bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A18: Syndecan-1 is required for oncogenic Kras-driven PDAC tumorigenesis and maintenance
Authors: Yao Wantong , Wang Wei , Taguchi Ayumu , Kapoor Avnish , Momin Amin , Jiang Hong , Rose Johnathon , Celiktas Muge , Deem Angela , Hanash Samir , DePinho Ronald , Ying Haoqiang , Draetta Giulio 
Published: October 2015

Abstract
Although the universal presence of KRAS mutations and their critical role in human pancreatic ductal adenocarcinoma (PDAC) designates it as an ideal therapeutic target, oncogenic KRAS (KRAS*) is still regarded as ‘undruggable’ to date. Therefore, to identify therapeutic points of intervention, it is critical to understand the impact of KRAS*-mediated pathways on in vivo tumor pathogenesis. We have recently generated an inducible KrasG12D-driven (iKRAS*) mouse PDAC model and established a critical role for sustained KRAS* activity in tumor maintenance, providing a model to characterize pathways required for KRAS*-dependent tumorigenicity. Cell surface proteins are relatively accessible and can provide candidates for biomarker discovery, as well as be utilized as therapeutic targets. To characterize the KRAS*-specific organization of cell surface proteins toward the development of possible diagnostic or therapeutic tools, we conducted an unbiased surfaceome analysis of tumor cells in the presence and absence of KRAS* signaling using the iKRAS* mouse PDAC model. Syndecans (SDC), a family of heparin sulfate proteoglycans, were identified as candidates whose membrane expression is correlated with KRAS* activity. Specifically, Syndecan-1 (SDC1) expression was upregulated in response to KRAS* induction in acinar-ductal metaplasia (ADM) and early pancreatic intraepithelial neoplasia (PanIN), but not in cerulein-induced chronic pancreatitis. Moreover, SDC1 membrane expression was abolished upon KRAS* extinction, and our data indicated that the MAPK pathway, but not the PI3K pathway, drives KRAS*-mediated SDC1 surface localization. Supportive of our findings, it has been shown that SDC1 expression is increased in premalignant and malignant pancreatic lesions of primary human PDAC, as well as in various other KRAS*-driven pancreatic cancer mouse models. To further study the role of SDC1 in KRAS*-driven pancreatic cancers, we generated an SDC1-knockout mouse model and crossed with LSL-KrasG12D-PDAC models. Our preliminary data indicate that genetic ablation of SDC1 expression effectively suppressed KRAS*-driven PDAC initiation and progression. The mechanisms of KRAS*-mediated SDC1 membrane localization and its impact on PDAC initiation and progression will be further explored.
Citation Format: Wantong Yao, Wei Wang, Ayumu Taguchi, Avnish Kapoor, Amin Momin, Hong Jiang, Johnathon Rose, Muge Celiktas, Angela Deem, Samir Hanash, Ronald DePinho, Haoqiang Ying, Giulio Draetta. Syndecan-1 is required for oncogenic Kras-driven PDAC tumorigenesis and maintenance. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A18.
Abstract A24: CD133 initiates tumors, induces epithelial-mesenchymal transition, and increases metastasis in pancreatic cancer
Authors: Nomura Alice , Banerjee Sulagna , Sangwan Veena , Chugh Rohit , Dudeja Vikas , Vickers Selwyn M. , Saluja Ashok K. 
Published: October 2015

