bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B115: PD0332991 induces epithelial to mesenchymal transition in pancreatic cancer
Authors: Imasuen I. E. , Gore A. Jesse , Korc M. 
Published: October 2015

Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains the fourth leading cause of cancer-related death among both men and women in the United States, with an overall survival rate of 6%. Moreover, the median survival in PDAC is only five to six months, underscoring the need for improved therapies. Cancer cell proliferation and cell cycle dysregulation is a major target in cancer treatment. Cyclin-dependent kinase (CDK) and cyclin inhibitors act as anti-proliferative agents that target upregulated cell-cycle progression proteins in various tumors. The efficacy of PD0332991, a CDK4/6 inhibitor, is currently being investigated in clinical trials in patients with retinoblastoma protein (Rb)-positive breast, ovarian, and non-small-cell lung cancers, but has not yet been examined for treatment in PDAC. We have recently shown that PD0332991 inhibits cell proliferation in PDAC cell lines but initiates epithelial to mesenchymal transition (EMT) and induces cancer cell invasion in some of these cells. Using human PDAC tissues and tissues from genetically engineered mouse models (GEMMs) of PDAC, we also recently showed that loss of RB function is common in PDAC. To further assess the therapeutic potential of PD0332991 in PDAC, we now compared its effects in PANC-1 human PDAC cells (wild-type RB1 gene) and in murine PDAC cells devoid of RB that were derived from a GEMM expressing mutant KRASG12D (KRC mice). In PANC-1 cells, PD0332991 (1 μM) inhibited proliferation and induced EMT. By contrast, in KRC 1022-4 murine PDAC cells, the same concentration of PD0332991 induced EMT without altering proliferation. Moreover, removal of PD0332991 from the incubation medium reversed its growth inhibitory actions in PANC-1 cells, but did not reverse its effects on EMT in either PANC-1 or KRC 1022-4 cells. Taken together, these findings suggest that PD0332991 may exert long-term deleterious effects in patients with PDAC limiting its potential therapeutic use in this deadly cancer, except in conjunction with agents that target EMT.
This study was supported, in part, by NCI grant R37-075059 to MK.
Citation Format: I. E. Imasuen, A. Jesse Gore, M. Korc. PD0332991 induces epithelial to mesenchymal transition 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 B115.
Abstract B122: Hypoxia-inducible factor (HIF)-1α directly activates the leptin receptor (Ob-R) in pancreatic cancer cells
Authors: Ren He , Jia Lingling , Hao Jihui 
Published: October 2015

Abstract
The aim of this study is to investigate the regulatory mechanism of Ob-R in pancreatic cancer cells. we found that HIF-1α expression was correlated with Ob-R in both pancreatic cancer cell lines and tissues. Overexpression of HIF-1α and hypoxia upregulated the expression of Ob-R in pancreatic cancer cells. When hypoxia-inducible factor (HIF)-1α gene was silenced in vitro, the expression of Ob-R was significantly decreased. Furthermore, HIF-1α directly bound to the hypoxia-responsive element (HRE) located in Ob-R gene promoter (-828/-832) and activated the transcription. Finally, we demonstrated that silence of HIF-1α gene reversed the inhibitory effect of leptin/ObR in pancreatic cancer cells. Taken together, our results indicated that HIF-1α directly regulated Ob-R expression in pancreatic cancer, which might be a valuable therapeutic target to pancreatic cancer.
Note: This abstract was not presented at the conference.
Citation Format: He Ren, Lingling Jia, Jihui Hao. Hypoxia-inducible factor (HIF)-1α directly activates the leptin receptor (Ob-R) in pancreatic cancer cells. [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 B122.
Abstract B18: MicroRNA-21 is involved in pancreatic cancer fibroblast tumor supportiveness
Authors: Nguyen Andrew Hieu , Li Luyi , Toste Paul , Wu Nanping , Donahue Timothy R. 
Published: October 2015

Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by poor survival despite current medical and surgical therapies and has a propensity towards subclinical metastasis even with resectable disease. The tumor microenvironment consists of a network of supporting cells, including tumor-associated fibroblasts (TAFs), which promote tumor invasion and metastasis, and contribute to PDAC’s extremely poor prognosis. MicroRNAs (miRs) have recently emerged as critical players in post-transcriptional regulation of pathways in cancer biology. In this study, we identified miRs in fibroblasts induced by PDAC tumor cells (TCs). Further, we study the stable suppression of one of these miRs in TAFs and the effects upon fibroblast migration and invasion, as well as tumor cell proliferation.
Methods: Primary pancreatic fibroblasts were cultured with MIA PaCa-2 TC conditioned media and RNA was analyzed by the NanoString MicroRNA Expression Assay. Stable miR knockdown (KD) was achieved with a stably expressed shRNA anti-microRNA by lentiviral vector. Migration was determined by an 18 hour scratch assay and 24 hour invasion by modified Boyden chamber. TC proliferation was measured by MTT assay. In vivo tumor growth was evaluated by subcutaneous TC and TAF co-implantation in NSG mice.
Results: In primary pancreatic fibroblasts, MIA PaCa-2 tumor cells induced 62 miRs &gt;50% increase or 30% decrease in expression. The most prevalent induced miR with 2-fold increase in expression was miR-21. miR-21 KD in TAFs was achieved by introducing stable expression of anti-miR-21, which resulted in a 75% decrease in expression (P&lt;0.001). miR-21 KD TAFs had a &gt;50% decreased ability to migrate (p&lt;0.001) and were 67% less invasive (p&lt;0.001). miR-21 KD TAF conditioned media induced less rapid TC proliferation (p&lt;0.05). Further, in an in vivo model of tumor proliferation, TCs co-implanted with miR-21 KD TAFs showed 45% decreased tumor size (P&lt;0.05), compared to controls.
Conclusions: Pancreatic cancer TCs can induce tumor supportive miRs in TAFs. miR-21 KD in PDAC TAFs results in decreased TAF migration and invasion, as well as reduced ability to support in vitro and in vivo tumor growth.
Citation Format: Andrew Hieu Nguyen, Luyi Li, Paul Toste, Nanping Wu, Timothy R. Donahue. MicroRNA-21 is involved in pancreatic cancer fibroblast tumor supportiveness. [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 B18.
Abstract B24: Targeting pancreatic ductal adenocarcinoma acidic microenvironment
Authors: Cruz-Monserrate Zobeida , Roland Christina L. , Deng Defeng , Arumugam Thiruvengadam , Moshnikova Anna , Andreev Oleg A. , Reshetnyak Yana , Logsdon Craig D. 
Published: October 2015

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in the USA, accounting for ~40,000 deaths annually. The dismal prognosis for PDAC is largely due to its late diagnosis. Currently, the most sensitive diagnosis of PDAC requires invasive procedures, such as endoscopic ultrasonography, which has inherent risks and accuracy that is highly operator dependent. Here we took advantage of a general characteristic of solid tumors, the acidic microenvironment that is generated as a by-product of metabolism, to develop a novel approach of using pH (Low) Insertion Peptides (pHLIPs) for imaging of PDAC. We show that fluorescently labeled pHLIPs can localize and specifically detect PDAC in human xenografts as well as PDAC and PanIN lesions in genetically engineered mouse models. This novel approach may improve detection, differential diagnosis and staging of PDAC
Citation Format: Zobeida Cruz-Monserrate, Christina L. Roland, Defeng Deng, Thiruvengadam Arumugam, Anna Moshnikova, Oleg A. Andreev, Yana Reshetnyak, Craig D. Logsdon. Targeting pancreatic ductal adenocarcinoma acidic microenvironment. [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 B24.
Abstract B34: Diagnostics of pancreatic duct hypertension by the serotonin-stimulated magnetic resonance cholangiopancreatography
Authors: Kashintsev Alexey , Pavelets Konstantin , Kokhanenko Nikolai , Imyanitov Evgeny 
Published: October 2015

