bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A06: Identification of tumor-specific antibodies using phage display selections on pancreatic ductal organoids
Authors: Oni Tobiloba E. , Bautista Carmelita , Nelson Bryce , Tuveson David A. 
Published: December 2016

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with a five year survival rate at 6%. The high mortality of this disease is associated with its late diagnosis. Developing accurate means of early detection will allow for curative surgery and significantly improve patient outcomes. Monoclonal antibodies against tumor-associated neoepitopes are promising tools for identifying novel biomarkers due to their exquisite specificity.
To generate antibodies specific to pancreatic tumor cells, we have adapted previously established screening methods with synthetic phage displayed Fab libraries to the pancreatic ductal organoid system, a recently developed ex vivo platform for culturing both normal and malignant pancreatic tissue. This antibody screen employs negative selection of Fabs binding normal organoids to eliminate those cell surface markers elevated during normal ductal cell proliferation, a state similar to the proliferation observed in the pancreas during inflammatory conditions. This is significant because the ability of novel biomarkers to accurately detect pancreatic cancer depends on their capacity to distinguish PDAC from benign diseases of the pancreas.
Using this method, we have isolated five unique Fabs that preferentially bind cell surface antigens on tumor but not normal organoids derived from human PDAC and non-diseased patients respectively. Characterization of the cognate antigens of these antibodies and validation of their binding to human tissue are ongoing. We demonstrate that pancreatic ductal organoids provide a systematic platform to screen antibody libraries for the discovery of biomarkers specific to the neoplastic state.
Citation Format: Tobiloba E. Oni, Carmelita Bautista, Bryce Nelson, David A. Tuveson.{Authors}. Identification of tumor-specific antibodies using phage display selections on pancreatic ductal organoids. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A06.
Abstract A25: Pancreatic cancer cells scavenge complex lipids from stroma in the hypoxic tumor microenvironment
Authors: Jong Petrus R. de , Campos Alejandro D. , Shanahan Sean-Luc , Richardson Adam , Powis Garth 
Published: December 2016

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is non-resectable in 85% of cases and highly resistant to chemotherapy, resulting in a poor 5-year survival (5-7%). Understanding the metabolic vulnerabilities of PDAC in the harsh tumor microenvironment (TME) may lead to novel therapeutic approaches with improved clinical efficacy. The pancreatic TME is characterized by widespread desmoplasia represented by alpha-smooth muscle actin-positive fibroblasts, pancreatic stellate cells and extracellular matrix components, among others. Up to 90% of the pancreatic tumor mass consists of non-neoplastic cells, and high interstitial pressures and poor perfusion both result in severe hypoxia, leading to a more malignant PDAC phenotype. We hypothesized that these conditions lead to specific metabolic constrains in oncogene-driven, rapidly proliferating PDAC cells that experience high levels of stress, in contrast to the surrounding quiescent stromal cells. We used co-culturing of PDAC (MIAPaCa2) and stromal (NIH/3T3) cells in transwell systems as a robust and reproducible model of cell contact-independent interactions in the pancreatic TME. A commercial metabolic profiling platform (Metabolon) and 13C-based flux assays were used to study changes in metabolite levels in both cell types in normoxia or hypoxia (1% O2). We found that hypoxia induced similar metabolic changes in the PDAC and stromal cells, suggesting that hypoxia-regulated metabolic rewiring is independent of cell-type. Interestingly, the metabolic effects of co-culturing were predominantly observed in the stromal compartment, e.g. enhanced glycogenolysis, metabolite changes indicative of gluconeogenesis, and increased dipeptide levels, all reminiscent of a ‘starvation’ phenotype. In contrast, the tumor cells maintained a mixed anabolic and catabolic phenotype, as shown by elevated intracellular levels of essential amino acids and ribonucleotide triphosphates, representative of a ‘feeding’ phenotype. Importantly, a unique dependence on complex lipid species was observed in cancer cells with reciprocal changes in stromal cells. These data suggest that pancreatic cancer cells reprogram stromal cells to ‘feed off’ the metabolic capacity of non-neoplastic cells in the tumor microenvironment, thereby inducing the release of diffusable metabolites to satisfy their specific catabolic needs.
Citation Format: Petrus R. de Jong, Alejandro D. Campos, Sean-Luc Shanahan, Adam Richardson, Garth Powis.{Authors}. Pancreatic cancer cells scavenge complex lipids from stroma in the hypoxic tumor microenvironment. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A25.
Abstract A30: Chronic inflammation induces severe stromal damage and early pancreatic tumors in mice with activated Akt1 and KRas
Authors: Gitto Sarah B. , Cline Kathryn A. , Khaled Amr S. , Altomare Deborah A. 
Published: December 2016

