bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A24: Gene expression along the glycolysis-cholesterol synthesis axis and outcome in pancreatic cancer
Authors: Karasinska Joanna M. , Topham James T. , Kalloger Steve E. , Jang Gun Ho , Denroche Robert E. , Culibrk Luka , Williamson Laura M. , Wong Hui-li , Lee Michael K.C. , O'Kane Grainne M. , Moore Richard A. , Mungall Andrew J. , Moore Malcolm J. , Warren Cassia , Metcalfe Andrew , Notta Faiyaz , Knox Jennifer J. , Gallinger Steven , Laskin Janessa , Marra Marco A. , Jones Steven J.M. , Renouf Daniel J. , Schaeffer David F. 
Published: March 2020

Abstract
Reprogramming of metabolic pathways allows cancer cells to survive and thrive in the tumor microenvironment. Glycolysis-inducing factors including oncogenic KRAS mutations, loss of function in TP53 and hypoxia are prevalent in PDAC. Cholesterol and its metabolites support tumor cell growth and the mevalonate pathway, which uses glycolysis products for de novo cholesterol synthesis, has been found to be upregulated in cancer. However, whether intertumoral heterogeneity in these metabolic networks influences outcome in pancreatic cancer has not been well established. We profiled the expression of glycolytic and cholesterogenic genes in 325 resected and metastatic pancreatic ductal adenocarcinoma (PDAC) tumors and identified four distinct subgroups: quiescent, glycolytic, cholesterogenic, and mixed. Glycolytic tumors were associated with the shortest median survival in resectable and metastatic disease settings. Patients with cholesterogenic tumors had the longest median survival. KRAS and MYC amplified tumors had higher expression of glycolytic genes than tumors with normal or lost copies of these oncogenes. The mitochondrial uptake of pyruvate, the end product of glycolysis, facilitates the generation of acetyl-CoA for cholesterol synthesis. PDAC tumors with a glycolytic gene signature had the lowest expression of mitochondrial pyruvate carriers MPC1 and MPC2. Glycolytic and cholesterogenic gene expression correlated with the expression of reported prognostic PDAC subtype classifier genes. Our results indicate that PDAC tumors have unique metabolic profiles that influence disease outcome and provide functional correlate to previously identified subtypes. The findings also raise the possibility of a shift in balance between the glycolytic and cholesterogenic pathways as a factor in PDAC progression and a potential target for therapy.
Citation Format: Joanna M. Karasinska, James T. Topham, Steve E. Kalloger, Gun Ho Jang, Robert E. Denroche, Luka Culibrk, Laura M. Williamson, Hui-li Wong, Michael K.C. Lee, Grainne M. O'Kane, Richard A. Moore, Andrew J. Mungall, Malcolm J. Moore, Cassia Warren, Andrew Metcalfe, Faiyaz Notta, Jennifer J. Knox, Steven Gallinger, Janessa Laskin, Marco A. Marra, Steven J.M. Jones, Daniel J. Renouf, David F. Schaeffer. Gene expression along the glycolysis-cholesterol synthesis axis and outcome in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr A24.
Abstract A29: Bicompartmental regulation of disease-related gene networks by histone deacetylase inhibition curbs pancreatic cancer progression
Authors: Liang Gaoyang , Hah Nasun , Shi Yu , Truitt Morgan L. , Antal Corina E. , Atkins Annette R. , Fraser Cory , Banayo Ester , Bashi Senada , Dai Yang , Sherman Mara , Liddle Christopher , Yu Ruth T. , Hunter Tony , Han Haiyong , Hoff Daniel D. Von , Downes Michael , Evans Ronald M. 
Published: March 2020

