ·Departments of Surgery and Oncology, Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, AB T2N 4N1, Canada. · Departments of Genomic Medicine, Melanoma Medical Oncology, Bioinformatics and Computational Biology, Pathology, and Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA. · University of California Santa Cruz, Santa Cruz, CA 95064, USA. · The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. · Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z 4S6, Canada. · Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI 49503, USA. · Departments of Genetics and Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. · Blueprint Medicines, 38 Sidney Street, Cambridge, MA 02139, USA. · Divisions of Gastroenterology and Hepatology and Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. · Memorial Sloan Kettering Cancer Center, New York, NY 10005, USA. · University of Alabama at Birmingham, Birmingham, AL 35294, USA; HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA. · The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA. · Departments of Genetics and Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. · USC/Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA. · Division of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ 85054, USA. · Departments of Hematology and Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. · Departments of Pathology and Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. · National Cancer Institute, Bethesda, MD 20892, USA. · Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. · Biotech Research and Innovation Centre, Department of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark. Electronic address: jesper.andersen@bric.ku.dk. · Departments of Pathology and Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. Electronic address: bardeesy.nabeel@mgh.harvard.edu. · Divisions of Gastroenterology and Hepatology and Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. Electronic address: roberts.lewis@mayo.edu. · Departments of Genomic Medicine, Melanoma Medical Oncology, Bioinformatics and Computational Biology, Pathology, and Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: lkwong@mdanderson.org. ·Cell Rep · Pubmed #28297679.

ABSTRACT: Cholangiocarcinoma (CCA) is an aggressive malignancy of the bile ducts, with poor prognosis and limited treatment options. Here, we describe the integrated analysis of somatic mutations, RNA expression, copy number, and DNA methylation by The Cancer Genome Atlas of a set of predominantly intrahepatic CCA cases and propose a molecular classification scheme. We identified an IDH mutant-enriched subtype with distinct molecular features including low expression of chromatin modifiers, elevated expression of mitochondrial genes, and increased mitochondrial DNA copy number. Leveraging the multi-platform data, we observed that ARID1A exhibited DNA hypermethylation and decreased expression in the IDH mutant subtype. More broadly, we found that IDH mutations are associated with an expanded histological spectrum of liver tumors with molecular features that stratify with CCA. Our studies reveal insights into the molecular pathogenesis and heterogeneity of cholangiocarcinoma and provide classification information of potential therapeutic significance.

12 Article mTORC2 Signaling Drives the Development and Progression of Pancreatic Cancer. 2016

Driscoll, David R / Karim, Saadia A / Sano, Makoto / Gay, David M / Jacob, Wright / Yu, Jun / Mizukami, Yusuke / Gopinathan, Aarthi / Jodrell, Duncan I / Evans, T R Jeffry / Bardeesy, Nabeel / Hall, Michael N / Quattrochi, Brian J / Klimstra, David S / Barry, Simon T / Sansom, Owen J / Lewis, Brian C / Morton, Jennifer P. ·Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts. · CRUK Beatson Institute, Glasgow, United Kingdom. · Department of Pathology and Microbiology, Nihon University School of Medicine, Tokyo, Japan. · Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom. · Cancer Center, Massachusetts General Hospital, Boston, Massachusetts. · CRUK Cambridge Institute, Cambridge, United Kingdom. · Biozentrum, University of Basel, Basel, Switzerland. · Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York. · AstraZeneca, Macclesfield, United Kingdom. · CRUK Beatson Institute, Glasgow, United Kingdom. o.sansom@beatson.gla.ac.uk Brian.Lewis@umassmed.edu. · Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts. o.sansom@beatson.gla.ac.uk Brian.Lewis@umassmed.edu. · Cancer Center, University of Massachusetts Medical School, Worcester, Massachusetts. ·Cancer Res · Pubmed #27758884.

