bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A65: Initiation of pancreatic metaplasia requires ADAM17-mediated autocrine signaling, not paracrine signaling derived from macrophages
Authors: Wen Hui-Ju , Crawford Howard C. 
Published: December 2016

Abstract
Acinar-to-ductal metaplasia (ADM) has been frequently seen in the damaged pancreatic tissues. It is also associated with PanIN lesions in PDAC samples derived from human and mouse and has been shown to act as a preneoplastic lesion in mice. Therefore, understanding the mechanisms of lesion formation at the earliest phase would provide needed information for studying pancreatic tumorigenesis. Previously, we have shown that EGFR activity is required for metaplastic duct formation and KRas-induced pancreatic tumorigenesis. In addition, a prominent macrophage infiltration has been shown to be important in the early phase of lesion formation. To investigate the origin of EGFR ligands for EGFR activation during ADM formation in vivo, we examined the metaplasia formation by administration of cerulein in the mice with the conditional knockout of a key EGFR ligand sheddase ADAM17 in the pancreas (ADAM17fl/fl;Ptf1aCre/+) or in the myeloid cells (ADAM17fl/fl;LysM-Cre). With 2 weeks cerulein treatment, wild type and ADAM17fl/fl;LysM-Cre mice showed a similar degree of metaplastic and fibrotic response. However, the mice with ADAM17-null pancreas displayed significant protection from chronic pancreatitis induced by cerulein, including a lack of significant macrophage infiltration, making the analysis of any additional contribution from macrophage derived EGFR ligands. To remedy this, we conditionally knocked out HB-EGF (Heparin-binding EGF-like growth factor) one of the most robustly expressed EGFR ligands in macrophages using LysM-Cre. We examined cerulein-induced metaplasia in HB-EGFfl/fl;LysM-Cre mice. Compared to wild type mice, HB-EGFfl/fl;LysM-Cre mice showed a similar degree of metaplastic and fibrotic response and a decrease in cell proliferation; moreover, myeloid cell-specific ablation of HB-EGF dramatically delayed the healing and the restoration of normal pancreatic epithelium after cessation of cerulein treatment. These results indicate that an ADAM17/EGFR ligand/EGFR autocrine loop derived from pancreatic parenchymal cells is required for metaplastic duct formation, and macrophage-derived HBEGF acting in a paracrine fashion contributes to cell survival and tissue remodeling.
Citation Format: Hui-Ju Wen, Howard C. Crawford.{Authors}. Initiation of pancreatic metaplasia requires ADAM17-mediated autocrine signaling, not paracrine signaling derived from macrophages. [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 A65.
Abstract A68: Oncogenic Kras prevents myeloid cell-mediated pancreatic tissue repair
Authors: Zhang Yaqing , Yan Wei , Mathew Esha , Kane Kevin T. , Magliano Marina Pasca di 
Published: December 2016

Abstract
The iKras* mouse model of pancreatic cancer allows inducible and reversible expression of oncogenic Kras, and is thus perfectly suited to determine the role of Kras at different stages of carcinogenesis. KRAS has emerged as a targeted interest for study by the NCI; elucidating Kras-dependent signaling pathways and understanding the role of epithelial cells harboring oncogenic Kras in modulating essential components of the tumor microenvironment will provide new opportunities to attack KRAS driven cancers.
Using this model, we have demonstrated that, in addition to epithelial changes, the accumulation of a fibro-inflammatory stroma is continuously dependent on oncogenic Kras. Pancreatic Intraepithelial Neoplasia (PanIN), the precursor lesion to pancreatic cancer, is characterized by the accumulation of a fibro-inflammatory stroma rich in myeloid cell infiltrates. Here, we generated p48Cre; TetO-KrasG12D; Rosa26rtTa-IRES-EGFP; CD11b-diphtheria toxin (DT) receptor (iKras*;CD11b-DTR) mice that allow us to deplete myeloid cells during the onset and progression of PanINs. We show that myelois infiltration and polarization is dependent on oncogenic Kras both during the initiation and the progression of PanINs. Furthermore, signals derived from oncogenic Kras–expressing cells regulate the polarization of myeloid cells, maintaining them in a pro-tumor status. We show that myeloid cells are required for the initiation and progression of pancreatic cancer precursor lesions by regulating the inflammatory microenvironment and the extracellular matrix (ECM) deposition in pancreatic neoplasia. Inactivation of oncogenic Kras leads to a change in polarization of myeloid cells, which take on a pro-repair phenotype. Finally, by ablating myeloid cells upon inactivation of oncogenic Kras we show that pro-repair myeloid cells are required for pancreas remodeling and repair by regulating ECM degradation and epithelial cell survival involving activation of multiple signaling pathways in both stromal and epithelial compartments. Thus, the interplay between epithelial cells expressing oncogenic Kras and myeloid cells determines the balance between carcinogenesis and tissue remodeling, a finding that could be exploited to favor repair at the expense of tumor progression.
Citation Format: Yaqing Zhang, Wei Yan, Esha Mathew, Kevin T. Kane, Marina Pasca di Magliano.{Authors}. Oncogenic Kras prevents myeloid cell-mediated pancreatic tissue repair. [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 A68.
Abstract A85: Metabolic wiring dictates GOT1 dependency in pancreatic cancer
Authors: Lyssiotis Costas A. 
Published: December 2016