Abstract
Inflammation and the immune environment is implicated as a risk for pancreatic ductal adenocarcinoma (PDAC), especially in chronic conditions. However, a mechanistic link is unknown. Recently, radiotherapy followed by immune checkpoint inhibitors are being tested and show promising results, thereby introducing immune modulation as a new investigational area for the treatment of pancreatic cancer. A potential barrier is that pancreatic fibrosis and desmoplastic reactivity are common characteristics of PDAC and makes therapeutic delivery difficult. To define how inflammation and desmoplasia effects the immune-pancreatic stromal environment and progression of PDAC, we have chronically injected caerulein into genetically engineered mice that we previously showed spontaneously develop PDAC through the cooperation of mutant active Akt1 and KRas. We show that injected Akt1Myr/KRasG12D mice have increased tissue remodeling, stellate cell activation, collagen production, and mucin production when compared to KRasG12D mice. They also have increased ductal proliferation, accelerated tumor formation, and increased immune cell infiltration in the pancreas ducts and stroma compared to control PBS- and caerulein-injected KRasG12D mice. Pro-inflammatory cytokines and macrophages likely activate stellate cells, which in turn facilitate additional cytokines to enhance a pro-tumor immune environment. Other than macrophages, the role that innate immune cells contribute to pancreatic cancer has not been well studied. Ongoing studies will delineate the immune cell infiltration, cytokine levels, and the effect on tumor formation in double mutant Akt1Myr/KRasG12D mice. Understanding the mechanisms by which inflammation affects tumor formation can lead to strategies to inhibit pro-tumor changes, impede PDAC development and improve overall patient survival.
Citation Format: Sarah B. Gitto, Kathryn A. Cline, Amr S. Khaled, Deborah A. Altomare.{Authors}. Chronic inflammation induces severe stromal damage and early pancreatic tumors in mice with activated Akt1 and KRas. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A30.
Abstract A40: Gene expression profiling of pancreatic cancer precursors directly from formalin fixed paraffin embedded (FFPE) tissue without nucleic acid extraction
Authors: Smiley Sheila , Marginean Celia , Lo Bryan 
Published: December 2016

Abstract
Gene expression analysis of pancreatic intraepithelial neoplasia (PanINs), the pancreatic ductal adenocarcinoma precursor, has been challenging because extracting and purifying RNA from pancreatic tissue is difficult. Since the pancreas is rich in ribonucleases and PanINs are typically very small lesions, attempts to purify RNA of sufficient quality and quantity for microarray or RNAseq are usually unsuccessful. This is especially true if the starting material is formalin fixed paraffin embedded tissue, where the fixation process introduces further degradation of the RNA. We sought to solve this problem of PanIN gene expression profiling by using the HTG Edgeseq instrument platform. This instrument is designed to work with small FFPE specimens and perform RNA profiling even when RNA is partially degraded by employing a novel extraction free hybridization approach. In our pilot study, we show that the HTG Edgeseq can be used to profile ~2500 genes from a cohort of microdissected low and high grade PanIN from FFPE of human pancreatic adenocarcinoma resections. We speculate that most of these PanIN lesions would not have been amenable to other gene expression methodologies and that the PanIN data from the HTG Edgeseq will contribute to our understanding of the molecular pathways that underlie pancreatic cancer.
Citation Format: Sheila Smiley, Celia Marginean, Bryan Lo.{Authors}. Gene expression profiling of pancreatic cancer precursors directly from formalin fixed paraffin embedded (FFPE) tissue without nucleic acid extraction. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A40.
Abstract A44: Coordination of stress signals by the lysine methyltransferase SMYD2 promotes pancreatic cancer
Authors: Mazur Pawel K. , Reynoird Nicolas , Stellfeld Timo , Flores Natasha M. , Lofgren Shane M. , Carlson Scott M. , Brambilla Elisabeth , Hainaut Pierre , Kaznowska Ewa B. , Arrowsmith Cheryl H. , Khatri Purvesh , Stresemann Carlo , Gozani Or , Sage Julien 
Published: December 2016