ABSTRACT: mTOR signaling controls several critical cellular functions and is deregulated in many cancers, including pancreatic cancer. To date, most efforts have focused on inhibiting the mTORC1 complex. However, clinical trials of mTORC1 inhibitors in pancreatic cancer have failed, raising questions about this therapeutic approach. We employed a genetic approach to delete the obligate mTORC2 subunit Rictor and identified the critical times during which tumorigenesis requires mTORC2 signaling. Rictor deletion resulted in profoundly delayed tumorigenesis. Whereas previous studies showed most pancreatic tumors were insensitive to rapamycin, treatment with a dual mTORC1/2 inhibitor strongly suppressed tumorigenesis. In late-stage tumor-bearing mice, combined mTORC1/2 and PI3K inhibition significantly increased survival. Thus, targeting mTOR may be a potential therapeutic strategy in pancreatic cancer. Cancer Res; 76(23); 6911-23. ©2016 AACR.

13 Article NRF2: Translating the Redox Code. 2016

Tummala, Krishna S / Kottakis, Filippos / Bardeesy, Nabeel. ·Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA. · Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA. Electronic address: Bardeesy.Nabeel@mgh.harvard.edu. ·Trends Mol Med · Pubmed #27555347.

ABSTRACT: Cancer requires mechanisms to mitigate reactive oxygen species (ROS) generated during rapid growth, such as induction of the antioxidant transcription factor, Nrf2. However, the targets of ROS-mediated cytotoxicity are unclear. Recent studies in pancreatic cancer show that redox control by Nrf2 prevents cysteine oxidation of the mRNA translational machinery, thereby supporting efficient protein synthesis.

14 Article SIRT6 Suppresses Pancreatic Cancer through Control of Lin28b. 2016

Kugel, Sita / Sebastián, Carlos / Fitamant, Julien / Ross, Kenneth N / Saha, Supriya K / Jain, Esha / Gladden, Adrianne / Arora, Kshitij S / Kato, Yasutaka / Rivera, Miguel N / Ramaswamy, Sridhar / Sadreyev, Ruslan I / Goren, Alon / Deshpande, Vikram / Bardeesy, Nabeel / Mostoslavsky, Raul. ·The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; The MGH Center for Regenerative Medicine, Harvard Medical School, Boston, MA 02114, USA. · The MGH Center for Regenerative Medicine, Harvard Medical School, Boston, MA 02114, USA. · Broad Technology Labs (BTL), The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. · The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA. · Department of Molecular Biology, The Massachusetts General Hospital, Boston, MA 02114, USA; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. · The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; The MGH Center for Regenerative Medicine, Harvard Medical School, Boston, MA 02114, USA; The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address: rmostoslavsky@mgh.harvard.edu. ·Cell · Pubmed #27180906.

ABSTRACT: Chromatin remodeling proteins are frequently dysregulated in human cancer, yet little is known about how they control tumorigenesis. Here, we uncover an epigenetic program mediated by the NAD(+)-dependent histone deacetylase Sirtuin 6 (SIRT6) that is critical for suppression of pancreatic ductal adenocarcinoma (PDAC), one of the most lethal malignancies. SIRT6 inactivation accelerates PDAC progression and metastasis via upregulation of Lin28b, a negative regulator of the let-7 microRNA. SIRT6 loss results in histone hyperacetylation at the Lin28b promoter, Myc recruitment, and pronounced induction of Lin28b and downstream let-7 target genes, HMGA2, IGF2BP1, and IGF2BP3. This epigenetic program defines a distinct subset with a poor prognosis, representing 30%-40% of human PDAC, characterized by reduced SIRT6 expression and an exquisite dependence on Lin28b for tumor growth. Thus, we identify SIRT6 as an important PDAC tumor suppressor and uncover the Lin28b pathway as a potential therapeutic target in a molecularly defined PDAC subset. PAPERCLIP.

15 Article Intra-pancreatic Distal Bile Duct Carcinoma is Morphologically, Genetically, and Clinically Distinct from Pancreatic Ductal Adenocarcinoma. 2016

Deshpande, Vikram / Konstantinidis, Ioannis T / Castillo, Carlos Fernandez-Del / Hezel, Aram F / Haigis, Kevin M / Ting, David T / Bardeesy, Nabeel / Goyal, Lipika / Zhu, Andrew X / Warshaw, Andrew L / Lillemoe, Keith D / Ferrone, Cristina R. ·Department of Pathology, Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114, USA. vdeshpande@mgh.harvard.edu. · Department of Surgery, Massachusetts General Hospital, Boston, MA, USA. · Department of Oncology, Massachusetts General Hospital, Boston, MA, USA. · Department of Pathology, Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114, USA. ·J Gastrointest Surg · Pubmed #26956004.

