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Pancreatic Neoplasms: HELP
Articles by Andrew S. Liss
Based on 13 articles published since 2010
(Why 13 articles?)
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Between 2010 and 2020, Andrew Liss wrote the following 13 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Review Sonic Hedgehog in pancreatic cancer: from bench to bedside, then back to the bench. 2012

Rosow, David E / Liss, Andrew S / Strobel, Oliver / Fritz, Stefan / Bausch, Dirk / Valsangkar, Nakul P / Alsina, Janivette / Kulemann, Birte / Park, Joo Kyung / Yamaguchi, Junpei / LaFemina, Jennifer / Thayer, Sarah P. ·Pancreatic Biology Laboratory, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA. ·Surgery · Pubmed #22770959.

ABSTRACT: -- No abstract --

2 Clinical Trial Circulating tumor cells found in patients with localized and advanced pancreatic cancer. 2015

Kulemann, Birte / Pitman, Martha B / Liss, Andrew S / Valsangkar, Nakul / Fernández-Del Castillo, Carlos / Lillemoe, Keith D / Hoeppner, Jens / Mino-Kenudson, Mari / Warshaw, Andrew L / Thayer, Sarah P. ·From the *Department of Surgery and †Andrew L. Warshaw Institute for Pancreatic Cancer Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA; ‡Department of Surgery, University Hospital Freiburg, Freiburg, Germany; §Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA; and ║Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE. ·Pancreas · Pubmed #25822154.

ABSTRACT: OBJECTIVES: Isolation of circulating tumor cells (CTCs) holds the promise of diagnosing and molecular profiling cancers from a blood sample. Here, we test a simple new low-cost filtration device for CTC isolation in patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: Peripheral blood samples drawn from healthy donors and PDAC patients were filtered using ScreenCell devices, designed to capture CTCs for cytologic and molecular analysis. Giemsa-stained specimens were evaluated by a pancreatic cytopathologist blinded to the histological diagnosis. Circulating tumor cell DNA was subjected to KRAS mutational analysis. RESULTS: Spiking experiments demonstrated a CTC capture efficiency as low as 2 cells/mL of blood. Circulating tumor cells were identified by either malignant cytology or presence of KRAS mutation in 73% of 11 patients (P = 0.001). Circulating tumor cells were identified in 3 of 4 patients with early (≤American Joint Committee on Cancer stage IIB) and in 5 of 7 patients with advanced (≥ American Joint Committee on Cancer stage III) PDAC. No CTCs were detected in blood from 9 health donors. CONCLUSIONS: Circulating tumor cells can be found in most patients with PDAC of any stage, whether localized, locally advanced, or metastatic. The ability to capture, cytologically identify, and genetically analyze CTCs suggests a possible tool for the diagnosis and characterization of genetic alterations of PDAC.

3 Article Stromal Microenvironment Shapes the Intratumoral Architecture of Pancreatic Cancer. 2019

Ligorio, Matteo / Sil, Srinjoy / Malagon-Lopez, Jose / Nieman, Linda T / Misale, Sandra / Di Pilato, Mauro / Ebright, Richard Y / Karabacak, Murat N / Kulkarni, Anupriya S / Liu, Ann / Vincent Jordan, Nicole / Franses, Joseph W / Philipp, Julia / Kreuzer, Johannes / Desai, Niyati / Arora, Kshitij S / Rajurkar, Mihir / Horwitz, Elad / Neyaz, Azfar / Tai, Eric / Magnus, Neelima K C / Vo, Kevin D / Yashaswini, Chittampalli N / Marangoni, Francesco / Boukhali, Myriam / Fatherree, Jackson P / Damon, Leah J / Xega, Kristina / Desai, Rushil / Choz, Melissa / Bersani, Francesca / Langenbucher, Adam / Thapar, Vishal / Morris, Robert / Wellner, Ulrich F / Schilling, Oliver / Lawrence, Michael S / Liss, Andrew S / Rivera, Miguel N / Deshpande, Vikram / Benes, Cyril H / Maheswaran, Shyamala / Haber, Daniel A / Fernandez-Del-Castillo, Carlos / Ferrone, Cristina R / Haas, Wilhelm / Aryee, Martin J / Ting, David T. ·Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. · Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA. · Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA. · Division of Rheumatology, Allergy, and Immunology, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA 02114, USA. · Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Center for Engineering in Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02114, USA. · Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA. · Clinic of Surgery, UKSH Campus Lübeck, Germany. · Institute of Pathology, University Medical Center Freiburg, Germany. · Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. · Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Division of Rheumatology, Allergy, and Immunology, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA 02114, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. · Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA. Electronic address: aryee.martin@mgh.harvard.edu. · Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address: dting1@mgh.harvard.edu. ·Cell · Pubmed #31155233.