Abstract
A challenge for effective pancreatic ductal adenocarcinoma (PDAC) therapy is to target the aggressive neoplasm that is shrouded by the dense fibrotic stroma. Epigenetic modulation has the potential to regulate genes or gene networks causing disease phenotypes. Here we show that the HDAC inhibitor entinostat (Ent) provides therapeutic benefits by regulating the gene networks important for PDAC in both the stromal and epithelial compartments. While an HDAC inhibitor is anticipated to broadly open chromatin and activate genes, in stromal pancreatic stellate cells (PSCs), Ent unexpectedly restricts chromatin accessibility on and represses the gene networks essential for PSC activation, leading to proliferation arrest and reduced myofibroblast properties, including lower production of extracellular matrix and inflammatory and protumorigenic cytokines. Furthermore, Ent also attenuates the transcriptional responses of cancer-associated fibroblasts (CAFs) to injury-related cytokines from the tumor microenvironment including TGF-beta and TNF-alpha. In the neoplastic epithelium, Ent induces cytostasis and de novo vulnerability in DNA repair pathways by systematically suppressing cell cycle and DNA repair genes. Notably, the bicompartmental effects of Ent were found to arrest cancer progression, prolong survival, and synergize with DNA damage-inducing agent cisplatin in genetically engineered mouse model (GEMM) of PDAC. Overall, our study not only establishes Ent as a novel therapeutic agent for PDAC but also reveals the mechanisms underlying its benefits.
Citation Format: Gaoyang Liang, Nasun Hah, Yu Shi, Morgan L. Truitt, Corina E. Antal, Annette R. Atkins, Cory Fraser, Ester Banayo, Senada Bashi, Yang Dai, Mara Sherman, Christopher Liddle, Ruth T. Yu, Tony Hunter, Haiyong Han, Daniel D. Von Hoff, Michael Downes, Ronald M. Evans. Bicompartmental regulation of disease-related gene networks by histone deacetylase inhibition curbs pancreatic cancer progression [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr A29.
Abstract A42: Single-cell RNA-seq analysis of human pancreatic ductal adenocarcinoma identifies a novel cell type expressing the intestinal stem cell marker OLFM4
Authors: Rao Manisha , Nemajerova Alice , Li Jinyu , Gao Mei , Oh Ki , Moffit Richard , Kim Joseph , Georgakis George , Sasson Aaron , Bialkowkska Agnieszka , Powers Scott 
Published: March 2020

Abstract
Pancreatic ductal adenomcarcinoma (PDAC) is one of the most lethal forms of cancer with a 5-year survival rate of 8%. To determine the composition of different cell types in PDAC, we performed single-cell RNA-sequencing (scRNA-seq) analysis of two resected patient tumors. Nine distinct cell types were identified: (1) ductal carcinoma cells expressing mutant KRAS, (2) normal pancreatic islet cells, (3) B-lymphocytes, (4) macrophages, (5) mast cells, (6) nerve cells, (7-8) two types of cancer-associated fibroblasts (CAFs), and (9) a previously unidentified epithelial type with distinctly high expression of OLFM4 and CRISP3. Histologic analysis of human PDAC and chronic pancreatitis (CP) tissue sections confirmed the presence of this distinct cell type and furthermore demonstrated that it corresponded to inflamed/injured ducts and early pancreatic intraepithelial neoplasms (PanINs) but that actual PDACs did not express OLFM4. CRISP3 was not always expressed in this new cell type, but the expression of OLFM4 was always detected in these histologic structures. This distinct pancreatic epithelial cell type was also observed in mouse models for chronic pancreatitis and in mutant-KRAS induced PanINs. We hypothesize that inflammation-induced OLFM4 expression helps drive PanIN formation, and that its expression could be exploited for early PDAC detection. We are currently performing functional studies using organoids to address the role that OLFM4 might play in generation of this distinct cell type.
Citation Format: Manisha Rao, Alice Nemajerova, Jinyu Li, Mei Gao, Ki Oh, Richard Moffit, Joseph Kim, George Georgakis, Aaron Sasson, Agnieszka Bialkowkska, Scott Powers. Single-cell RNA-seq analysis of human pancreatic ductal adenocarcinoma identifies a novel cell type expressing the intestinal stem cell marker OLFM4 [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr A42.
Abstract A48: Genetic ablation of microRNA-21 profoundly remodels stroma and shortens survival of K-Ras-driven pancreatic cancer mouse models
Authors: Schipper Josh , Beddows Ian , Kiupel Matti , Conejo-Garcia Jose , Sempere Lorenzo 
Published: March 2020