Abstract
CD133 has been implicated as a cancer stem cell (CSC) surface marker in several malignancies including pancreatic cancer, however, the functional role in the cancer stem cell remains elusive. In this study, we overexpressed CD133 CSC marker in a cell line with minimal endogenous CD133 in order to determine its functional role within a cancer context. We determined that CD133 expression led to increased tumorigenicity down to 10 cells. Progression of tumors derived from cells overexpressing CD133 increased in volume quicker than controls. Additionally, the number of lesions and sites of metastasis were increased in the orthotopic tumors derived from CD133 overexpressing cells. In vitro, CD133 expression induced epithelial-mesenchymal transition (EMT). Mesenchymal marker genes such as SNAI1, ZEB1, CDH2, and VIM increased upon CD133 overexpression and led to increased in vitro invasion by Boyden chamber invasion assay. Furthermore, our results indicate EMT induction and increased invasiveness were mediated by increased NF-κB activation upon CD133 overexpression, as inhibition of NF-κB mitigated these effects. In conclusion, this study demonstrated a functional role of CD133 in pancreatic cancer: its expression increases tumorigenicity; induces EMT; and increases invasion and metastasis.
Citation Format: Alice Nomura, Sulagna Banerjee, Veena Sangwan, Rohit Chugh, Vikas Dudeja, Selwyn M. Vickers, Ashok K. Saluja. CD133 initiates tumors, induces epithelial-mesenchymal transition, and increases metastasis in pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A24.
Abstract A37: MSI is not an important feature in early onset pancreatic carcinoma
Authors: Zanten Monica AJ Van , Kempers Marlies JE , Ligtenberg Marjolijn JL , Nagtegaal Iris D. 
Published: October 2015

Abstract
Background and Aim: There is scant information on pancreatic cancer occurring at young age. About 5 to 10 percent of patients with pancreatic cancer have a family history of pancreatic cancer, which is partially due to defined hereditary syndromes like Lynch syndrome. Recently, we have identified deletions of the 3’ end of the EPCAM gene as a novel cause of this hereditary syndrome. In the cohort of patients with EPCAM deletions a relatively high number of pancreatic cancers and duodenal cancers were observed. We therefore aimed to assess whether development of pancreatic or duodenal cancer at young age might be an indication of EPCAM-associated Lynch syndrome.
Methods: We searched the Dutch Pathology Registry (PALGA) to identify all patients who were diagnosed with pancreatic carcinoma (PC), ampulla of Vater carcinoma (VC) or duodenal carcinoma (DC) before the age of 50 in The Netherlands between January 2000 and December 2012. Immunohistochemical analysis was used to analyze mismatch repair (MMR)- and EPCAM-protein expression. MS-status was determined by a panel of 5 mononucleotide repeats in cases with an aberrant MMR protein pattern. Furthermore, multiplex ligation-dependent probe amplification will be performed in case of an absent EPCAM staining or loss of MSH2 and MSH6 protein expression.
Results: An aberrant MMR-IHC for PMS2 combined with microsatellite instability (MSI) was identified in 1 of 48 (2%) PC diagnosed before age 50. In 24 VC patients, one tumor (4%) showed MSI with absence of both MLH1 and PMS2 staining. This patient had a history of colon carcinoma at the age of 43 years. All patients showed a normal immunohistochemical staining for MSH2 and MSH6. EPCAM protein expression was present in all cases, except one case with an anaplastic pancreas carcinoma where EPCAM was absent in the vimentine-positive area of the tumor. Eight out of 22 DC tumors (36%) showed a MMR-defective phenotype with MSI, of which 2 with an aberrant MSH2 and MSH6 staining and a positive EPCAM protein expression. One of these two patients had a history of colon carcinoma at the age of 24 and 26 years.
Conclusion: This nationwide study cohort suggests that early onset pancreatic cancer and ampulla of Vater cancer are at most rarely associated with (EPCAM-associated) Lynch syndrome, in contrast to early onset duodenal cancer.
Citation Format: Monica AJ Van Zanten, Marlies JE Kempers, Marjolijn JL Ligtenberg, Iris D. Nagtegaal. MSI is not an important feature in early onset pancreatic carcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A37.
Abstract A38: Adiponectin receptor agonists cause inhibition of pancreatic cancer proliferation
Authors: Mendonsa Alisha , Gorden Lee , VanSaun Michael Nathan 
Published: October 2015