ABSTRACT: Single-cell technologies have described heterogeneity across tissues, but the spatial distribution and forces that drive single-cell phenotypes have not been well defined. Combining single-cell RNA and protein analytics in studying the role of stromal cancer-associated fibroblasts (CAFs) in modulating heterogeneity in pancreatic cancer (pancreatic ductal adenocarcinoma [PDAC]) model systems, we have identified significant single-cell population shifts toward invasive epithelial-to-mesenchymal transition (EMT) and proliferative (PRO) phenotypes linked with mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3) signaling. Using high-content digital imaging of RNA in situ hybridization in 195 PDAC tumors, we quantified these EMT and PRO subpopulations in 319,626 individual cancer cells that can be classified within the context of distinct tumor gland "units." Tumor gland typing provided an additional layer of intratumoral heterogeneity that was associated with differences in stromal abundance and clinical outcomes. This demonstrates the impact of the stroma in shaping tumor architecture by altering inherent patterns of tumor glands in human PDAC.

4 Article Image-Based Profiling of Patient-Derived Pancreatic Tumor-Stromal Cell Interactions Within a Micropatterned Tumor Model. 2018

Mukundan, Shilpaa / Sharma, Kriti / Honselmann, Kim / Singleton, Amy / Liss, Andrew / Parekkadan, Biju. ·1 Department of Biomedical Engineering, Rutgers, The State University of New Jersey, Piscataway, NJ, USA. · 2 Department of Surgery, Andrew L. Warshaw Institute for Pancreatic Cancer Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. · 3 Center for Surgery, Bioengineering, and Innovation, Department of Surgery, Massachusetts General Hospital, Harvard Medical School and the Shriners Hospitals for Children, Boston, MA, USA. · 4 Cancer Institute of New Jersey, New Brunswick, NJ, USA. ·Technol Cancer Res Treat · Pubmed #30348057.

ABSTRACT: Pancreatic cancer is one of the most aggressive cancers with a 5-year patient survival rate of 8.2% and limited availability of therapeutic agents to target metastatic disease. Pancreatic cancer is characterized by a dense stromal cell population with unknown contribution to the progression or suppression of tumor growth. In this study, we describe a microengineered tumor stromal assay of patient-derived pancreatic cancer cells to study the heterotypic interactions of patient pancreatic cancer cells with different types of stromal fibroblasts under basal and drug-treated conditions. The population dynamics of tumor cells in terms of migration and viability were visualized as a functional end point. Coculture with cancer-associated fibroblasts increased the migration of cancer cells when compared to dermal fibroblasts. Finally, we imaged the response of a bromodomain and extraterminal inhibitor on the viability of pancreatic cancer clusters surrounding by stroma in microengineered tumor stromal assay. We visualized a codynamic reduction in both cancer and stromal cells with bromodomain and extraterminal treatment compared to the dimethyl sulfoxide-treated group. This study demonstrates the ability to engineer tumor-stromal assays with patient-derived cells, study the role of diverse types of stromal cells on cancer progression, and precisely visualize a coculture during the screening of therapeutic compounds.

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 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.