Abstract
The tumor microenvironment of pancreatic cancer adenocarcinoma (PDAC) is highly desmoplastic with distinct tumor-restraining and tumor-promoting fibroblast subpopulations. Re-education rather than indiscriminate elimination of these fibroblasts has emerged as a new strategy for combination therapy. Here, we studied global loss of profibrotic noncoding regulatory microRNA-21 (miR-21) in K-Ras-driven genetically engineered mouse models of PDAC. We generated mouse strains carrying wild-type or knockout alleles of Mir-21 in a well-characterized K-Ras-driven, p53-deleted PDAC model (LSL-KrasG12D; p53lox/+;Pdx1-Cre, KPC). Even though miR-21 expression was upregulated in cancer cells and cancer-associated fibroblasts in KPC tumors, global loss of miR-21 activity did not inhibit tumor growth. Strikingly, loss of miR-21 accelerated tumor initiation via mucinous cystic neoplastic lesions and progression to locally advanced invasive carcinoma from which animals precipitously succumbed at an early age. We uncovered a cell-autonomous requirement of miR-21 activity for induction of tumor-restraining myofibroblasts, whose absence led to a profound remodeling of the stroma and massive infiltrate of tumor-permissive immune cells. Low miR-21 expression negatively correlated with a fibroblast gene expression signature and positively with an immune cell gene expression signature in TCGA PDAC data set (n = 156) mirroring findings in genetic models. In vitro and in vivo isograft experiments showed that miR-21 activity was dispensable for cancer cell growth but required for complete execution of TGF-b-mediated programs. Our results suggest that modulation of miR-21 activity may provide a novel therapeutic opportunity to affect the composition of fibroblast subpopulations and enhance current chemotherapy and/or immunotherapy treatments.
Citation Format: Josh Schipper, Ian Beddows, Matti Kiupel, Jose Conejo-Garcia, Lorenzo Sempere. Genetic ablation of microRNA-21 profoundly remodels stroma and shortens survival of K-Ras-driven pancreatic cancer mouse models [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr A48.
Abstract A51: Using single-cell gene expression profiles to determine the cellular landscape of pancreatic ductal adenocarcinoma
Authors: Sirihorachai Veerin R. , Kemp Samantha B. , Magliano Marina Pasca Di 
Published: March 2020

Abstract
A key feature of pancreatic cancer is the extensive fibroinflammatory stroma that constitutes the bulk of the tumor volume. The stroma includes fibroblasts, extracellular matrix, and abundant infiltrating immune cells. The latter are largely suppressive immune cells, including regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages. Data from our laboratory and many others show that immune cells are a key determinant of pancreatic cancer progression and metastasis. Previous data from the lab showed that the immune infiltration in the pancreas is regulated by signals deriving from oncogenic Kras-expressing epithelial cells. We tested the hypothesis that oncogenic Kras, through activation of its effector pathway MAPK/ERK, directly regulates the accumulation of suppressive myeloid and lymphoid cells at the premetastatic niche. We used a doxycycline-inducible, reversible iKras* cell line derived from genetically engineered mouse model to modulate expression of Kras in orthotopically implanted tumors. We used the 10X Genomics platform for single-cell RNAseq to distinguish populations of cells collected from the tumors in both the Kras-On and Kras-Off groups at single-cell resolution. Using the Seurat R package, we analyzed the data from the two groups using unsupervised clustering methods to define clusters of cells based on their gene expression data. We then broadly defined these populations using cell type-specific gene expression patterns. Our next step is to define subpopulations of cells on which we can perform differential expression analyses to determine the changes in gene expression between the Kras-On and Kras-Off groups.
Citation Format: Veerin R. Sirihorachai, Samantha B. Kemp, Marina Pasca Di Magliano. Using single-cell gene expression profiles to determine the cellular landscape of pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr A51.
Abstract B02: Tissue-specific innate lymphoid cells are novel targets for pancreatic cancer immunotherapy
Authors: Leung Joanne , Rojas Luis A , Ruan Jennifer , Zhao Julia , Gasmi Billel , Sethna Zachary , Ramnarain Anita , Bhanot Umesh , Askan Gokce , Gururajan Murali , Elyada Ela , Park Youngkyu , Tuveson David A. , Gonen Mithat , Leach Steven D. , Wolchok Jedd D. , DeMatteo Ronald P. , Merghoub Taha , Balachandran Vinod P. , Moral John Alec 
Published: March 2020