ABSTRACT: PURPOSE: Differentiating intra-pancreatic distal bile duct carcinoma invading the pancreas from pancreatic ductal adenocarcinomas (PDAC) surrounding the distal common bile duct (CBD) can be challenging. Our aim is to identify clinical, morphological, and genetic features characteristic of intra-pancreatic distal bile duct carcinoma. METHODS: Clinicopathologic data of 550 patients undergoing a pancreaticoduodenectomy between September 1990 and May 2008 were reviewed. KRAS status was assessed with mass-spectrometric genotyping. RESULTS: Ninety-seven patients with intra-pancreatic adenocarcinomas surrounding the CBD were identified; slides were available for 80. Two relationships with the CBD were recognized as follows: type I (n = 42): cancer grew concentrically around the CBD and type II (n = 38): cancer grew asymmetrically around the CBD. Type I adenocarcinomas were associated with high-grade biliary dysplasia (45 vs. 13 %; p = 0.003); type II were associated with high-grade pancreatic intra-epithelial neoplasia (PanIN-2 or -3) (39 vs. 9 %; p = 0.003). Type I tumors had a better median survival (46 months) compared to type II (23 months) or other PDAC (20 months) (p < 0.001). Mutated KRAS was identified in 3/26 (11 %) type I and 20/21 (95 %) type II cancers (p < 0.001). There may be poorer survival in the presence of a KRAS mutation than wild-type KRAS (22.9 vs. 41.6 months; p = 0.3). CONCLUSIONS: Distal periductal adenocarcinomas fall into two distinct groups with biologic, morphologic and genetic differences. Those growing symmetrically around the CBD are more likely to be intra-pancreatic distal bile duct carcinomas and are associated with improved survival whereas cancers with asymmetric growth are more likely to have KRAS mutations and to be PDACs. These findings facilitate a more accurate histopathological diagnosis, which could improve patient selection for therapeutic trials.

16 Article TGF-β Tumor Suppression through a Lethal EMT. 2016

David, Charles J / Huang, Yun-Han / Chen, Mo / Su, Jie / Zou, Yilong / Bardeesy, Nabeel / Iacobuzio-Donahue, Christine A / Massagué, Joan. ·Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. · The Rockefeller University, New York, NY 10065, USA. · Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA. · Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. · Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: j-massague@ski.mskcc.org. ·Cell · Pubmed #26898331.

ABSTRACT: TGF-β signaling can be pro-tumorigenic or tumor suppressive. We investigated this duality in pancreatic ductal adenocarcinoma (PDA), which, with other gastrointestinal cancers, exhibits frequent inactivation of the TGF-β mediator Smad4. We show that TGF-β induces an epithelial-mesenchymal transition (EMT), generally considered a pro-tumorigenic event. However, in TGF-β-sensitive PDA cells, EMT becomes lethal by converting TGF-β-induced Sox4 from an enforcer of tumorigenesis into a promoter of apoptosis. This is the result of an EMT-linked remodeling of the cellular transcription factor landscape, including the repression of the gastrointestinal lineage-master regulator Klf5. Klf5 cooperates with Sox4 in oncogenesis and prevents Sox4-induced apoptosis. Smad4 is required for EMT but dispensable for Sox4 induction by TGF-β. TGF-β-induced Sox4 is thus geared to bolster progenitor identity, whereas simultaneous Smad4-dependent EMT strips Sox4 of an essential partner in oncogenesis. Our work demonstrates that TGF-β tumor suppression functions through an EMT-mediated disruption of a lineage-specific transcriptional network.