8 Article Cytologic characteristics of circulating epithelioid cells in pancreatic disease. 2017

Rosenbaum, Matthew W / Cauley, Christy E / Kulemann, Birte / Liss, Andrew S / Castillo, Carlos Fernandez-Del / Warshaw, Andrew L / Lillemoe, Keith D / Thayer, Sarah P / Pitman, Martha B. ·Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts. · Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts. · Department of Surgery, University Hospital Freiburg, Freiburg, Germany. · Division of Surgical Oncology, Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska. ·Cancer Cytopathol · Pubmed #28257167.

ABSTRACT: BACKGROUND: Circulating epithelioid cells (CECs), also known as circulating tumor, circulating cancer, circulating epithelial, or circulating nonhematologic cells, are a prognostic factor in various malignancies that can be isolated via various protocols. In the current study, the authors analyzed the cytomorphologic characteristics of CECs isolated by size in a cohort of patients with benign and malignant pancreatic diseases to determine whether cytomorphological features could predict CEC origin. METHODS: Blood samples were collected from 9 healthy controls and 171 patients with pancreatic disease who were presenting for surgical evaluation before treatment. Blood was processed with the ScreenCell size-based filtration device. Evaluable CECs were analyzed in a blinded fashion for cytomorphologic characteristics, including cellularity; nucleoli; nuclear size, irregularity, variability, and hyperchromasia; and nuclear-to-cytoplasmic ratio. Statistical differences between variables were analyzed via the Fisher exact test. RESULTS: No CECs were identified among the 9 normal healthy controls. Of the 115 patients with CECs (positive or suspicious for), 25 had nonmalignant disease and 90 had malignancy. There were no significant differences in any of the cytologic criteria noted between groups divided by benign versus malignant, neoplastic versus nonneoplastic, or pancreatic ductal adenocarcinoma versus neuroendocrine tumor. CONCLUSIONS: CECs were observed in patients with malignant and nonmalignant pancreatic disease, but not in healthy controls. There were no morphologic differences observed between cells from different pancreatic diseases, suggesting that numerous conditions may be associated with CECs in the circulation and that care must be taken not to overinterpret cells identified by cytomorphology as indicative of circulating tumor cells of pancreatic cancer. Additional studies are required to determine the origin and clinical significance of these cells. Cancer Cytopathol 2017;125:332-340. © 2017 American Cancer Society.

9 Article Loss of Trefoil Factor 2 From Pancreatic Duct Glands Promotes Formation of Intraductal Papillary Mucinous Neoplasms in Mice. 2016

Yamaguchi, Junpei / Mino-Kenudson, Mari / Liss, Andrew S / Chowdhury, Sanjib / Wang, Timothy C / Fernández-Del Castillo, Carlos / Lillemoe, Keith D / Warshaw, Andrew L / Thayer, Sarah P. ·Department of Surgery, Andrew L. Warshaw Institute for Pancreatic Cancer Research, Massachusetts General Hospital, Boston, Massachusetts. · Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts. · Division of Surgical Oncology and the Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska. · Division of Digestive and Liver Diseases and Irving Cancer Research Center, Columbia University Medical Center, New York, New York. · Department of Surgery, Andrew L. Warshaw Institute for Pancreatic Cancer Research, Massachusetts General Hospital, Boston, Massachusetts; Division of Surgical Oncology and the Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska. Electronic address: sarah.thayer@unmc.edu. ·Gastroenterology · Pubmed #27523981.