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the classic cold tumor, with few tumor-infiltrating activated CD8+ T cells, a major barrier to immunotherapy. Strategies to convert cold PDACs to hot can enable more effective immunotherapies. To identify targets that can convert cold PDACs to hot, we compared a large cohort of rare long-term PDAC survivors with hot tumors to short-term survivors with cold tumors. Surprisingly, hot PDACs were enriched not only in activated CD8+ T cells, but also in group-2 innate lymphoid cells (ILC2s), a class of largely tissue-resident, cytokine-producing innate lymphocyte that potentiates T cell immunity in local tissues. We identified that tumor ILC2s (TILC2s) infiltrate human and mouse PDACs, and TILC2 frequency and tumor expression of the ILC2-activating ligand interleukin (IL)-33 positively correlate with tumor immune cytolytic activity, and long-term patient survival. Using PDAC mouse models, we discovered that the IL33-ILC2 axis activates pancreatic tissue-specific antitumor T-cell immunity. Host IL33 deficiency attenuated TILC2 expansion and CD8+ T-cell activation, accelerating tumor growth in orthotopic PDACs but not heterotopic skin implanted PDACs where TILC2s lack the IL33 receptor. Acute ILC2 depletion partially phenocopied the tissue-specific phenotype of IL33 deficiency, with impaired rejection of immunogenic orthotopic but not heterotopic skin PDACs. Treatment with recombinant IL33 (rIL33), but not with the ILC1-activating ligand rIL18, increased TILC2 frequencies, activated CD8+ T cells, and abrogated orthotopic but not heterotopic PDAC establishment in &gt;70% of mice. Taken together, these studies identify ILC2s as novel anticancer immune cells for PDAC immunotherapy. Strategies to activate tissue-specific ILC2s may be a promising immunotherapeutic approach for PDAC.
Citation Format: Joanne Leung, Luis A Rojas, Jennifer Ruan, Julia Zhao, Billel Gasmi, Zachary Sethna, Anita Ramnarain, Umesh Bhanot, Gokce Askan, Murali Gururajan, Ela Elyada, Youngkyu Park, David A. Tuveson, Mithat Gonen, Steven D. Leach, Jedd D. Wolchok, Ronald P. DeMatteo, Taha Merghoub, Vinod P. Balachandran, John Alec Moral. Tissue-specific innate lymphoid cells are novel targets for pancreatic cancer immunotherapy [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr B02.
Abstract B03: Targeting tumor-intrinsic metabolic node in pancreatic cancer causes tumor regression, remodels extracellular matrix, and sensitizes to anti-PD1 therapy
Authors: Sharma Nikita S. , Gupta Vineet K. , Garrido Vanessa , Hadad Roey , Durden Brittany , Kesh Kousik , Ferrantella Anthony , Giri Bhuwan , Dudeja Vikas , Saluja Ashok , Banerjee Sulagna 
Published: March 2020

Abstract
Background: Pancreatic adenocarcinoma (PDAC) is an extremely immunosuppressive and heterogenous neoplasm for which immune checkpoint inhibitor therapy has not been very successful. Hexosamine biosynthesis pathway (HBP), a shunt pathway of glycolysis, is a metabolic node in cancer cells that can promote survival pathways on one hand and also influence the extracellular matrix in the tumor microenvironment. Our study aims to sensitize pancreatic cancer to anti PD-1 therapy by targeting the HBP pathway.
Methods: 6-Diazo-5-oxo L-norleucine or DON was used as a GFAT inhibitor. Tetracycline-inducible GFAT knockout cell lines were made using S2-VP10 as the parent cell line.
Results: High-dose monotherapy of DON (1mg/kg/3days a week) caused significant decrease in tumor volume in immunocompetent KPC mice along with significant reduction in metastasis and circulating tumor cells. Circulating tumor cells (CTCs) were also found to be significantly reduced in DON-treated mice as compared to control, leading to reduced metastasis. Combination of low-dose DON (0.5mg/kg/3 days a week) with low-dose anti PD-1 (100 μgX3 times) caused an impressive reduction in tumor volume along with an increase in survival in KPC tumor-bearing mice. Flow-based analysis of tumor cells show a significant influx of CD8+ T cells along with an increase in M1 polarization of macrophages. Survival study of CD8 knockout mice (CD8KO), orthotopically implanted with KPC and fibroblast cells, show that at low doses DON loses its anticancer effect in absence of CD8 as demonstrated by decrease in survival in CD8KO mice as compared to tumor-bearing wild-type mice.
Conclusion: Novel therapeutic strategies that can make PDAC more amenable to immune therapy are urgently needed. In this context, our study is extremely timely as it targets specific metabolic pathways in cancer cells to overcome immune resistance and sensitize the tumor to anti-PD1 therapy.
Citation Format: Nikita S. Sharma, Vineet K. Gupta, Vanessa Garrido, Roey Hadad, Brittany Durden, Kousik Kesh, Anthony Ferrantella, Bhuwan Giri, Vikas Dudeja, Ashok Saluja, Sulagna Banerjee. Targeting tumor-intrinsic metabolic node in pancreatic cancer causes tumor regression, remodels extracellular matrix, and sensitizes to anti-PD1 therapy [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr B03.
Abstract B19: Targeting ATM to sensitize pancreatic cancer to immunotherapy and radiotherapy
Authors: Green Michael , Zhang Qiang , Lang Xueting , Lei Yu , Lawrence Theodore S. , Zou Weiping , Morgan Meredith A. 
Published: March 2020