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a lethal form of cancer with few therapeutic options. We find that levels of the lysine methyltransferase SMYD2 are elevated in precancerous lesions and PDAC and that SMYD2 normally promotes Ras-driven development of PDAC. Notably, loss of SMYD2 correlates with diminished inflammation in PDAC and we identify the stress-response kinase MAPKAPK3 as a new and physiologically relevant SMYD2 substrate. Inhibition of MAPKAPK3 impedes PDAC growth, identifying a potential new kinase target in PDAC. Finally, we show that inhibition of SMYD2 cooperates with standard chemotherapy to treat PDAC cells and tumors. Together, our findings suggest new roles for SMYD2 in inflammation and stress responses, and identify SMYD2 and MAPKAPK3 as potential therapeutic targets to treat pancreatic cancer.
Citation Format: Pawel K. Mazur, Nicolas Reynoird, Timo Stellfeld, Natasha M. Flores, Shane M. Lofgren, Scott M. Carlson, Elisabeth Brambilla, Pierre Hainaut, Ewa B. Kaznowska, Cheryl H. Arrowsmith, Purvesh Khatri, Carlo Stresemann, Or Gozani, Julien Sage.{Authors}. Coordination of stress signals by the lysine methyltransferase SMYD2 promotes pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A44.
Abstract A49: Pharmacological inhibition of PIM kinases in combination with chemotherapeutic drugs decreases cell viability of pancreatic cancer cells
Authors: Nixon Brittany K. , He Qingping , Singh Vandana , Compton Sarah A. , Warner Steve , Bearss David , Sexton Jonathan Z. , Baines Antonio T. 
Published: December 2016

Abstract
Current drug treatments have proven ineffective in pancreatic ductal adenocarcinoma (PDAC) as chemoresistance is a common occurrence in this disease. In order to improve survival rates, a combination treatment regimen of anti-cancer drugs will most likely be needed. The oncogenic serine/threonine PIM kinase family has been shown to regulate drug resistance in various cancers, including pancreatic cancer. Several PIM kinase inhibitors have been developed over the years and tested against a number of cancers, including solid tumors. Previous studies in our laboratory have shown a potential synergistic effect on cell viability of PDAC cells when treated with the PIM kinase inhibitor SGI-1776 and gemcitabine. Unfortunately, due to medical problems occurring during Phase I clinical trials , clinical studies using SGI-1776 were terminated. This led to the development by Tolero Pharmaceuticals of a more selective second generation PIM kinase inhibitor, TP-3654. However, to our knowledge no research has been conducted on the interaction of TP-3654 with gemcitabine or other FDA-approved chemotherapeutics. To address this concern, a 384-well high-content cell viability assay was designed to assess synergism between TP-3654 and the National Cancer Institute (NCI) catalog of 88 FDA-approved chemotherapeutics. Using high-content automated microscopy and image analysis, we acquired total cell counts and other important cellular data, such as nuclear and cell morphology. While some drug combinations with TP-3654 proved ineffective, decreased cell viability was observed in several drug classes, including hormonal agents, mTOR inhibitors, and alkylating agents. Compounds causing significant cytotoxicity in combination with TP-3654 were further evaluated to not only confirm synergism, but to potentially understand the cellular mechanisms and signaling pathways involved. Additional studies will include testing TP-3654 with non-chemotherapeutic compounds and purified natural products. The results of these studies could be used to help develop better drug combination strategies to treat pancreatic cancer and increase the survival rate of patients.
Citation Format: Brittany K. Nixon, Qingping He, Vandana Singh, Sarah A. Compton, Steve Warner, David Bearss, Jonathan Z. Sexton, Antonio T. Baines.{Authors}. Pharmacological inhibition of PIM kinases in combination with chemotherapeutic drugs decreases cell viability of pancreatic cancer cells. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A49.
Abstract A50: Genotype tunes PDAC tension to induce matricellular-fibrosis and tumor aggression
Authors: Laklai Hanane , Miroshnikova Yekaterina , Pickup Michael , Collisson Eric , Grace Kim , Barrett Alex , Hill Ryan , Lakins Johnathon , Schlaepfer David , Mouw Janna , LeBleu Valerie , Novitskiy Sergey , Johansen Julie , Poli Valeria , Kalluri Rahgu , Wood Laura , Hebrok Matthias , Hansen Kirk , Moses Harold , Weaver Valerie 
Published: December 2016