Abstract
Background: Serotonin is a neurotransmitter and humoral enhancer which stimulates the pancreatic secretion. Unlike secretin serotonin doesn’t change the proteinogramm of pancreatic juice1. Pancreatic and periampullary tumors can cause the dilatation of the main pancreatic duct. Its partial stenosis can remain undiagnosed on conventional MRCP. Increasing secretion of pancreatic juice after serotonin stimulation can improve the diagnosis, particularly the location and length of a lesion.
Method: Eighteen patients with pancreatic cancer (n=14) and tumor of papilla Vateri (n=4) were included into the study. Median age was 64.9 years with range 45-84 years. Serotonin (0,01mg/kg) was administered perorally (n=2), intramuscularly (n=2), or intravenously with dilution (n=5) and without it (n=9). MRCP was performed before the drug application and 7 minutes after that.
Results: In cases where serotonin was administered perorally, intramuscularly or intravenously with dilution we have not received any significant results (Tab. 1). The positive results were obtained in 5 (55.6%) of 9 cases when MRCP was performed 7 minutes after intravenous administration of concentrated solution. The mean increase in width of the main pancreatic duct was 1.1 mm (range 0.9-1.9 mm).
Conclusion: The method of serotonin-stimulated MRCP can improve the diagnosis of pancreatic ductal hypertension. In these 5 cases the presented technique allowed us to detect the size and localization of a lesion more precisely: tumor of a papilla (n=2), cancer of a pancreatic head (n=3) including one case with involvement of the pancreatic body. In cases of primary ductal dilatation more than 5 mm (n=3) we have not received any positive results, so these patients were excluded from the study.
Note: This abstract was not presented at the conference.
Citation Format: Alexey Kashintsev, Konstantin Pavelets, Nikolai Kokhanenko, Evgeny Imyanitov. Diagnostics of pancreatic duct hypertension by the serotonin-stimulated magnetic resonance cholangiopancreatography. [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 B34.
Abstract B42: Metabolic changes, associated with loss of the tumor suppressor LKB1, promote tumorigenesis
Authors: Kottakis Filippos , Nicolay Brandon N. , Julia Nagle M. , Liesa Marc , Sirihai Orian S. , Dyson Nicholas J. , Bardeesy Nabeel 
Published: October 2015

Abstract
The LKB1 tumor suppressor encodes a serine/threonine kinase that serves as a master regulator of energy metabolism. Germline mutations in LKB1 cause the Peutz-Jeghers polyposis and cancer syndrome and are associated with a high risk of pancreatic cancer development. Despite being the subject of extensive investigation for more than 15 years, the primary mechanisms of LKB1-mediated tumor suppression remain poorly defined. The best-characterized function of LKB1 in cell physiology is to coordinate adaptation to a drop in ATP stores, shutting down multiple biosynthetic processes and favoring catabolic pathways, thereby restoring cellular energy charge. Since LKB1 has pleiotropic effects on cell polarity, migration, and inflammation in addition to cell metabolism, it remains uncertain to what extent LKB1-mediated tumor suppression involves its roles in metabolic reprogramming. In this regard, LKB1 inactivation renders cells vulnerable to a number of metabolic stress stimuli such as glucose deprivation or reactive oxygen species (ROS), indicating that alterations in metabolic control may decrease, rather than increase, the fitness of LKB1 deficient cells. To resolve these questions, we have conducted comprehensive metabolic profiling and functional studies that revealed that LKB1 inactivation results in greatly improved efficiency of nutrient acquisition and utilization, which fuels accelerated cell growth and tumorigenesis. By using a series of primary epithelial culture systems and genetically engineered mouse models coupled with integrative metabolic profiling and flux analyses, we find that LKB1 loss potentiates glucose uptake and glycolysis, and diverts a significant amount of glycolytic intermediates toward biosynthetic processes. Most notably fatty acid and nucleotide pools are greatly expanded upon LKB1 inactivation. This extensive metabolic reprogramming results in a shift in the nutrient requirements of LKB1 mutant cells including a reduced dependence on select exogenous amino acids and greatly increased need for glutamine and glucose. Collectively, our studies uncover adaptive metabolic changes conferred by LKB1 inactivation and suggest potential targetable vulnerabilities of LKB1 mutant cancers.
Citation Format: Filippos Kottakis, Brandon N. Nicolay, Nagle M. Julia, Marc Liesa, Orian S. Sirihai, Nicholas J. Dyson, Nabeel Bardeesy. Metabolic changes, associated with loss of the tumor suppressor LKB1, promote tumorigenesis. [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 B42.
Abstract B45: Pancreatic cancers depend on a non-canonical glutamine metabolism pathway
Authors: Lyssiotis Costas A. , Son Jaekyoung , Mancias Joesph D. , Ying Haoqiang , Cantley Lewis C. , Kimmelman Alec C. 
Published: October 2015