17 Article Transcriptional control of autophagy-lysosome function drives pancreatic cancer metabolism. 2015

Perera, Rushika M / Stoykova, Svetlana / Nicolay, Brandon N / Ross, Kenneth N / Fitamant, Julien / Boukhali, Myriam / Lengrand, Justine / Deshpande, Vikram / Selig, Martin K / Ferrone, Cristina R / Settleman, Jeff / Stephanopoulos, Gregory / Dyson, Nicholas J / Zoncu, Roberto / Ramaswamy, Sridhar / Haas, Wilhelm / Bardeesy, Nabeel. ·Center for Cancer Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. · Center for Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. · Department of Medicine, Harvard Medical School, Boston, Massachusetts 02114, USA. · Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. · Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. · Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. · Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, California 94720, USA. ·Nature · Pubmed #26168401.

ABSTRACT: Activation of cellular stress response pathways to maintain metabolic homeostasis is emerging as a critical growth and survival mechanism in many cancers. The pathogenesis of pancreatic ductal adenocarcinoma (PDA) requires high levels of autophagy, a conserved self-degradative process. However, the regulatory circuits that activate autophagy and reprogram PDA cell metabolism are unknown. Here we show that autophagy induction in PDA occurs as part of a broader transcriptional program that coordinates activation of lysosome biogenesis and function, and nutrient scavenging, mediated by the MiT/TFE family of transcription factors. In human PDA cells, the MiT/TFE proteins--MITF, TFE3 and TFEB--are decoupled from regulatory mechanisms that control their cytoplasmic retention. Increased nuclear import in turn drives the expression of a coherent network of genes that induce high levels of lysosomal catabolic function essential for PDA growth. Unbiased global metabolite profiling reveals that MiT/TFE-dependent autophagy-lysosome activation is specifically required to maintain intracellular amino acid pools. These results identify the MiT/TFE proteins as master regulators of metabolic reprogramming in pancreatic cancer and demonstrate that transcriptional activation of clearance pathways converging on the lysosome is a novel hallmark of aggressive malignancy.

18 Article Bmi1 is required for the initiation of pancreatic cancer through an Ink4a-independent mechanism. 2015

Bednar, Filip / Schofield, Heather K / Collins, Meredith A / Yan, Wei / Zhang, Yaqing / Shyam, Nikhil / Eberle, Jaime A / Almada, Luciana L / Olive, Kenneth P / Bardeesy, Nabeel / Fernandez-Zapico, Martin E / Nakada, Daisuke / Simeone, Diane M / Morrison, Sean J / Pasca di Magliano, Marina. ·Department of Surgery. · Program in Cell and Molecular Biology, Medical Scientist Training Program. · Program in Cell and Molecular Biology. · Department of Pathology, Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA, Present address: Department of Pathology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China. · Medical Scientist Training Program. · Departments of Medicine and Pathology, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA. · Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, MN 55905, USA. · Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. · Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. · Department of Surgery, Department of Molecular and Integrative Physiology, Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA. · Children's Research Institute, Department of Pediatrics, and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA and. · Department of Surgery, Program in Cell and Molecular Biology, Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA and marinapa@umich.edu. ·Carcinogenesis · Pubmed #25939753.

ABSTRACT: Epigenetic dysregulation is involved in the initiation and progression of many epithelial cancers. BMI1, a component of the polycomb protein family, plays a key role in these processes by controlling the histone ubiquitination and long-term repression of multiple genomic loci. BMI1 has previously been implicated in pancreatic homeostasis and the function of pancreatic cancer stem cells. However, no work has yet addressed its role in the early stages of pancreatic cancer development. Here, we show that BMI1 is required for the initiation of murine pancreatic neoplasia using a novel conditional knockout of Bmi1 in combination with a Kras(G12D)-driven pancreatic cancer mouse model. We also demonstrate that the requirement for Bmi1 in pancreatic carcinogenesis is independent of the Ink4a/Arf locus and at least partially mediated by dysregulation of reactive oxygen species. Our data provide new evidence of the importance of this epigenetic regulator in the genesis of pancreatic cancer.

