bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B20: The necrosome promotes pancreatic Oncogenesis via CXCL1 and mincle-induced immune Suppression
Authors: Seifert Lena , Werba Gregor , Tiwari Shaun , Giao Ly Nancy Ngoc , Alqunaibit Dalia , Alothman Sara , Daley Donnele , Hundeyin Mautin , Mani Vishnu R. , Barilla Rocky , Miller George 
Published: December 2016

Abstract
Neoplastic pancreatic epithelial cells are widely believed to die via Caspase 8-dependantapoptotic cell death and chemotherapy is thought to further promote tumor apoptosis. Conversely, disruption of apoptosis is a basic modality cancer cells exploit for survival. However, the role of necroptosis, or programmed necrosis, in pancreatic ductal adenocarcinoma (PDA) is uncertain. There are a multitude of potential inducers of necroptosis in PDA including ligation of TNFR1, CD95, TRAIL receptors, Toll-like receptors, ROS, and Chemotherapeutics. We doscovered that the principal components of the necrosome, RIP1 and RIP3, are highly expressed in PDA and are further upregulated by chemotherapy. Blockade of the necrosome in vitro promoted cancer cell proliferation and induced an aggressive oncogenic phenotype. However, belying these findings, in vivo RIP3 deletion or RIP1 inhibition was protective against oncogenic progression and was associated with the development of a highly immunogenic myeloid and T cell infiltrate. The immune-suppressive tumor microenvironment (TME) associated with intact RIP1/RIP3 signaling was in-part contingent on necroptosis-induced CXCL1 expression whereas CXCL1 blockade was protective against PDA. Moreover, we found that cytoplasmic SAP130 was expressed in PDA in a RIP1/RIP3-dependent manner, and Mincle – its cognate receptor – was upregulated in tumor-infiltrating myeloid cells. Mincle ligation by SAP130 promoted oncogenesis whereas Mincle deletion was protective and phenocopied the immunogenic reprogramming of the TME characteristic of RIP3 deletion. Cellular depletion experiments suggested that whereas inhibitory macrophages promote tumorigenesis in PDA, they lose their immune-suppressive effects in the context of RIP3 or Mincle deletion. As such, T cells which are dispensable to PDA progression in hosts with intact RIP3 or Mincle signaling become reprogrammed into indispensable mediators of anti-tumor immunity in absence of RIP3 or Mincle. Our work describes parallel networks of necroptosis-induced CXCL1 and Mincle signaling which critically promote macrophage-induced adaptive immune suppression enabling PDA progression.
Citation Format: Lena Seifert, Gregor Werba, Shaun Tiwari, Ly Nancy Ngoc Giao, Dalia Alqunaibit, Sara Alothman, Donnele Daley, Mautin Hundeyin, Vishnu R. Mani, Rocky Barilla, George Miller.{Authors}. The necrosome promotes pancreatic Oncogenesis via CXCL1 and mincle-induced immune Suppression. [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 B20.
Abstract B25: Activation of Wnt/β-catenin signaling pathway enhances pancreatic cancer development and the malignant potential via up-regulation of Cyr61/CCN1
Authors: Sano Makoto , Driscoll David R. , DeJesus-Monge Wilfredo E. , Quattrochi Brian , Appleman Victoria A. , Ou Jianhong , Zhu Lihua Julie , Yoshida Nao , Yamazaki Shintaro , Takayama Tadatoshi , Sugitani Masahiko , Nemoto Norimichi , Klimstra David S. , Lewis Brian C. 
Published: December 2016

Abstract
Pancreatic ductal adenocarcinoma (PDAC), a poor prognostic cancer, commonly develops following activating mutations in the KRAS oncogene. Activation of the Wnt signaling pathway is also commonly observed in PDAC. To ascertain the impact of postnatal activation of the Wnt signaling pathway in PDAC development, we combined the elastase-tva-based RCAS-TVA pancreatic cancer model with the established LSL-KrasG12D, Ptf1a-cre model. Delivery of RCAS viruses encoding β-cateninS37A and Wnt1 stimulated the progression of premalignant PanIN and PDAC development. Indeed, mice injected with RCAS-β-cateninS37A and Wnt1 had reduced survival relative to RCAS-GFP controls (P &lt; 0.05). Active β-catenin or its DNA-binding partner TCF4 enhanced PDAC cell proliferation, soft-agar colony formation, as well as migration and invasion activity. In contrast, these phenotypes were significantly blocked by the introduction of Icat, an inhibitor of the β-catenin/TCF4 interaction. Meanwhile, we identified Cyr61/CCN1 as a target molecule for Wnt/β-catenin signaling pathway in PDAC. Nuclear β-catenin and Cyr61/CCN1 expression were predominantly detected in moderately to poorly differentiated murine and human PDAC. Indeed, nuclear β-catenin and Cyr61/CCN1-positivity independently correlated with poor prognosis (P &lt; 0.01). Knockdown of Cyr61/CCN1 in a β-catenin-activated PDAC cell line reduced soft agar, migration and invasion activity. Together, these data suggest that the Wnt/β-catenin signaling pathway enhances pancreatic cancer development and malignancy in part via up-regulation of Cyr61/CCN1.