Abstract
Adiponectin is an anti-atherogenic hormone which is typically decreased in the setting of obesity, diabetes, and pancreatitis. Adiponectin and/or its receptor levels have been inversely correlated with risk for pancreatic cancer. The purpose of this study was to determine the effect of adiponectin on pancreatic cancer cells and to investigate the primary molecular pathways that it regulates. We have previously shown that pancreatic cancer cells primarily produce adiponectin receptor 1. In our current studies, recombinant adiponectin and a novel small molecular adiponectin agonist, AdipoRon, were used to stimulate human and murine pancreatic cancer cell lines in vitro. Proliferation was assessed through an EdU incorporation assay, metabolism was measured through MTT, and apoptosis was assessed through Annexin V staining. Results demonstrate that adiponectin stimulation leads to a decrease in proliferation of pancreatic cancer cells. Further, AdipoRon elicits a more potent suppression of proliferation and an additional increase in apoptosis. To better understand the molecular mechanisms activated by adiponectin stimulation, we performed western blot analysis of treated cells. We were able to confirm that AMPK was a direct target of both adiponectin and AdipoRon. Further, we were able to show that FBS stimulated phosphorylation of Akt was diminished in the presence of AdipoRon. Our data demonstrate that adiponectin and adiponectin receptor agonists act in a suppressive manner against pancreatic cancer cell proliferation. Current studies will determine whether adiponectin agonists can additionally decrease proliferation in vivo.
Citation Format: Alisha Mendonsa, Lee Gorden, Michael Nathan VanSaun. Adiponectin receptor agonists cause inhibition of pancreatic cancer proliferation. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A38.
Abstract A42: Paracrine regulation of the pancreatic cancer epigenome
Authors: Sherman Mara H. , Collisson Eric , Downes Michael , Evans Ronald M. 
Published: October 2015

Abstract
Development of pancreatic ductal adenocarcinoma (PDAC) follows an increasingly well-defined series of genetic events in the pancreatic epithelium. Less well understood are the steps orchestrating the exuberant desmoplasia that accompanies every case of PDAC. This accumulation of stromal components arises from and is maintained by the reciprocal interactions between genetically altered tumor cells and adjacent stroma. Pancreatic stellate cells (PSCs) are myofibroblast-like cells activated by tissue damage and implicated in wound healing. Recent work suggests that PSCs are key primary drivers of the desmoplastic reaction that characterizes the disease, possibly through their established secretory capacity. We wished to explore the paracrine effects of PSC secreted factors on gene expression in pancreatic cancer cells. To investigate the global gene expression changes induced by stromal factors, PDAC cell lines were grown in “a-stromal” or “stromal” conditions. The addition of structural and diffusible PSC-derived factors significantly altered expression of thousands of genes in the cancer genome, suggesting that these factors exert genome-wide effects on the epigenetic state to so broadly affect transcription level. Stromal inputs lead to broad hyperacetylation of histones in the PDAC epigenome, particularly on gene-activating lysines on histone tails. These epigenetic events coincided with induction of genes implicated in anabolic metabolism, the glycosylation pathway, and inflammation. The gene expression changes induced by stromal factors overlap with those previously identified following oncogenic Kras, suggesting functional complementarity between cell-autonomous and microenvironmental cues characteristic of PDAC. As epigenome modification results in changes in gene expression through the functions of readers, we tested a small molecule inhibitor of a family of epigenetic readers for the capacity to inhibit gene expression changes downstream of stromal factors. Paracrine induction of pro-growth and inflammatory genes was inhibited by this small molecule, suggesting that acetyl-lysine readers serve as key transducers of stromal inputs to drive alterations in gene expression in pancreatic cancer cells. Inhibition of acetyl-lysine sensing reduced pancreatic tumor growth and associated inflammation in vivo, with significant reduction in expression of genes implicated in macromolecule biosynthesis and tumor-permissive immune regulation. This work supports further investigation of epigenetic modulators, in combination with targeted drugs or immunotherapeutic approaches, for the treatment of PDAC.
Citation Format: Mara H. Sherman, Eric Collisson, Michael Downes, Ronald M. Evans. Paracrine regulation of the pancreatic cancer epigenome. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A42.
Abstract A45: Understanding the roles of extracellular matrix proteins in pancreatic ductal adenocarcinoma progression and metastasis
Authors: Tian Chenxi , Olund Daniel , Tuveson David , Hynes Richard O. 
Published: October 2015