19 Article Combined MEK and PI3K inhibition in a mouse model of pancreatic cancer. 2015

Alagesan, Brinda / Contino, Gianmarco / Guimaraes, Alex R / Corcoran, Ryan B / Deshpande, Vikram / Wojtkiewicz, Gregory R / Hezel, Aram F / Wong, Kwok-Kin / Loda, Massimo / Weissleder, Ralph / Benes, Cyril H / Engelman, Jeffrey / Bardeesy, Nabeel. ·Cancer Center, Massachusetts General Hospital, Boston, MA 02114. · Center for Molecular Imaging Research, Massachusetts General Hospital, Boston, MA 02114. · Department of Radiology, Harvard Medical School, Boston, MA 02115. · Department of Medicine, Harvard Medical School, Boston, MA 02115. · Department of Pathology, Massachusetts General Hospital, Boston, MA 02114. · Department of Pathology, Harvard Medical School, Boston, MA 02115. · Department of Medical Oncology, Dana-Farber Cancer Institute, Boston MA 02215. · Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115. ·Clin Cancer Res · Pubmed #25348516.

ABSTRACT: PURPOSE: Improved therapeutic approaches are needed for the treatment of pancreatic ductal adenocarcinoma (PDAC). As dual MEK and PI3K inhibition is presently being used in clinical trials for patients with PDAC, we sought to test the efficacy of combined targeting of these pathways in PDAC using both in vitro drug screens and genetically engineered mouse models (GEMM). EXPERIMENTAL DESIGN: We performed high-throughput screening of >500 human cancer cell lines (including 46 PDAC lines), for sensitivity to 50 clinically relevant compounds, including MEK and PI3K inhibitors. We tested the top hit in the screen, the MEK1/2 inhibitor, AZD6244, for efficacy alone or in combination with the PI3K inhibitors, BKM120 or GDC-0941, in a Kras(G12D)-driven GEMM that recapitulates the histopathogenesis of human PDAC. RESULTS: In vitro screens revealed that PDAC cell lines are relatively resistant to single-agent therapies. The response profile to the MEK1/2 inhibitor, AZD6244, was an outlier, showing the highest selective efficacy in PDAC. Although MEK inhibition alone was mainly cytostatic, apoptosis was induced when combined with PI3K inhibitors (BKM120 or GDC-0941). When tested in a PDAC GEMM and compared with the single agents or vehicle controls, the combination delayed tumor formation in the setting of prevention and extended survival when used to treat advanced tumors, although no durable responses were observed. CONCLUSIONS: Our studies point to important contributions of MEK and PI3K signaling to PDAC pathogenesis and suggest that dual targeting of these pathways may provide benefit in some patients with PDAC. Clin Cancer Res; 21(2); 396-404. ©2014 AACR.

20 Article Single-cell RNA sequencing identifies extracellular matrix gene expression by pancreatic circulating tumor cells. 2014

Ting, David T / Wittner, Ben S / Ligorio, Matteo / Vincent Jordan, Nicole / Shah, Ajay M / Miyamoto, David T / Aceto, Nicola / Bersani, Francesca / Brannigan, Brian W / Xega, Kristina / Ciciliano, Jordan C / Zhu, Huili / MacKenzie, Olivia C / Trautwein, Julie / Arora, Kshitij S / Shahid, Mohammad / Ellis, Haley L / Qu, Na / Bardeesy, Nabeel / Rivera, Miguel N / Deshpande, Vikram / Ferrone, Cristina R / Kapur, Ravi / Ramaswamy, Sridhar / Shioda, Toshi / Toner, Mehmet / Maheswaran, Shyamala / Haber, Daniel A. ·Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02114, USA. · Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; Department of Surgery, Harvard Medical School, Boston, MA 02114, USA; Department of Health Sciences, University of Genoa, 16126 Genoa, Italy. · Center for Engineering in Medicine, Harvard Medical School, Boston, MA 02114, USA; Department of Surgery, Harvard Medical School, Boston, MA 02114, USA. · Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; Department of Radiation Oncology, Harvard Medical School, Boston, MA 02114, USA. · Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; Department of Surgery, Harvard Medical School, Boston, MA 02114, USA; Department of Pathology, Harvard Medical School, Boston, MA 02114, USA. · Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; Department of Pathology, Harvard Medical School, Boston, MA 02114, USA. · Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; Department of Surgery, Harvard Medical School, Boston, MA 02114, USA. · Center for Engineering in Medicine, Harvard Medical School, Boston, MA 02114, USA. · Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; Department of Surgery, Harvard Medical School, Boston, MA 02114, USA. Electronic address: maheswaran@helix.mgh.harvard.edu. · Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02114, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address: haber@helix.mgh.harvard.edu. ·Cell Rep · Pubmed #25242334.