Citation Format: Makoto Sano, David R. Driscoll, Wilfredo E. DeJesus-Monge, Brian Quattrochi, Victoria A. Appleman, Jianhong Ou, Lihua Julie Zhu, Nao Yoshida, Shintaro Yamazaki, Tadatoshi Takayama, Masahiko Sugitani, Norimichi Nemoto, David S. Klimstra, Brian C. Lewis.{Authors}. Activation of Wnt/β-catenin signaling pathway enhances pancreatic cancer development and the malignant potential via up-regulation of Cyr61/CCN1. [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 B25.
Abstract B28: Dynamic interplay between type I collagen signaling and invasion in pancreatic cancer
Authors: Shields Mario A. , Maguin Pascal , Dallas Sarah L. , Egeblad Mikala 
Published: December 2016

Abstract
The stroma of pancreatic cancer can restrict as well as promote tumor progression. Why the stroma exhibits these paradoxical functions remains unclear. One of the major components of the pancreatic cancer stroma is fibrillar type I collagen. High levels of collagen in primary tumor specimens have been associated with poor survival and resistance to therapy in pancreatic cancer patients.
To determine the effects of type I collagen on cancer cell behavior, we performed intravital confocal microscopic imaging in mice. We used mice that expressed GFPtopaz fused to the α2 chain of type I collagen under control of a 3.6kb fragment of the COL1A1 promoter [α2(I)-col-GFP mice]. Live imaging of pancreatic tumors, formed after orthotopic injection of cells derived from the classical KPC mouse models, showed that type I collagen architecture in the tumors was heterogeneous. Strikingly, we observed that invasive cancer cells migrated out of the tumors on linear type I collagen. Linearization of collagen fibers through cross-linking, catalyzed by lysyl oxidases (LOXs), is inversely correlated with metastasis-free survival in breast cancer. However, in our pancreatic cancer model, inhibiting LOX promoted collagen linearization, tumor growth and metastatic spread. Elevated collagen-mediated signaling, through activation of focal adhesion kinase (FAK) and discoidin domain receptor (DDR1), was also observed in the tumors treated with lysyl oxidase inhibitor. Lysyl oxidase inhibition also promoted cell contractility as shown by elevated phosphorylated mysosin light chain 2 (p-MLC2) in vivo and by in collagen contractility assays in vitro. TGF-β signaling is a potent stimulator of collagen secretion and of invasive behavior, and it is aberrantly regulated in pancreatic cancer. We observed that lysyl oxidase inhibitor increased phosphorylated Smad3, a downstream effector of TGF-β signaling. Together, our data suggest that the influence of collagen on tumor behavior depends on its architecture. In areas of linear collagen, we find high cancer cell motility out of the tumors and this correlates with increased FAK and TGF-β signaling activity. The architecture-specific function of collagen could potentially explain the paradoxical role for the stroma in pancreatic cancer progression.
Citation Format: Mario A. Shields, Pascal Maguin, Sarah L. Dallas, Mikala Egeblad.{Authors}. Dynamic interplay between type I collagen signaling and invasion in 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 B28.
Abstract B38: Clinical translation of nuclear export inhibitor in metastatic pancreatic cancer
Authors: Azmi Asfar S. , Muqbil Irfana , Aboukameel Amro , Kauffman Michael , Shacham Sharon , Mohammad Ramzi M. , Philip Philip A. 