Abstract
Pancreatic Ductal Adenocarcinoma (PDA) is an extremely aggressive disease. The 5-year survival rate is a shockingly low 8%, a number that has hardly increased in the last 30 years. This owes in large part to the fact that effective treatment options for PDA do not exist. A hallmark of pancreatic cancers, and one that contributes to this resistance, is the metabolic environments that they create locally and systemically. Pancreatic tumors exist in a highly inflammatory environment, are under severe physical and oxidative stress, and do not have functional vasculature to deliver oxygen and nutrients. Despite these unfavorable circumstances for growth, these tumors thrive. Clearly metabolism is rewired in unique ways to facilitate survival and growth in this unusual and hostile environment. Based on this framework, we have been mapping the metabolic pathways in PDA to identify aspects of metabolism that are unique or highly over-utilized.
Previously, we defined a novel pathway used by PDA cells to maintain redox balance via NADPH generation. Inhibition of a central enzyme in this pathway, cytosolic aspartate aminotransferase (GOT1), dramatically impairs growth in vitro and in vivo. Importantly, these effects can be completely reversed by supplying PDA cells with antioxidants. We also found that this pathway is regulated by mutant KRAS in PDA and, accordingly, non-transformed pancreatic epithelial cells are unresponsive to GOT1 inhibition. Subsequently, we interrogated GOT1 dependence in another KRAS transformed cancer, colon cancer, and found that they, like non-transformed cells, do not respond to GOT1 inhibition. Through a detailed series of metabolomics and functional assays, we ultimately found that colon cancers bypass GOT1 dependence favoring flux through ATP citrate lyase (ACL), a mechanism dictated not at the transcriptional level but by the metabolic wiring in these cells. Furthermore, ACL knockdown dramatically sensitizes colon cancer cells to GOT1 inhibition mediated redox and growth defects. In addition to revealing novel aspects of tissue specific metabolic pathway regulation, this analysis also illustrated novel metabolic dependencies that can be exploited for therapeutic gain.
Citation Format: Costas A. Lyssiotis.{Authors}. Metabolic wiring dictates GOT1 dependency 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 A85.
Abstract A88: The synthetic triterpenoid CDDO-Imidazolide reduces immune cell infiltration and cytokine secretion in the KC mouse model of pancreatic cancer
Authors: Leal Ana Sofia , Sporn Michael B. , Pioli Patricia A. , Liby Karen T. 
Published: December 2016