ABSTRACT: Circulating tumor cells (CTCs) are shed from primary tumors into the bloodstream, mediating the hematogenous spread of cancer to distant organs. To define their composition, we compared genome-wide expression profiles of CTCs with matched primary tumors in a mouse model of pancreatic cancer, isolating individual CTCs using epitope-independent microfluidic capture, followed by single-cell RNA sequencing. CTCs clustered separately from primary tumors and tumor-derived cell lines, showing low-proliferative signatures, enrichment for the stem-cell-associated gene Aldh1a2, biphenotypic expression of epithelial and mesenchymal markers, and expression of Igfbp5, a gene transcript enriched at the epithelial-stromal interface. Mouse as well as human pancreatic CTCs exhibit a very high expression of stromal-derived extracellular matrix (ECM) proteins, including SPARC, whose knockdown in cancer cells suppresses cell migration and invasiveness. The aberrant expression by CTCs of stromal ECM genes points to their contribution of microenvironmental signals for the spread of cancer to distant organs.

21 Article Stromal response to Hedgehog signaling restrains pancreatic cancer progression. 2014

Lee, John J / Perera, Rushika M / Wang, Huaijun / Wu, Dai-Chen / Liu, X Shawn / Han, Shiwei / Fitamant, Julien / Jones, Phillip D / Ghanta, Krishna S / Kawano, Sally / Nagle, Julia M / Deshpande, Vikram / Boucher, Yves / Kato, Tomoyo / Chen, James K / Willmann, Jürgen K / Bardeesy, Nabeel / Beachy, Philip A. ·Institute for Stem Cell Biology and Regenerative Medicine,Division of Oncology, Department of Medicine. · Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114; · Molecular Imaging Program, Department of Radiology, Stanford University School of Medicine, Stanford, CA 94305; · Institute for Stem Cell Biology and Regenerative Medicine. · Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114; and. · Department of Chemical and Systems Biology, and. · Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114; pbeachy@stanford.edu Bardeesy.Nabeel@mgh.harvard.edu. · Institute for Stem Cell Biology and Regenerative Medicine,Department of Biochemistry,Howard Hughes Medical Institute, Stanford, CA 94305 pbeachy@stanford.edu Bardeesy.Nabeel@mgh.harvard.edu. ·Proc Natl Acad Sci U S A · Pubmed #25024225.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) is the most lethal of common human malignancies, with no truly effective therapies for advanced disease. Preclinical studies have suggested a therapeutic benefit of targeting the Hedgehog (Hh) signaling pathway, which is activated throughout the course of PDA progression by expression of Hh ligands in the neoplastic epithelium and paracrine response in the stromal fibroblasts. Clinical trials to test this possibility, however, have yielded disappointing results. To further investigate the role of Hh signaling in the formation of PDA and its precursor lesion, pancreatic intraepithelial neoplasia (PanIN), we examined the effects of genetic or pharmacologic inhibition of Hh pathway activity in three distinct genetically engineered mouse models and found that Hh pathway inhibition accelerates rather than delays progression of oncogenic Kras-driven disease. Notably, pharmacologic inhibition of Hh pathway activity affected the balance between epithelial and stromal elements, suppressing stromal desmoplasia but also causing accelerated growth of the PanIN epithelium. In striking contrast, pathway activation using a small molecule agonist caused stromal hyperplasia and reduced epithelial proliferation. These results indicate that stromal response to Hh signaling is protective against PDA and that pharmacologic activation of pathway response can slow tumorigenesis. Our results provide evidence for a restraining role of stroma in PDA progression, suggesting an explanation for the failure of Hh inhibitors in clinical trials and pointing to the possibility of a novel type of therapeutic intervention.