Published: December 2016

Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains a deadly disease in urgent need of newer therapeutic modalities. PDAC tumors are very heterogeneous and carry alterations in many critical pathways rendering the design of therapy against a single pathway unrealistic. The disease requires a broad form of therapy that can target the activation of multiple tumor suppressor proteins (TSPs) simultaneously. We have shown that over-expression of the nuclear exporter protein CRM1 in PDAC leads to functional inactivation of TSPs (such as FOXO3a, p27, Par-4 and p53) through their mislocalization to the cytoplasmic compartment. We clearly demonstrated that targeted inhibition of CRM1 by CRISPR/Cas9 validated Specific Inhibitor of Nuclear Export (SINE) KPT-330/Selinexor can restore the function of multiple TSPs leading to PDAC cell death and tumor inhibition in orthotopic models. More significantly, our findings show that SINE synergize with gemcitabine (GEM) and nab-paclitaxel leading to enhanced PDAC growth inhibition, apoptosis, and spheroid disintegration of PDAC derived cancer stem cells (CSCs) that undergo epithelial-to-mesenchymal transition (EMT). The observed synergy was due in part to enhanced nuclear localization of TSPs and suppression of CSC markers alongside reversal of EMT markers. RNA from quadruplet combination treatment samples were subjected to Agilent HT12 microarrays and differentially expressed genes (p&lt;0.01) were subjected to pathway analysis. Our computational analysis demonstrated reversal of immune suppressive networks and suppression of CSC sustaining networks. Most importantly we observed activation of fibroblast specific cell death pathways highlighting an as of yet unexplored role of CRM1 in sustaining fibroblast growth that is recognized to support high desmoplastic reaction (DR) in PDAC. Our multi-model pre-clinical work has led to the approval of a Phase Ib/II clinical study involving GEM-nab-paclitaxel-Selinexor for metastatic PDAC (NCT02178436).
Citation Format: Asfar S. Azmi, Irfana Muqbil, Amro Aboukameel, Michael Kauffman, Sharon Shacham, Ramzi M. Mohammad, Philip A. Philip.{Authors}. Clinical translation of nuclear export inhibitor in metastatic 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 B38.
Abstract B59: Black raspberries inhibit pancreatic carcinogenesis by suppressing Raf/MEK/ERK/STAT3 signaling pathways and promoting apoptosis
Authors: Pan Pan , Skaer Chad W. , Wang Hsin-Tzu , Tsai Susan , Oshima Kiyoko , Huang Yi-Wen , Wang Li-Shu 
Published: December 2016

Abstract
Background: Despite improved understanding of the pathophysiology of pancreatic ductal adenocarcinoma (PDAC) in the past two decades, PDAC has an extremely low 5-year survival rate (7%). However, diets rich in fruits and vegetables have been reported to reduce the risk of cancer development. We previously demonstrated that black raspberries (BRBs) have chemopreventive effects in human colorectal cancer patients and mouse models of colorectal cancer. Our current study aimed to investigate the potential effects of BRBs against PDAC in mice.
Methods: Mice that carry a constitutively activated KrasLSL.G12D/+ oncogene and loss-of-function Trp53LSL.R172H/+ tumor-suppressor gene in the pancreas (KrasLSL.G12D/+-Trp53LSL.R172H/+-Pdx-1-Cre) spontaneously develop PDAC that recapitulates the human PDAC. Four-week-old KrasLSL.G12D/+-Trp53LSL.R172H/+-Pdx-1-Cre mice were given a control diet or a control diet supplemented with 5% BRBs. In addition, luciferase-transfected human Panc-1 (Panc-1-Luc) cells were orthotopically injected into the pancreas of nonobese, diabetic, severe combined immunodeficient (NOD.SCID) mice. Four weeks after the inoculation of Panc-1-Luc cells, the NOD.SCID mice were given a control diet or a control diet supplemented with 5% BRBs for 6 weeks. Gross tumor volume of orthotopic pancreatic tumors was measured.
Results: The 4-week-old KrasLSL.G12D/+-Trp53LSL.R172H/+-Pdx-1-Cre mice developed pancreatic intraepithelial neoplasia (PanIN) lesions, which are the precancerous lesions of PDAC, and they were fed control or 5% BRB diet. Kaplan-Meier survival analysis showed that 5% BRBs significantly prolonged the survival of those PDAC mice with a median survival of 189 days versus 154 days for the mice fed the control diet. Molecular studies suggested that 5% BRBs suppress the Raf/MEK/ERK/STAT3 pathway, which is the downstream of Kras activation, and inhibit cancer cell proliferation in pancreatic tumor tissues. In addition, 5% BRBs significantly decreased the gross tumor volume of orthotopic tumors produced by injecting Panc-1-Luc cells into the pancreas. Orthotopic pancreatic tumors in BRB-treated NOD.SCID mice had a higher rate of apoptosis than tumors from mice fed the control diet.