Abstract
Fibrosis compromises pancreatic ductal carcinoma (PDAC) treatment and contributes to patient mortality. Nevertheless, anti-stromal therapies for pancreatic cancer patients have had mixed results, suggesting there are multifaceted, anti and pro-tumorigenic roles of fibrosis in tumor pathogenesis. We found that human PDACs lacking epithelial TGFβ activity have elevated epithelial Stat3 activity and develop a stiffer, matricellular-enriched fibrosis that associates with high epithelial tension and shorter patient survival. Using several Kras-driven mouse models, we found that both the loss of TGFβ signaling and elevated β1 integrin mechanosignaling engage a positive feedback loop whereby Stat3 signaling modulates pancreatic cancer malignancy by increasing matricellular fibrosis and tissue tension. By contrast, epithelial Stat3 ablation attenuated pancreatic malignancy by reducing the stromal stiffening and epithelial contractility induced by loss of TGFβ signaling. In PDAC patient biopsies, higher matricellular protein and activated Stat3 associated with SMAD4 mutation and shorter survival. The findings implicate epithelial actomyosin tension and matricellular fibrosis in the aggressiveness of SMAD4 mutant pancreatic tumors, and highlight Stat3 as a key driver of the phenotype. These data illustrate how tumor genotype can directly tune tissue mechanics and support the development of genotype-driven, anti-stromal therapies targeting PDAC.
Citation Format: Hanane Laklai, Yekaterina Miroshnikova, Michael Pickup, Eric Collisson, Kim Grace, Alex Barrett, Ryan Hill, Johnathon Lakins, David Schlaepfer, Janna Mouw, Valerie LeBleu, Sergey Novitskiy, Julie Johansen, Valeria Poli, Rahgu Kalluri, Laura Wood, Matthias Hebrok, Kirk Hansen, Harold Moses, Valerie Weaver.{Authors}. Genotype tunes PDAC tension to induce matricellular-fibrosis and tumor aggression. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A50.
Abstract A61: CAF-derived ANXA6+-exosomes support pancreatic cancer aggressiveness and serve as a circulating biomarker
Authors: Leca Julie , Martinez Sebastien , Lac Sophie , Nigri Jeremy , Secq Veronique , Rubis Marion , Dusetti Nelson , Loncle Celine , Roques Julie , Pietrasz Daniel , Garcia Stéphane , Granjeaud Samuel , Ouaissi Mehdi , Bachet Jean-Baptiste , Brun Christine , Iovanna Juan L. , Zimmermann Pascale , Vasseur Sophie , Tomasini Richard 
Published: December 2016