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most common causes of cancer-related death, and is characterized by accumulation of excessive extracellular matrix (ECM). Although the ECM of tumors, such as PDAC, has long been known to have major effects on behavior of both tumor and stromal cells, including invasion, angiogenesis, metastasis, and resistance to therapy, the detailed composition of the ECM in PDAC tumor progression and metastasis are not understood. To study the involvement of ECM proteins in PDAC primary tumor growth and the tissue-specific metastasis program, I modified the comprehensive ECM proteomic approach by Mass Spectrometry (MS) recently developed in our lab to profile the ECM changes during PDAC progression in both the LSL-KrasG12D/+; LSL-Trp53R127H/+; Pdx-1-Cre (KPC) mouse models of PDAC and human patient samples. We will compare ECM profiles from normal pancreas, pancreatitis, early and late pancreatic intraepithelial neoplasia (PanIN) stages, and PDAC. Initial MS identified between 100 and 140 ECM proteins in samples representing each stage. The combination of mouse models and human samples will allow me to uncover critical ECM changes during PDAC progression and metastasis and, furthermore, to investigate and understand the functional consequences of such changes. The ongoing studies will characterize the ECM of PDAC in detail and provide novel insights into diagnosis, prognosis and treatments of this very difficult disease.
Citation Format: Chenxi Tian, Daniel Olund, David Tuveson, Richard O. Hynes. Understanding the roles of extracellular matrix proteins in pancreatic ductal adenocarcinoma progression and metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A45.
Abstract A67: Defining signaling pathways governing metastatic potential in pancreas cancer
Authors: Whittle Martin C. , Carlson Markus , Hingorani Sunil R. 
Published: October 2015

Abstract
Pancreas cancer is an aggressively metastatic disease in which circulating tumor cells (CTC) often colonize distant organs long before diagnosis. Approximately 45% of patients present at diagnosis with metastatic disease, and this increases to 90% at the time of death. Even after surgical resection of the primary tumor, local and distant recurrence develops in approximately two thirds of cases. These sobering statistics highlight the need to define mechanisms and vulnerabilities of metastasis that can be targeted to improve patient outcomes. To better understand the process of pancreatic cancer metastasis, we study the KrasLSL-G12D/+; Trp53LSL-R172H/+; Pdx1-Cre (KPC) model of autochthonous pancreas cancer. KPC mice spontaneously develop invasive and metastatic disease to numerous sites, including the liver and lungs, at rates similar to those seen in humans. Lineage tracing, performed by selectively expressing fluorescent reporters in pancreatic cells of KPC mice, has revealed a rare population of CTC that may be precursors to these metastatic foci. Building on this model, we show that alteration of TGFβ pathway components significantly affects the metastatic potential of autochthonous tumors, and that the timing and balance of signaling is critical in the metastatic process. These differences in metastatic potential are reflected in the numbers and functional properties of the respective CTC. Our distinct models with drastically different metastatic potentials provide clues to understanding the signaling mechanisms driving metastasis in pancreas cancer.
Citation Format: Martin C. Whittle, Markus Carlson, Sunil R. Hingorani. Defining signaling pathways governing metastatic potential in pancreas cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A67.
Abstract A76: Loss of GLI1 accelerates pancreatic cancer progression in the KPC mouse model
Authors: Mills Lisa D. , Zhang Lizhi , Marler Ronald J. , Svingen Phyllis A. , Fernandez-Barena Maite , Dave Maneesh , Bamlet William , McWilliams Robert , Faubion William A. , Fernandez-Zapico Martin E. 
Published: October 2015