Conclusions: These results support the hypothesis that BRBs have the clinical potential to delay pancreatic cancer progression by suppressing cancer cell proliferation and/or promoting apoptosis.
Citation Format: Pan Pan, Chad W. Skaer, Hsin-Tzu Wang, Susan Tsai, Kiyoko Oshima, Yi-Wen Huang, Li-Shu Wang.{Authors}. Black raspberries inhibit pancreatic carcinogenesis by suppressing Raf/MEK/ERK/STAT3 signaling pathways and promoting apoptosis. [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 B59.
Abstract B64: Using pancreatic organoids to infer therapeutic resistance and sensitivity
Authors: Tiriac Herve* , Ponz-Sarvise Mariano* , Corbo Vincenzo* , Frese Kristopher K.* , Engle Dannielle D.* , Ohlund Daniel , Oni Tobiloba , Hwang Chang-il , Handly-Santana Abram , Alagesan Brinda , Filippini Dea , Wright Kevin , Yu Kenneth H. , Park Youngkyu , Tuveson David A. 
Published: December 2016

Abstract
Pancreatic ductal adenocarcinoma (PDA) is a lethal disease with a 5-year survival rate less than 6%. The late diagnosis of the disease and poor efficacy of systemic treatments are major factors for this poor prognosis, and highlight the need for novel PDA models better able to predict resistance/sensitivity to treatment. To fulfill this need, our laboratory developed a three-dimensional culture system that enables the rapid growth of both mouse and human pancreatic ductal organoids. Organoids can be established from healthy or neoplastic tissues using both large (surgical material) and small (fine needle biopsy) samples, thereby providing a novel platform for therapeutic testing for all stages of disease. In this study, we use organoids to evaluate the therapeutic efficacy of the simultaneous inhibition of MEK and AKT kinases, which are activated in PDA by KRAS mutations. Tumor-derived organoids were resistant to both single agents and combination treatment. Genetically engineered mouse models of pancreatic cancer (KPC) also only exhibited a brief response to dual inhibition of MEK and AKT. To assess the potential mechanism of resistance, we evaluated the activation of a number of receptor tyrosine kinases by interrogating both mouse and organoid treated tissues. Members of the ERBB family were activated in KPC animals and tumor-derived organoids treated with both MEK and AKT inhibitors. Accordingly, the addition of an irreversible pan-ERBB inhibitor to the combination of MEK and AKT inhibitors, or MEK inhibitor alone, prevented ERBB-mediated resistance and improved tumor sensitivity to therapeutic intervention. This new therapeutic strategy is efficacious both ex-vivo and in vivo using human tumor-derived organoids and their associated transplant model. Finally, we show that human PDA organoids can be used in high throughput therapeutic screening for the identification of patient-specific therapeutic sensitivities. In summary, pancreatic organoids represent a system that can be used to predict drug sensitivity as well as to identify mechanism of resistance.
*Equal contribution
Citation Format: Herve Tiriac*, Mariano Ponz-Sarvise*, Vincenzo Corbo*, Kristopher K. Frese*, Dannielle D. Engle*, Daniel Ohlund, Tobiloba Oni, Chang-il Hwang, Abram Handly-Santana, Brinda Alagesan, Dea Filippini, Kevin Wright, Kenneth H. Yu, Youngkyu Park, David A. Tuveson.{Authors}. Using pancreatic organoids to infer therapeutic resistance and sensitivity. [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 B64.