ABSTRACT: BACKGROUND & AIMS: Little is known about the origin of pancreatic intraductal papillary mucinous neoplasms (IPMN). Pancreatic duct glands (PDGs) are gland-like outpouches budding off the main pancreatic ducts that function as a progenitor niche for the ductal epithelium; they express gastric mucins and have characteristics of side-branch IPMNs. We investigated whether PDGs are a precursor compartment for IPMNs and the role of Trefoil factor family 2 (TFF2)-a protein expressed by PDGs and the gastric mucosa that are involved in epithelial repair and tumor suppression. METHODS: We obtained pancreatectomy specimens from 20 patients with chronic pancreatitis, 13 with low-grade side-branch IPMNs, and 15 patients with PDAC; histologically normal pancreata were used as controls (n = 18). Samples were analyzed by immunohistochemistry to detect TFF1 and TFF2 and cell proliferation. We performed mitochondrial DNA mutational mapping studies to determine the cell lineage and fate of PDG cells. Pdx1-Cre;LSL-KRAS RESULTS: Histologic analysis of human samples revealed gastric-type IPMN to comprise 2 molecularly distinct layers: a basal crypt segment that expressed TFF2 and overlying papillary projections. Proliferation occurred predominantly in the PDG-containing basal segments. Mitochondrial mutation mapping revealed a 97% match between the profiles of proliferating PDG cells and their overlying nonproliferative IPMN cells. In contrast to KC mice, 2-month-old KC/Tff2 CONCLUSIONS: In histologic analyses of human IPMNs, we found PDGs to form the basal segment and possibly serve as a progenitor compartment. TFF2 has tumor-suppressor activity in the mouse pancreas and prevents formation of mucinous neoplasms.

10 Article Regulation of GLI Underlies a Role for BET Bromodomains in Pancreatic Cancer Growth and the Tumor Microenvironment. 2016

Huang, Yinshi / Nahar, Sabikun / Nakagawa, Akifumi / Fernandez-Barrena, Maite G / Mertz, Jennifer A / Bryant, Barbara M / Adams, Curtis E / Mino-Kenudson, Mari / Von Alt, Kate N / Chang, Kevin / Conery, Andrew R / Hatton, Charlie / Sims, Robert J / Fernandez-Zapico, Martin E / Wang, Xingpeng / Lillemoe, Keith D / Fernández-Del Castillo, Carlos / Warshaw, Andrew L / Thayer, Sarah P / Liss, Andrew S. ·Departments of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, P.R. China. Department of Surgery and the Andrew L. Warshaw, MD, Institute for Pancreatic Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. · Department of Surgery and the Andrew L. Warshaw, MD, Institute for Pancreatic Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. · Division of Oncology Research, Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, Minnesota. · Constellation Pharmaceuticals, Cambridge, Massachusetts. · Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. · Departments of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, P.R. China. Departments of Gastroenterology, Shanghai First People's Hospital, Shanghai Jiatong University School of Medicine, Shanghai, P.R. China. · Department of Surgery and the Andrew L. Warshaw, MD, Institute for Pancreatic Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. aliss@mgh.harvard.edu sarah.thayer@unmc.edu. ·Clin Cancer Res · Pubmed #27169995.

ABSTRACT: PURPOSE: The initiation, progression, and maintenance of pancreatic ductal adenocarcinoma (PDAC) results from the interplay of genetic and epigenetic events. While the genetic alterations of PDAC have been well characterized, epigenetic pathways regulating PDAC remain, for the most part, elusive. The goal of this study was to identify novel epigenetic regulators contributing to the biology of PDAC. EXPERIMENTAL DESIGN: In vivo pooled shRNA screens targeting 118 epigenetic proteins were performed in two orthotopic PDAC xenograft models. Candidate genes were characterized in 19 human PDAC cell lines, heterotopic xenograft tumor models, and a genetically engineered mouse (GEM) model of PDAC. Gene expression, IHC, and immunoprecipitation experiments were performed to analyze the pathways by which candidate genes contribute to PDAC. RESULTS: In vivo shRNA screens identified BRD2 and BRD3, members of the BET family of chromatin adaptors, as key regulators of PDAC tumor growth. Pharmacologic inhibition of BET bromodomains enhanced survival in a PDAC GEM model and inhibited growth of human-derived xenograft tumors. BET proteins contribute to PDAC cell growth through direct interaction with members of the GLI family of transcription factors and modulating their activity. Within cancer cells, BET bromodomain inhibition results in downregulation of SHH, a key mediator of the tumor microenvironment and canonical activator of GLI. Consistent with this, inhibition of BET bromodomains decreases cancer-associated fibroblast content of tumors in both GEM and xenograft tumor models. CONCLUSIONS: Therapeutic inhibition of BET proteins offers a novel mechanism to target both the neoplastic and stromal components of PDAC. Clin Cancer Res; 22(16); 4259-70. ©2016 AACR.