Abstract
Pancreatic ductal adenocarcinoma (PDA) is one of deadliest human malignancies with a median survival barely reaching 6 months post-diagnosis. Such epidemiologic data highlight the urgent need to refine current therapies by integrating recent available knowledge on PDA biology. The malignant progression of PDA is characterized by the presence of an exuberant intra-tumoral microenvironment mainly composed of cancer associated fibroblasts (CAFs) and immune cells. This compartment interacts with pancreatic tumor cells surrounded by dense matrix and hypoxic areas, and affects their behavior through a poorly understood network. Indeed, cellular crosstalk between stromal and tumor cells is of major importance in pancreatic ductal adenocarcinoma (PDA). Here, by analyzing the proteomic stromal signature of human PDA, we highlight a possible contribution of the ANXA6/LRP1/TSP1 complex in such crosstalk. Following in vivo validations and stromal localization of each three candidates, we demonstrated that the formation of this complex is restricted to cancer associated fibroblasts (CAFs) cultured under physiopathological conditions (co-culture with macrophages, under hypoxia and lipid deprivation). Increased PDA aggressiveness is dependent on the uptake by tumor cells of CAFs-derived ANXA6+-exosomes. Targeting of ANXA6, and the relevant complex, in CAFs impairs PDA and metastasis occurrence while injection of ANXA6+-exosomes enhances tumorigenesis. Detection of ANXA6+-exosomes in serum is restricted to PDA patients and can distinguish PDA grade. Our data reveal a new CAF-tumor cell crosstalk supported by ANXA6+-exosomes and highlight a therapeutic target and an interesting biomarker for PDA.
Citation Format: Julie Leca, Sebastien Martinez, Sophie Lac, Jeremy Nigri, Veronique Secq, Marion Rubis, Nelson Dusetti, Celine Loncle, Julie Roques, Daniel Pietrasz, Stéphane Garcia, Samuel Granjeaud, Mehdi Ouaissi, Jean-Baptiste Bachet, Christine Brun, Juan L. Iovanna, Pascale Zimmermann, Sophie Vasseur, Richard Tomasini.{Authors}. CAF-derived ANXA6+-exosomes support pancreatic cancer aggressiveness and serve as a circulating biomarker. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A61.
Abstract A63: Human pancreatic cells have distinct aspects in induction of acinar to ductal metaplasia
Authors: Liu Jun , Akanuma Naoki , Sun Luzhe , Wang Pei 
Published: December 2016

Abstract
Multiple animal studies suggest that pancreatitis-induced acinar-to-ductal metaplasia (ADM) is a key event for the initiation of pancreatic ductal adenocarcinoma (PDAC) tumorigenesis. However, until now, there has not been an adequate system to explore the mechanisms of ADM induction in humans. To address this problem, we have developed a flow cytometry-based, high resolution lineage tracing method to analyse ADM in primary human cells. Using a set of cell surface markers, we have successfully defined and purified human acinar, ductal and acinar-to-ductal transdifferentiated (AD) cells. A Matrigel-based 3D culture system which suppresses spontaneous ADM was developed to identify ADM inducers of primary human acinar cells. In contrast to the effect in mouse acinar cells, TGF-β1 efficiently converted human acinar cells to AD cells in a SMAD-dependent manner. Consistently, phospho-SMAD3 (p-SMAD3) expression was significantly increased in acinar cells from human pancreatitis samples, supporting an important role of the TGF-β/SMAD axis for human ADM in vivo. Furthermore, all known inducers of ADM in mice did not promote ADM in human cells, highlighting fundamental differences between the species. Capitalizing on our ability to separate different cell populations for functional analysis, we found that AD cells gained transient proliferative capacity. More interestingly, while oncogenic KRAS did not induce acinar cell proliferation, it did sustain proliferation of AD cells, suggesting that oncogenic KRAS requires ADM-associated-changes to promote PDAC initiation. This ADM model provides a novel platform to explore the mechanisms involved in the development of human pancreatic diseases.
Grant Support: Support received from the Cancer Prevention and Research Institute of Texas (P. Wang). Jun Liu received support by way of the training grant (RP140105) from the Cancer Prevention and Research Institute of Texas.
Citation Format: Jun Liu, Naoki Akanuma, Luzhe Sun, Pei Wang.{Authors}. Human pancreatic cells have distinct aspects in induction of acinar to ductal metaplasia. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A63.