Abstract
Survival rates for pancreatic cancer remain at 7-8%, and as the incidence and deaths are expected to increase, new drugs are needed for the prevention and treatment of this devastating disease. LSL-KrasG12D/+;Pdx-1-Cre (KC) mice replicate the genetics, symptoms and histopathology found in human pancreatic cancer. Immune cells infiltrate into the pancreas of these mice and produce inflammatory cytokines that promote tumor growth. This process can be accelerated with the administration of lipopolysaccharide (LPS) or caerulein so KC mice at 9 weeks of age were injected once a week for 4 weeks with LPS (4mg/kg). One or four weeks after the LPS injections, plasma, pancreas and spleens were collected. KC mice were particularly sensitive to the effects of LPS, as only 48% of the KC mice survived an LPS challenge while 100% of wildtype (WT) mice survived. Survival was increased when KC mice were pre-treated with the triterpenoid CDDO-Imidazolide (CDDO-Im) (71% survival). LPS increased the percentage of CD45+ immune cells in the pancreas and immunosuppressive Gr1+ myeloid derived suppressor cells (MDSC) in the spleen of KC mice. In contrast, CDDO-Im decreased the infiltration of CD45+ cells into the pancreas and the percentage of Gr1+ MDSC in the spleen of KC mice challenged with LPS. Levels of inflammatory cytokine levels also were markedly higher in KC mice vs. WT mice challenged with LPS. Pre-treatment with CDDO-Im decreased the production of IL-6, CCL-2, VEGF, and G-CSF in the KC mice. These cytokines are prognostic markers in pancreatic cancer or play important roles in the progression of this disease. Disrupting inflammation during tumorigenesis with drugs such as CDDO-Im might be useful for preventing pancreatic cancer, especially in high risk populations.
Citation Format: Ana Sofia Leal, Michael B. Sporn, Patricia A. Pioli, Karen T. Liby.{Authors}. The synthetic triterpenoid CDDO-Imidazolide reduces immune cell infiltration and cytokine secretion in the KC mouse model of 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 A88.
Abstract B04: NRF2 regulates serine biosynthesis in pancreatic ductal adenocarcinoma
Authors: DeNicola Gina M. , Chen Pei-Hsuan , Mullarky Edouard , Chio Christine , Asara John M. , Minna John D. , Tuveson David A. , DeBerardinis Ralph J. , Cantley Lewis C. 
Published: December 2016

Abstract
Tumors have high energetic and anabolic needs for rapid growth and proliferation, and the serine biosynthetic pathway has recently been identified as an important source of metabolic intermediates for these processes. We recently demonstrated that a substantial fraction of NSCLC cell lines displayed significant serine/glycine biosynthetic activity due to KEAP1 and NRF2 mutations (DeNicola et al. Nature Genetics 2015). We demonstrated that NRF2 regulates glucose flux to serine by controlling transcription of serine biosynthetic genes through the transcription factor ATF4. Importantly, elevated expression of these genes conferred poor prognosis in human NSCLC. Thus, a substantial fraction of human NSCLC activates an NRF2-dependent transcriptional network that regulates serine and glycine metabolism and is linked to clinical aggressiveness.
Pancreatic ductal adenocarcinoma (PDAC) also demonstrates high NRF2 activity due to mutations in KRAS and high MAPK signaling (DeNicola et al. Nature 2011). We demonstrate that serine biosynthesis enzyme expression is elevated in a mouse model of PDAC and that NRF2 regulates PHGDH expression in human PDAC cell lines. Furthermore, PDAC cell lines are resistant to serine starvation. PHGDH knockdown impairs the growth of tumor organoid orthotopic transplants, and the role of PHGDH in tumor maintenance is currently being investigated. These results suggest that the serine biosynthesis pathway is regulated by NRF2 in multiple cancers and may be an important therapeutic target.
Citation Format: Gina M. DeNicola, Pei-Hsuan Chen, Edouard Mullarky, Christine Chio, John M. Asara, John D. Minna, David A. Tuveson, Ralph J. DeBerardinis, Lewis C. Cantley.{Authors}. NRF2 regulates serine biosynthesis in 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 B04.
Abstract B11: Development of orthotopically grafted organoid models to study pancreatic cancer progression
Authors: Hwang Chang-Il , Lee EunJung , Oni Tobiloba , Park Youngkyu , Tuveson David A. 
Published: December 2016