11 Article KRAS mutations in pancreatic circulating tumor cells: a pilot study. 2016

Kulemann, Birte / Liss, Andrew S / Warshaw, Andrew L / Seifert, Sindy / Bronsert, Peter / Glatz, Torben / Pitman, Martha B / Hoeppner, Jens. ·Department of Surgery, University of Freiburg Medical Center, Hugstetter Str. 55, D-79106, Freiburg, Germany. birte.kulemann@uniklinik-freiburg.de. · Department of Surgery & Andrew L. Warshaw, MD Institute for Pancreatic Cancer Research, Massachusetts General Hospital/ Harvard Medical School, Boston, MA, USA. · Department of Surgery, University of Freiburg Medical Center, Hugstetter Str. 55, D-79106, Freiburg, Germany. · Department of Pathology, University of Freiburg Medical Center, Freiburg, Germany. · Comprehensive Cancer Center, University of Freiburg Medical Center, Freiburg, Germany. · Department of Pathology, Massachusetts General Hospital, Boston, MA, USA. ·Tumour Biol · Pubmed #26684803.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is most often diagnosed in a metastatic stage. Circulating tumor cells (CTC) in the blood are hypothesized as the means of systemic dissemination. We aimed to isolate and characterize CTC to evaluate their significance as prognostic markers in PDAC. Blood obtained from healthy donors and patients with PDAC before therapy was filtered with ScreenCell® filtration devices for size-based CTC isolation. Captured cells were analyzed by immunofluorescence for an epithelial to mesenchymal transition (EMT) marker (zinc finger E-box binding homebox 1 (ZEB1)) and an epithelial antigen (cytokeratin (CK)). Molecular analysis of parallel specimens evaluated the KRAS mutation status of the CTC. The survival of each patient after study was recorded. As demonstrated by either cytology or finding of a KRAS mutation, CTC were detected in 18 of 21 patients (86 %) with proven PDAC: 8 out of 10 patients (80 %) with early stage (UICC IIA/IIB) and 10 out of 11 (91 %) with late stage (UICC III/IV) disease. CTC were not found in any of the 10 control patients (p < 0.001). The presence of CTC did not adversely affect median survival: 16 months in CTC-positive (n = 18) vs. 10 months in CTC-negative (n = 3) patients. Neither ZEB1 nor cytological characteristics correlated with overall survival, although ZEB1 was found almost exclusively in CTC of patients with established metastases. Patients with a CTC KRAS mutation (CTC-KRAS (mut)) had a substantially better survival, 19.4 vs. 7.4 months than patients with wild type KRAS (p = 0.015). With ScreenCell filtration, CTC are commonly found in PDAC (86 %). Molecular and genetic characterization, including mutations such as KRAS, may prove useful for prognosis.

12 Article Circulating Epithelial Cells in Patients with Pancreatic Lesions: Clinical and Pathologic Findings. 2015

Cauley, Christy E / Pitman, Martha B / Zhou, Jiahua / Perkins, James / Kuleman, Birte / Liss, Andrew S / Fernandez-Del Castillo, Carlos / Warshaw, Andrew L / Lillemoe, Keith D / Thayer, Sarah P. ·Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA; Warshaw Institute for Pancreatic Cancer Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA. Electronic address: ccauley@partners.org. · Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA. · Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA; Warshaw Institute for Pancreatic Cancer Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA. · Division of Surgical Oncology, Department of Surgery, University of Nebraska Medical Center, Omaha, NE. ·J Am Coll Surg · Pubmed #26209458.