Abstract B69: Tuft cell signaling can induce pancreatic inflammation and promote pancreatic ductal adenocarcinoma
Authors: Hoffman Megan T. , Gao Shan , Crawford Howard 
Published: December 2016

Abstract
The tuft cell is a chemosensory cell type that can interpret signals from luminal surfaces throughout the body in order to activate downstream effectors. One clear effector pathway of the tuft cell promotes a type-two immune response in the intestine after parasitic infection, suggesting that this cell population has the ability to communicate with the immune system. Furthermore, tuft cells have also been shown to activate sensory nerve fibers to lead to the production of a neuroinflammatory signal in the nasal epithelium. Therefore, tuft cells can promote effector inflammatory responses through direct immune cell signaling and through sensory nerve fibers. Pancreatic ductal adenocarcinoma (PDA) is characterized by a robust stromal reaction, a large component of which is composed of an immune response. It has been previously studied that this inflammatory response can function to promote both the initiation and progression of PDA. One mechanism by which inflammatory cells can be recruited to the pancreas is through neuroinflammatory pathways. Work with collaborators has shown that pancreatic sensory neurons are required for the progression of PDA, as ablation of this cell type significantly prolongs survival. Interestingly, tuft cells in the metaplastic pancreas have been shown to appear during transdifferentiation and progression to PDA. These tuft cells also possess key signaling elements that have the potential to mediate the response to extracellular signals, such as α-gustducin and TRPM5. Metaplastic tuft cells also produce the proteins necessary to make or release prostaglandins, acetylcholine and ATP, all of which can stimulate either a direct immunomodulatory signal or activate sensory nerve fibers. This leads us to hypothesize that tuft cells are a key mediator of signals to the stromal immune compartment and to sensory neurons in order to promote a robust immune response. In order to answer this question we are using chemosensory knockout animals to ablate critical signaling components of the chemosensory cascade to study the progression of PDA.
Citation Format: Megan T. Hoffman, Shan Gao, Howard Crawford.{Authors}. Tuft cell signaling can induce pancreatic inflammation and promote pancreatic ductal adenocarcinoma. [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 B69.
Abstract B70: RSPO2 Enhances Canonical Wnt Signaling to Confer Stemness-Associated Traits to Susceptible Pancreatic Cancer Cells
Authors: Ilmer Matthias , Wang Jing , Recio Alejandro , Werner Jens , Bazhin Alexandr , Alt Eckhard , Vykoukal Jody 
Published: December 2016

Abstract
Cancer stem cells (CSC) in pancreatic ductal adenocarcinomas (PDAC) present formidable challenges in the treatment of patients by escaping therapeutic intervention and seeding tumors through processes that remain incompletely understood. Here, we describe subpopulations of pancreatic cancer cells with high susceptibility to the recently described group of Wnt enhancer molecules, in particular R-Spondin 2 (RSPO2), which seem to drive primary and secondary pancreatic neoplasms.
PDAC cells responsive to RSPO2 stimuli upregulate canonical Wnt signaling activity as evidenced by Super-TOP/FOP luciferase assays and GFP-activity in cells transduced with a lentiviral Super-TOP-GFP reporter construct (7TGC). RSPO2-responsive cells (RSPO2pos) also possess properties indicative of CSCs, including tumor-initiating capacity and, more importantly, drug resistance in vivo. Cell populations with negligible Wnt activity preferentially express markers of differentiation. Furthermore, spontaneous response to extrinsic Wnt signals induced signaling networks comprising ERK1/2 and epithelial–mesenchymal transition (EMT) as shown by Western blot and RPPA analysis and led to a redistribution of Wnt enhancer receptors. In vivo, animals with RSPO2pos-derived tumors were bigger than RSPO2neg-derived tumors, harbored significantly more circulating tumor cells (CTCs), and higher number of exosomes in murine serum.
In this context, the latter findings suggest that RSPO2pos-cells could prepare secondary sites via exosomal priming and subsequently seed CSC-enriched CTCs for metastatic outgrowth at distant organs. RSPO2 gradients in the CSC niche might induce EMT for the developing CTCs. Hence, RSPO2 seems to play a prominent upstream role in regulating these interplays in the tumor and metastatic microenvironment.
In conclusion, our studies reveal adaptive aspects of pancreatic cancer stemness arising from populations of CSCs that misappropriate functional and responsive elements of archetypical self-renewal pathways. Blocking RSPO2-induced signaling pathways in conjunction with established chemotherapy could provide means to disrupt dynamic CSC processes and present novel therapeutic strategies for patients with PDAC.
Citation Format: Matthias Ilmer, Jing Wang, Alejandro Recio, Jens Werner, Alexandr Bazhin, Eckhard Alt, Jody Vykoukal.{Authors}. RSPO2 Enhances Canonical Wnt Signaling to Confer Stemness-Associated Traits to Susceptible 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 B70.