Abstract
Pancreatic ductal adenocarcinoma (PDA) is one of the most difficult human malignancies to treat. The 5-year survival rate of PDA patients is 7% and PDA is predicted to become the second leading cancer-related cause of death in the USA. A subset of potential tumor suppressor (Ts) genes was identified by genome-wide analysis of human PDA and insertional mutagenesis in genetically engineered mouse models (GEMMs). Since the functional validation of these genes in GEMMs is time-consuming and labor-intensive, we have developed a rapid and efficient “orthotopically grafted organoid’ (OGO) models in conjunction with RNAi and CRISPR/Cas9 technology to study PDA progression. Previously, we showed that OGO model represents the full spectrum of PDA progression in vivo upon orthotopic engraftment. Here, as a proof-of-concept experiment, we demonstrate that ablation of Trp53 by shRNA or gRNA in PanIN-derived organoids accelerates PDA progression upon transplantation. Therefore, OGO models should provide an excellent platform to study the functional role of genes in PDA progression in vivo.
Note: This abstract was not presented at the conference.
Citation Format: Chang-Il Hwang, EunJung Lee, Tobiloba Oni, Youngkyu Park, David A. Tuveson.{Authors}. Development of orthotopically grafted organoid models to study pancreatic cancer progression. [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 B11.
Abstract B17: BET inhibitors block pancreatic stellate cell collagen production and attenuate fibrosis in vivo
Authors: Kumar Krishan , DeCant Brian , Hattaway Hattaway Z. , Grippo Paul J. , Bentrem David J. , Ebine Kazumi , Munshi Hidayatullah G. 
Published: December 2016

Abstract
The fibrotic reaction, which can account for over 70% of the tumor mass, is a characteristic feature of the majority of human pancreatic ductal adenocarcinoma (PDAC) tumors. It is associated with proliferation of pancreatic stellate cells (PSCs), which are key regulators of collagen production and fibrosis in vivo. In this report we show that bromodomain-containing protein 4 (BRD4), a member of bromodomain and extraterminal (BET) family of proteins, is expressed in activated PSCs in human PDAC tumors. We also show that BET inhibitors and specific targeting of BRD4, in contrast to targeting of BRD2 and BRD3, decrease collagen production by primary PSCs isolated from human PDAC tumors. While BET inhibitors do not induce apoptosis of primary PSCs or affect α-SMA expression, BET inhibitors disrupt α-SMA filament organization in stellate cells. Additionally, BET inhibitors attenuate stellate cell activation, fibrosis and collagen production in vivo in a Kras mouse model of pancreatic tumorigenesis. Our results demonstrate that BET inhibitors regulate fibrosis partly by modulating PSC activation and function.
Citation Format: Krishan Kumar, Brian DeCant, Hattaway Z. Hattaway, Paul J. Grippo, David J. Bentrem, Kazumi Ebine, Hidayatullah G. Munshi.{Authors}. BET inhibitors block pancreatic stellate cell collagen production and attenuate fibrosis in vivo. [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 B17.
Abstract B31: The MUC4 oncomucin mediates resistance of human pancreatic cancer cells to FOLFIRINOX drugs
Authors: Skrypek Nicolas , Boukrout Nihad , Lahdaoui Fatima , Schulz Céline , Vasseur Romain , Duchêne Belinda , Seuningen Isabelle Van , Jonckheere Nicolas 
Published: December 2016