ABSTRACT: BACKGROUND: Circulating epithelial cell (CEC) isolation has provided diagnostic and prognostic information for a variety of cancers, previously supporting their identity as circulating tumor cells in the literature. However, we report CEC findings in patients with benign, premalignant, and malignant pancreatic lesions using a size-selective filtration device. STUDY DESIGN: Peripheral blood samples were drawn from patients found to have pancreatic lesions on preoperative imaging at a surgical clinic. Blood was filtered using ScreenCell devices, which were evaluated microscopically by a pancreatic cytopathologist. Pathologic data and clinical outcomes of these patients were obtained from medical records during a 1-year follow-up period. RESULTS: Nine healthy volunteers formed the control group and were found to be negative for CECs. There were 179 patients with pancreatic lesions that formed the study cohort. Circulating epithelial cells were morphologically similar in patients with a variety of pancreatic lesions. Specifically, CECs were identified in 51 of 105 pancreatic ductal adenocarcinomas (49%), 7 of 11 neuroendocrine tumors (64%), 13 of 21 intraductal papillary mucinous neoplasms (62%), and 6 of 13 patients with chronic pancreatitis. Rates of CEC identification were similar in patients with benign, premalignant, and malignant lesions (p = 0.41). In addition, CEC findings in pancreatic ductal adenocarcinoma patients were not associated with poor prognosis. CONCLUSIONS: Although CECs were not identified in healthy volunteers, they were identified in patients with benign, premalignant, and malignant pancreatic lesions. The presence of CECs in patients presenting with pancreatic lesions is neither diagnostic of malignancy nor prognostic for patients with pancreatic ductal adenocarcinoma.

13 Article Prognosis of invasive intraductal papillary mucinous neoplasm depends on histological and precursor epithelial subtypes. 2011

Mino-Kenudson, Mari / Fernández-del Castillo, Carlos / Baba, Yoshifumi / Valsangkar, Nakul P / Liss, Andrew S / Hsu, Maylee / Correa-Gallego, Camilo / Ingkakul, Thun / Perez Johnston, Rocio / Turner, Brian G / Androutsopoulos, Vasiliki / Deshpande, Vikram / McGrath, Deborah / Sahani, Dushyant V / Brugge, William R / Ogino, Shuji / Pitman, Martha B / Warshaw, Andrew L / Thayer, Sarah P. ·Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. mminokenudson@partners.org ·Gut · Pubmed #21508421.

ABSTRACT: OBJECTIVE: Invasive cancers arising from intraductal papillary mucinous neoplasm (IPMN) are recognised as a morphologically and biologically heterogeneous group of neoplasms. Less is known about the epithelial subtypes of the precursor IPMN from which these lesions arise. The authors investigate the clinicopathological characteristics and the impact on survival of both the invasive component and its background IPMN. DESIGN AND PATIENTS: The study cohort comprised 61 patients with invasive IPMN (study group) and 570 patients with pancreatic ductal adenocarcinoma (PDAC, control group) resected at a single institution. Multivariate analyses were performed using a stage-matched Cox proportional hazard model. RESULTS: The histology of invasive components of the IPMN cohort was tubular in 38 (62%), colloid in 16 (26%), and oncocytic in seven (12%). Compared with PDAC, invasive IPMNs were associated with a lower incidence of adverse pathological features and improved mortality by multivariate analysis (HR 0.58; 95% CI 0.39 to 0.86). In subtype analysis, this favourable outcome remained only for colloid and oncocytic carcinomas, while tubular adenocarcinoma was associated with worse overall survival, not significantly different from that of PDAC (HR 0.85; 95% CI 0.53 to 1.36). Colloid and oncocytic carcinomas arose only from intestinal- and oncocytic-type IPMNs, respectively, and were mostly of the main-duct type, whereas tubular adenocarcinomas primarily originated in the gastric background, which was often associated with branch-duct IPMN. Overall survival of patients with invasive adenocarcinomas arising from gastric-type IPMN was significantly worse than that of patients with non-gastric-type IPMN (p=0.016). CONCLUSIONS: Tubular, colloid and oncocytic invasive IPMNs have varying prognosis, and arise from different epithelial subtypes. Colloid and oncocytic types have markedly improved biology, whereas the tubular type has a course that resembles PDAC. Analysis of these subtypes indicates that the background epithelium plays an equally, if not more, important role in defining the biology and prognosis of invasive IPMNs.