Abstract
Cancer cells exhibit metabolic dependencies that distinguish them from their normal counterparts. Among these addictions is an increased utilization of the amino acid glutamine (Gln) to fuel anabolic processes. Recently, we reported the identification of a non-canonical pathway of Gln utilization in human pancreatic cancer cells that is required for tumor growth. While most cells utilize glutamate dehydrogenase (GLUD1) to convert Gln-derived glutamate (Glu) into alpha-ketoglutarate (alpha-KG) in the mitochondria to fuel the tricarboxylic acid cycle, pancreatic cancer cells rely on a distinct pathway that integrates the mitochondrial and cytosolic aspartate aminotransferases GOT2 and GOT1. By generating alpha-KG from Glu (in conjunction with the conversion of oxaloacetate into aspartate), GOT2 fuels anaplerosis in place of GLUD1. The Asp created is released into the cytosol and acted on by GOT1. This is subsequently used through a series of reactions to yield cytosolic NADPH from malic enzyme. Importantly, we have demonstrated that pancreatic cancers are strongly dependent on this series of reactions to maintain redox homeostasis which enables proliferation. Herein, we detail the subcellular compartmentalization and consequences of the aforementioned reactions on pancreatic cancer metabolism. We have also investigated the essentiality of this pathway in other contexts and find that pancreatic cancers have a uniform and unique reliance on this pathway, which may provide novel therapeutic approaches to treat these refractory tumors.
Citation Format: Costas A. Lyssiotis, Jaekyoung Son, Joesph D. Mancias, Haoqiang Ying, Lewis C. Cantley, Alec C. Kimmelman. Pancreatic cancers depend on a non-canonical glutamine metabolism pathway. [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 B45.
Abstract B50: Abrogating cholesterol esterification suppresses pancreatic cancer growth and metastasis mediated by caveolin-1
Authors: Li Junjie , Lee Seung-Young , Gu Dongsheng , Song Bing , Chen Shaoxiong , Konieczny Stephen , Ratliff Timothy , Liu Xiaoqi , Xie Jingwu , Cheng Ji-Xin 
Published: October 2015

Abstract
Pancreatic cancer is one of the most lethal human cancers due to the lack of early diagnosis and its high propensity for metastases. Recent advances in cancer metabolism research have manifested new promises for therapy. However, cholesterol metabolism in pancreatic cancer remains poorly understood. Here, by employing label-free Raman spectromicroscopy, we found an aberrant accumulation of cholesteryl ester (CE) in human pancreatic cancer tissues and cell lines, but not in normal ones. Our biochemical study revealed that accumulation of CE is a consequence of activated PI3K/Akt/mTOR pathway. Pharmaceutical blocking and genetic knockdown of the cholesterol esterification enzyme, acyl-CoA cholesterol acyltransferase-1 (ACAT-1), reduced pancreatic cancer cell proliferation, migration and invasion rate. In an orthotopic mouse model of pancreatic cancer, ACAT-1 inhibition significantly suppressed tumor growth and metastasis. Furthermore, we showed that ACAT-1 inhibition suppressed pancreatic cancer growth and metastasis by induction of intracellular free cholesterol toxicity and down-regulation of Akt and MAPK pathway mediated by caveolin-1. Collectively, our study opens a new opportunity for treating pancreatic cancer by targeting the altered cholesterol metabolism.
Citation Format: Junjie Li, Seung-Young Lee, Dongsheng Gu, Bing Song, Shaoxiong Chen, Stephen Konieczny, Timothy Ratliff, Xiaoqi Liu, Jingwu Xie, Ji-Xin Cheng. Abrogating cholesterol esterification suppresses pancreatic cancer growth and metastasis mediated by caveolin-1. [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 B50.
Abstract B56: Inactivation of LKB1-AMPK pathway is mediated by inflammation in pancreatic cancer
Authors: Aggarwal Sita , Wang Qingxia , Giri Shailendra , Hansel William 
Published: October 2015