Abstract
The role of the transcription factor GLI1 in pancreatic tumor initiation promoting the progression of preneoplastic lesions into tumors is well established. However, its function at later stages of pancreatic carcinogenesis remains poorly understood. To address this issue, we crossed the GLI1 knockout animal (GKO) with cre-dependent pancreatic activation of oncogenic KRAS concomitant with loss of the tumor suppressor TP53 (KPC). Interestingly, in this model, GLI1 played a tumor protective function, where survival of GKO/KPC mice was reduced compared to KPC littermates. Both cohorts developed pancreatic cancer without significant histopathological differences in survival studies. However, analysis of mice using ultrasound-based imaging at earlier time-points showed increased tumor burden in GKO/KPC mice. These animals have larger tumors, decreased body weight, increased lactate dehydrogenase production, and leukopenia. Expression studies identified FAS and FAS ligand as potential mediators of this phenomenon. The FAS /FASL axis, an apoptotic inducer, plays a role in the progression of pancreatic cancer, where its expression is usually lost or significantly reduced in advanced stages of the disease. Chromatin immunoprecipitation assays identified FAS and FASL as direct targets of GLI1 where GKO/KPC mice showed lower levels of this ligand compared to KPC animals. Furthermore, GLI1 overexpression and knockdown studies demonstrate a key regulatory role for GLI1 in both FAS and FASL expression. Finally, decreased levels of apoptosis were detected in the tumor tissue in the absence of GLI1 by TUNEL staining. Together, these findings define a novel pathway regulated by GLI1 controlling pancreatic tumor progression and provide a new theoretical framework to help the design and analysis of trials targeting GLI1-related pathways.
Citation Format: Lisa D. Mills, Lizhi Zhang, Ronald J. Marler, Phyllis A. Svingen, Maite Fernandez-Barena, Maneesh Dave, William Bamlet, Robert McWilliams, William A. Faubion, Martin E. Fernandez-Zapico. Loss of GLI1 accelerates pancreatic cancer progression in the KPC mouse model. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A76.
Abstract A85: Collagen triple helix repeat containing-1 enhances the aggressiveness of pancreatic tumor by increased cancer cell motility and adhesiveness
Authors: Sun-Hee Leem , Tae-Hong Kang , Woong Chung Jin , Yeonsil Hwang , Seokho Kim , Seok Koh Sang 
Published: October 2015

Abstract
Collagen triple helix repeat containing-1 (CTHRC1) is a secreted protein involved in vascular remodeling, bone formation and developmental morphogenesis. CTHRC1 is expressed in human cancers such as breast cancer and melanoma. In this study, we show that CTHRC1 is highly expressed in human pancreatic cancer tissues and plays a role in the progression and metastasis of the disease. CTHRC1 promoted primary tumor growth and metastatic spread of cancer cells to distant organs in orthotopic xenograft tumor mouse models. Overexpression of CTHRC1 in cancer cells resulted in increased motility and adhesiveness. CTHRC1 activated several key signaling molecules, including Src, focal adhesion kinase, paxillin, mitogen-activated protein kinase kinase (MEK), extracellular signal-regulated kinase and Rac1. Treatment of xenograft mice of pancreatic cancer cells with a CTHRC1-specific monoclonal antibody led to significantly smaller tumor sizes compared with those of untreated control mice. Collectively, our results suggest that CTHRC1 has a role in pancreatic cancer progression and metastasis by regulating migration and adhesion activities of cancer cells.
Citation Format: Leem Sun-Hee, Kang Tae-Hong, Chung Jin Woong, Hwang Yeonsil, Kim Seokho, Koh Sang Seok. Collagen triple helix repeat containing-1 enhances the aggressiveness of pancreatic tumor by increased cancer cell motility and adhesiveness. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A85.