22 Article CDK4/6 and IGF1 receptor inhibitors synergize to suppress the growth of p16INK4A-deficient pancreatic cancers. 2014

Heilmann, Andreas M / Perera, Rushika M / Ecker, Veronika / Nicolay, Brandon N / Bardeesy, Nabeel / Benes, Cyril H / Dyson, Nicholas J. ·Authors' Affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts. · Authors' Affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts dyson@helix.mgh.harvard.edu. ·Cancer Res · Pubmed #24986516.

ABSTRACT: Loss-of-function mutations in p16(INK4A) (CDKN2A) occur in approximately 80% of sporadic pancreatic ductal adenocarcinoma (PDAC), contributing to its early progression. Although this loss activates the cell-cycle-dependent kinases CDK4/6, which have been considered as drug targets for many years, p16(INK4A)-deficient PDAC cells are inherently resistant to CDK4/6 inhibitors. This study searched for targeted therapies that might synergize with CDK4/6 inhibition in this setting. We report that the IGF1R/IR inhibitor BMS-754807 cooperated with the CDK4/6 inhibitor PD-0332991 to strongly block proliferation of p16(INK4A)-deficient PDAC cells in vitro and in vivo. Sensitivity to this drug combination correlated with reduced activity of the master cell growth regulator mTORC1. Accordingly, replacing the IGF1R/IR inhibitor with the rapalog inhibitor temsirolimus broadened the sensitivity of PDAC cells to CDK4/6 inhibition. Our results establish targeted therapy combinations with robust cytostatic activity in p16(INK4A)-deficient PDAC cells and possible implications for improving treatment of a broad spectrum of human cancers characterized by p16(INK4A) loss.

23 Article DCLK1 marks a morphologically distinct subpopulation of cells with stem cell properties in preinvasive pancreatic cancer. 2014

Bailey, Jennifer M / Alsina, Janivette / Rasheed, Zeshaan A / McAllister, Florencia M / Fu, Ya-Yuan / Plentz, Ruben / Zhang, Hao / Pasricha, Pankaj J / Bardeesy, Nabeel / Matsui, William / Maitra, Anirban / Leach, Steven D. ·Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland; The McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts; Department of Internal Medicine, Medical University Hospital, Tuebingen, Germany. · Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland. · Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland; The McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address: stleach@jhmi.edu. ·Gastroenterology · Pubmed #24096005.

ABSTRACT: BACKGROUND & AIMS: As in other tumor types, progression of pancreatic cancer may require a functionally unique population of cancer stem cells. Although such cells have been identified in many invasive cancers, it is not clear whether they emerge during early or late stages of tumorigenesis. Using mouse models and human pancreatic cancer cell lines, we investigated whether preinvasive pancreatic neoplasia contains a subpopulation of cells with distinct morphologies and cancer stem cell-like properties. METHODS: Pancreatic tissue samples were collected from the KC(Pdx1), KPC(Pdx1), and KC(iMist1) mouse models of pancreatic intraepithelial neoplasia (PanIN) and analyzed by confocal and electron microscopy, lineage tracing, and fluorescence-activated cell sorting. Subpopulations of human pancreatic ductal adenocarcinoma (PDAC) cells were similarly analyzed and also used in complementary DNA microarray analyses. RESULTS: The microtubule regulator DCLK1 marked a morphologically distinct and functionally unique population of pancreatic cancer-initiating cells. These cells displayed morphological and molecular features of gastrointestinal tuft cells. Cells that expressed DCLK1 also expressed high levels of ATAT1, HES1, HEY1, IGF1R, and ABL1, and manipulation of these pathways in PDAC cell lines inhibited their clonogenic potential. Pharmacological inhibition of γ-secretase activity reduced the abundance of these cells in murine PanIN in a manner that correlated with inhibition of PanIN progression. CONCLUSIONS: Human PDAC cells and pancreatic neoplasms in mice contain morphologically and functionally distinct subpopulations that have cancer stem cell-like properties. These populations can be identified at the earliest stages of pancreatic tumorigenesis and provide new cellular and molecular targets for pancreatic cancer treatment and/or chemoprevention.