Abstract
Goal: The goal of this project is to determine if there is link between cancer cell metabolism and inflammation. LKB1is a known serine/threonine kinase tumor suppressor gene and it functions by sensing changes in cellular energy homeostasis and modulates anabolic and catabolic processes by activating its downstream kinase, AMP-activated protein kinase (AMPK). It is associated with Peutz-Jeghers syndrome, as well as various cancers including pancreatic cancer. Thus; it is a unique link between cell metabolism and inflammation.
Hypothesis: Our hypothesis is that LKB1-AMK succumbs to inactivation processes because of increased NF-κB expression in pancreatic cancer cells and is associated with increased pancreatic cancer growth.
Results: We tested five pancreatic cancer cells that express constitutive active NF-κB (pp65) and LKB1proteins by western blot analysis. In these cancer cells there was loss of active AMPK, phospho AMK (pAMPK) protein and its substrate pACC protein, suggesting a negative correlation between inflammation and loss of active AMPK. To strengthen this observation, we treated macrophage with LPS/IFNγ to create inflammatory environment and examined the protein levels of pp65, NF-κB regulated inflammatory gene (COX-2), pAMPK and pACC. We found that induction of pp65 and COX-2 are negatively correlated with pAMPK and pACC. To further support this observation we treated the pancreatic cancer cells with Metformin, a known activator of AMPK and our results clearly indicates that Metformin inhibits the proliferation of pancreatic cancer cells in a time-dependent manner. Metformin activates AMPK and ACC in pancreatic cancer cells. These data indicate that, compounds that activates LKB1-AMPK pathway can be beneficial in pancreatic cancer treatment.
Citation Format: Sita Aggarwal, Qingxia Wang, Shailendra Giri, William Hansel. Inactivation of LKB1-AMPK pathway is mediated by inflammation 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 B56.
Abstract B72: Developing drug combinations to co-target pancreatic cancer and its supporting stroma
Authors: Carapuça Elisabete Florencio , Gemenetzidis Emilios , Feig Christine , Tuveson David , Kocher Hemant 
Published: October 2015

Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by an intense desmoplastic stroma, due to the activation of pancreatic stellate cells (PSC). The activated PSC are characterized by a reduction of fat droplets, expression of α-smooth muscle actin (α-SMA), and an increased synthesis and secretion of several connective tissue components such as fibronectin (FN) and collagen type I. Aberrant stromal-epithelial interactions contribute to pancreatic cancer spread and metastasis raising the possibility that targeting the stroma may represent viable strategy for treating pancreatic cancer. Our group has shown that pancreatic cancer progression can be restrained via modulation of the stellate cells in the stroma.
Methods: Organotypic cultures (OT) were constructed to mimic human PDAC. Treatment of OT was performed to mimic human chemotherapy regimen cycles with all-trans retinoic acid (ATRA), targeting PSC, and the chemotherapeutic agent Gemcitabine (GEM), targeting pancreatic cancer cells (PCC). Furthermore, KPC mice (LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre) were treated with the combination of GEM and ATRA. Appropriate controls were used for both in vivo and in vitro assays using either drug alone or vehicle alone to dissect effect of individual drug. Both in vivo and in vitro assays were studied for various surrogate endpoints for chemotherapy efficacy.
Results:In the organotypic model, ATRA alone or in combination with GEM reduced cancer cell and stellate cell invasion. The same treatment also reduced cancer cell proliferation. Stellate cell activation, as measured by fibronectin production per stellate cell, was significantly reduced upon combination treatment with GEM/ATRA, in comparison to cultures treated with GEM or ATRA only. In the KPC mice model, ATRA alone or in combination with GEM caused stromal collapse. The same regimen treatment led to an increase in vascular density in the tumor area and a significant impairment of the tumor growth, when compared with mice treated with ATRA or GEM alone. The number of necrotic areas was also higher in tumors from mice treated with the combination treatment of GEM/ATRA. Further assessments are being carried out.
Conclusions:The combination treatment of all-trans retinoic acid and Gemcitabine may have a synergistic detrimental effect upon pancreatic cancer progression.
Citation Format: Elisabete Florencio Carapuça, Emilios Gemenetzidis, Christine Feig, David Tuveson, Hemant Kocher. Developing drug combinations to co-target pancreatic cancer and its supporting stroma. [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 B72.