Abstract
Combinatorial strategies are needed to overcome the resistance of pancreatic cancer to immune checkpoint blockade (ICB). DNA damage activates the innate immune response and improves ICB efficacy. We have studied the role of ATM, a core component of the DNA damage response, on pancreatic tumor immunogenicity in vitro and in vivo. Inhibition of ATM increased tumoral interferon signaling in a cGAS/STING-independent but TBK1 and SRC-dependent manner. The combination of ATM inhibition with radiation enhanced TBK1 activity, T1IFN production, and antigen presentation in vitro. Furthermore, ATM silencing enhanced T-cell trafficking in vivo and increased the sensitivity of pancreatic tumors to PD-L1 blocking antibody. The potential of ATM as a target for combinatorial strategy with ICB and radiation in pancreatic cancer will be discussed.
Citation Format: Michael Green, Qiang Zhang, Xueting Lang, Yu Lei, Theodore S. Lawrence, Weiping Zou, Meredith A. Morgan. Targeting ATM to sensitize pancreatic cancer to immunotherapy and radiotherapy [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr B19.
Abstract B21: Pharmacologic activation of G protein-coupled estrogen receptor inhibits pancreatic ductal adenocarcinoma
Authors: Natale Christopher , Li Jinyang , Dentchev Tzvete , Capell Brian , Seykora John , Stanger Ben , Ridky Todd 
Published: March 2020

Abstract
LNS8801 is a novel, orally bioavailable, small-molecule agonist of the G Protein Coupled Estrogen Receptor (GPER) being developed for the treatment of pancreatic ductal adenocarcinoma (PDAC) and other advanced cancers. Women have a lower incidence and improved clinical outcomes for most cancer types, including PDAC. The mechanistic basis for this sex difference is unknown. We hypothesized that estrogen signaling may be responsible, despite the fact that PDAC lacks classic nuclear estrogen receptors. Here we used murine syngeneic tumor models and human xenografts to determine that agonizing GPER on tumor cells inhibits PDAC. Systemically administered GPER agonists were well tolerated, induced tumor regression, significantly prolonged survival, and markedly increased the efficacy of PD-1 targeted immune therapy. Complete responses, observed with the GPER agonist alone or in combination with PD-1 targeted immune therapy, were associated with durable immune memory that protected against tumor rechallenge. Activation of GPER depleted c-Myc and programmed death ligand 1 (PD-L1) and increased tumor cell immunogenicity. These data, coupled with the wide tissue distribution of GPER and previous work showing that GPER activation inhibits other cancer types, suggest that GPER agonists may be useful against a range of cancers that are not classically considered sex hormone responsive, and that arise in tissues outside of the reproductive system.
Citation Format: Christopher Natale, Jinyang Li, Tzvete Dentchev, Brian Capell, John Seykora, Ben Stanger, Todd Ridky. Pharmacologic activation of G protein-coupled estrogen receptor inhibits pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr B21.