Abstract
Introduction: Pancreatic adenocarcinoma (PDAC) is one of the most deadly cancers in western countries with an extremely poor prognosis because of a lack of efficient therapeutic tools. Gemcitabine, a fluorinated analog of deoxycytidine, is the main chemotherapy in PDAC, but survival remains poor. FOLFIRINOX, a more aggressive protocol combining 5-fluorouracil (5-FU), irinotecan/SN-38, oxaliplatin and leucovorin, emerged as a new option in patients with metastatic pancreatic cancer. MUC4 is a membrane-bound oncomucin involved in pancreatic cancer (PC) pathogenesis and chemoresistance to gemcitabine. MUC4 is not expressed in healthy pancreas whereas its expression increases constantly during carcinogenetic progression. In this work, we aimed to decipher the involvement of MUC4 and associated cellular mechanisms in chemoresistance to FOLFIRINOX drugs.
Material and Methods: MUC4 expression was knocked down (KD) by stable ShRNA in CAPAN-1/-2 PC cells. IC50 and cell viability to FOLFIRINOX drugs were determined by tetrazolium salt (MTT) assays. Expression of genes involved in drug metabolism was assessed by quantitative RT-PCR (qRT-PCR) and Western blot. MiRnomes of Mock and MUC4-KD cells were determined using miRNA array (8x15K Agilent).
Results: MUC4 depletion in PC cells leads to an increase of sensitivity to 5-FU and to an increased resistance to oxaliplatin. Combined treatments of 5-FU and oxaliplatin (FOX) lead to an intermediate survival rate suggesting additional effects. This altered chemosensitivity is associated with an altered expression of drug transporters/channels and drug metabolism actors. Notably, an increase of CTR1 and ATP7B transporters and DPYD enzyme was observed in MUC4-KD cells. Furthermore, we have observed downregulation of miR-96-5p, miR-132-3p and miR-210 suggesting a possible link between MUC4 expression, drug resistance and regulation by miRNAs. The involvement of these molecules is currently validated by transient RNA interference and miRNA transfections.
Conclusion: this work led to the identification of proteins and miRNAs specifically involved in priming PC chemoresistance. These factors may represent critical therapeutic targets and also robust prognostic/predictive markers, and thus provide better healthcare and management of PC patients.
Citation Format: Nicolas Skrypek, Nihad Boukrout, Fatima Lahdaoui, Céline Schulz, Romain Vasseur, Belinda Duchêne, Isabelle Van Seuningen, Nicolas Jonckheere.{Authors}. The MUC4 oncomucin mediates resistance of human pancreatic cancer cells to FOLFIRINOX drugs. [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 B31.
Abstract B37: Mesothelin-targeted immunotoxin RG7787 (LMB-100) preferentially depletes secreted proteins and short-lived intracellular proteins to augment tumor cell killing by taxanes
Authors: Alewine Christine , Landsman Rebekah , Rudloff Michael , Kolyvas Emily , Chen Jinqiu , Pastan Ira 
Published: December 2016

Abstract
Mesothelin (MSLN) is a cell surface antigen expressed by a number of solid tumors including most pancreatic adenocarcinomas. RG7787 is a MSLN-targeted immunotoxin that is entering clinical testing for patients with advanced pancreatic cancer. RG7787 binds to MSLN on the cancer cell surface through a high affinity Fab and delivers a modified Pseudomonas exotoxin A (PE) payload into the cell cytosol. PE induces apoptosis by catalyzing the irreversible modification and inactivation of elongation factor-2 (EF-2), halting protein synthesis. This is a novel mechanism of action which produces synergistic tumor killing in combination with nab-paclitaxel in preclinical mouse models and in cell culture. Our goal is to understand the mechanism of this interaction. We have previously demonstrated that taxane does not increase delivery of RG7787 to tumors grown in mice and that taxane does not augment protein synthesis inhibition caused by RG7787. We hypothesized that RG7787 should deplete levels of secreted proteins and short-lived intracellular proteins and that insufficiencies of these factors may enhance taxane-mediated killing. To examine the effect of RG7787 on the pancreatic cancer secretome, we treated pancreatic cancer cells grown in culture or mice bearing tumor xenografts with RG7787 and used ELISA to examine levels of secreted proteins in conditioned medium and interstitial tumor fluid. We found that RG7787 treatment causes dose-dependent decreases in secreted proteins even at non-lethal doses. To demonstrate proof of principle that short-lived proteins are preferentially depleted, we created a reporter cell line co-expressing both GFP and a destabilized fluorescent Cherry protein (Cherry-PEST). We found that treatment with RG7787 reduced the levels of Cherry-PEST but not GFP in a dose-dependent fashion confirming our hypothesis. Consistent with this, we found that levels of the short-lived Bcl-2 family survival factor Mcl-1 are reduced in cells treated with the combination of RG7787 and taxane compared to taxane treatment alone. We conclude that RG7787 depletion of Mcl-1 primes cells for killing by taxane. We are now testing the combination of RG7787 (LMB-100) with nab-paclitaxel in a Phase IB/II trial for patients with pancreatic cancer.
Citation Format: Christine Alewine, Rebekah Landsman, Michael Rudloff, Emily Kolyvas, Jinqiu Chen, Ira Pastan.{Authors}. Mesothelin-targeted immunotoxin RG7787 (LMB-100) preferentially depletes secreted proteins and short-lived intracellular proteins to augment tumor cell killing by taxanes. [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 B37.