24 Article Targeting cathepsin E in pancreatic cancer by a small molecule allows in vivo detection. 2013

Keliher, Edmund J / Reiner, Thomas / Earley, Sarah / Klubnick, Jenna / Tassa, Carlos / Lee, Andrew J / Ramaswamy, Sridhar / Bardeesy, Nabeel / Hanahan, Douglas / Depinho, Ronald A / Castro, Cesar M / Weissleder, Ralph. ·Center for Systems Biology, Massachusetts General Hospital, Boston, MA 02114, USA. ·Neoplasia · Pubmed #23814481.

ABSTRACT: When resectable, invasive pancreatic ductal adenocarcinoma (PDAC) is most commonly treated with surgery and radiochemotherapy. Given the intricate local anatomy and locoregional mode of dissemination, achieving clean surgical margins can be a significant challenge. On the basis of observations that cathepsin E (CTSE) is overexpressed in PDAC and that an United States Food and Drug Administration (FDA)-approved protease inhibitor has high affinity for CTSE, we have developed a CTSE optical imaging agent [ritonavir tetramethyl-BODIPY (RIT-TMB)] for potential intraoperative use. We show nanomolar affinity [half maximal inhibitory concentration (IC50) of 39.9 ± 1.2 nM] against CTSE of the RIT-TMB in biochemical assays and intracellular accumulation and target-to-background ratios that allow specific delineation of individual cancer cells. This approach should be useful for more refined surgical staging, planning, and resection with curative intent.

25 Article Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. 2013

Son, Jaekyoung / Lyssiotis, Costas A / Ying, Haoqiang / Wang, Xiaoxu / Hua, Sujun / Ligorio, Matteo / Perera, Rushika M / Ferrone, Cristina R / Mullarky, Edouard / Shyh-Chang, Ng / Kang, Ya'an / Fleming, Jason B / Bardeesy, Nabeel / Asara, John M / Haigis, Marcia C / DePinho, Ronald A / Cantley, Lewis C / Kimmelman, Alec C. ·Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA. ·Nature · Pubmed #23535601.

ABSTRACT: Cancer cells have metabolic dependencies that distinguish them from their normal counterparts. Among these dependencies is an increased use of the amino acid glutamine to fuel anabolic processes. Indeed, the spectrum of glutamine-dependent tumours and the mechanisms whereby glutamine supports cancer metabolism remain areas of active investigation. Here we report the identification of a non-canonical pathway of glutamine use in human pancreatic ductal adenocarcinoma (PDAC) cells that is required for tumour growth. Whereas most cells use glutamate dehydrogenase (GLUD1) to convert glutamine-derived glutamate into α-ketoglutarate in the mitochondria to fuel the tricarboxylic acid cycle, PDAC relies on a distinct pathway in which glutamine-derived aspartate is transported into the cytoplasm where it can be converted into oxaloacetate by aspartate transaminase (GOT1). Subsequently, this oxaloacetate is converted into malate and then pyruvate, ostensibly increasing the NADPH/NADP(+) ratio which can potentially maintain the cellular redox state. Importantly, PDAC cells are strongly dependent on this series of reactions, as glutamine deprivation or genetic inhibition of any enzyme in this pathway leads to an increase in reactive oxygen species and a reduction in reduced glutathione. Moreover, knockdown of any component enzyme in this series of reactions also results in a pronounced suppression of PDAC growth in vitro and in vivo. Furthermore, we establish that the reprogramming of glutamine metabolism is mediated by oncogenic KRAS, the signature genetic alteration in PDAC, through the transcriptional upregulation and repression of key metabolic enzymes in this pathway. The essentiality of this pathway in PDAC and the fact that it is dispensable in normal cells may provide novel therapeutic approaches to treat these refractory tumours.

Next