bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C54: GATA6 level is a prognostic biomarker for pancreatic cancer in African American patients
Authors: Tang Haoyu , Sharma Anup , Nalbantoglu Ilke , Hasan Nesrin , Levchenko Andre , Ahuja Nita 
Published: March 2020

Abstract
Pancreatic cancer is expected to become the second leading cause of cancer-related deaths in the United States by 2030 (Weniger, Honselmann, Liss, 2018), while the limited knowledge about its pathophysiology leads to the current lack of accurate prognostic tool and satisfactory treatment. Transcription factor GATA6 is highlighted as an interesting target based on the TCGA dataset analysis of mutational burdens among 15 African American patients and 12 white patients with pancreatic cancer. A previous in vitro study revealed that GATA6 inhibited epithelial-mesenchymal transition through both direct transcriptional regulation and indirect regulation of other transcription factors (Martinelli et al., 2017). However, the correlation between GATA6 and pancreatic cancer prognosis has not been fully understood. In our study, we assessed the GATA6 protein expression levels using immunohistochemistry (IHC) of a tissue microarray from one white and four black patients. The phenotype of low GATA6 expression was only found in two of four black patients, while tumors with high GATA6 expression were found both in black and white patients. Noticeably, the patients with GATA6low phenotype demonstrated inferior survival compared to those with GATA6high phenotype, indicating GATA6 as a potential prognostic biomarker. A detailed study using more patient samples is ongoing. We also established two pancreatic cancer cell lines with specific GATA6 knockdown via the CRISPR/Cas9 method to continue investigating the role of GATA6 loss in the progress of the aggressive pancreatic cancer. Success in future work will potentially contribute to a useful prognostic tool as well as development of novel therapies for pancreatic cancer patients with GATA6low phenotype.
Citation Format: Haoyu Tang, Anup Sharma, Ilke Nalbantoglu, Nesrin Hasan, Andre Levchenko, Nita Ahuja. GATA6 level is a prognostic biomarker for pancreatic cancer in African American patients [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 C54.
Abstract C60: Combination of MEK and autophagy inhibition promotes tumor regression in the KPC mouse model of pancreatic cancer
Authors: Wasko Urszula N. , Sastra Stephen A. , Palermo Carmine F. , Olive Kenneth P. 
Published: March 2020

Abstract
Activating mutations of Kras are the main genetic drivers of pancreatic ductal adenocarcinoma (PDA) and are essential for its initiation and maintenance. It was recently shown that suppression of the Kras effectors Raf/Mek/Erk in the context of Kras-mutant pancreatic tumors leads to the increase of autophagic flux, suggesting that this inhibition may be enhancing PDA dependence on autophagy. Autophagy, a lysosome-mediated process, allows cells to degrade organelles and macromolecules and recycle the intermediates to sustain cell metabolism, critical for tumor growth. This discovery, made recently by two independent research teams, led to the development of a two-drug regimen that blocks MEK/ERK and autophagy pathways and produces consistent synergistic responses in cell lines, in several transplantation models, and in a human PDA patient. Here we present results from an intervention study performed in the K-rasLSL.G12D/+, p53LSL.R172H/+, Pdx1Cre (KPC) mice, a highly chemoresistant genetically engineered model of PDA. We found that a two-drug regimen of trametinib (MEK inhibitor) and hydroxychloroquine (autophagy inhibitor) induced frank regressions in all six animals treated to date—an unmatched response in this model. Tumor regressions ranging from 30% to 95% following treatment were sizable, as measured by longitudinal 3D high-resolution ultrasound, and these mice survived significantly longer than historical controls treated with saline under identical conditions. IHC performed on tumor tissues from treated mice showed decreased proliferation and increased apoptosis relative to untreated KPC pancreatic tumors. Some tumors exhibited substantially reduced phospho-ERK expression by IHC. Interestingly, some tumors that underwent large regressions exhibited positive staining for phospho-ERK in the residue tumor tissues, suggesting a mechanism of resistance through the reactivation of this downstream effector. Studies focused on mechanisms of acquired resistance are ongoing.
Citation Format: Urszula N. Wasko, Stephen A. Sastra, Carmine F. Palermo, Kenneth P. Olive. Combination of MEK and autophagy inhibition promotes tumor regression in the KPC mouse model of 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 C60.
Abstract I01: Mechanisms and consequences of pancreatic cancer stromal evolution
Authors: Sherman Mara 
Published: March 2020

Abstract
The mechanisms underlying evolution of tumor-associated stroma remain poorly understood. Pancreatic ductal adenocarcinoma (PDAC) is the archetype of a fibroinflammatory malignancy, with 50-90% of tumor volume occupied by a dense, desmoplastic stroma. Cancer-associated fibroblasts (CAFs) are the key cell type driving the stromal reaction in PDAC. Recent reports suggest that PDAC CAFs represent a heterogeneous population of cells from diverse origins, potentially including cell types that support and others that suppress tumor growth. Pancreatic stellate cells (PSCs) are lipid-storing cells in healthy pancreas that can transdifferentiate to an activated CAF phenotype. PSCs have been suggested as the predominant source of CAFs in the PDAC microenvironment. However, proper lineage tracing studies have never been performed, such that the relative contribution and specific functions of PSCs in the tumor microenvironment are unknown. We have taken advantage of a novel mouse model we developed to track PSC differentiation and function during pancreatic tumor progression in vivo. This model leverages the unique lipid-storing origin of PSC-derived CAFs, and enables their distinction from CAFs of non-PSC origin for the first time. We hypothesized that PSC-derived fibroblasts in the PDAC microenvironment are a proinflammatory and tumor-supportive subset of PDAC CAFs, and thus represent a viable therapeutic target. Our preliminary data support the notion that PSCs contribute to only a subset of the CAF population in the tumor microenvironment, and the functions of these distinct populations are entirely unknown. Our data also highlight a potential role for genetic alterations in the epithelial compartment in orchestration of stromal fibroblast evolution. Using our model, we have interrogated PDAC stromal heterogeneity and functional significance, analyzed the distinguishing features of CAF subpopulations from disparate origins, and determined the significance of genetic alterations in the epithelial compartment on stromal cell fate and function. Together, these studies have the potential to lay the foundation for development of stroma-targeted therapies based on careful lineage tracing and molecular data. These findings shed light on mechanisms of stromal evolution during pancreatic tumorigenesis, and potentially identify distinct CAF populations of relevance in additional solid tumors.
Citation Format: Mara Sherman. Mechanisms and consequences of pancreatic cancer stromal evolution [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 I01.
Abstract I02: Targeting Innate immunity in pancreatic carcinoma
Authors: Miller George 
Published: March 2020

Abstract
Pancreatic carcinoma has proven largely resistant to immunotherapies as strategies directly targeting T cells or their receptors have failed in early clinical trials. Basic research has shown that effector T-cell infiltration and phenotype in pancreatic cancer is controlled by diverse innate immune elements including dendritic cells, macrophages and other myeloid cells, and subsets of innate-like T cells. However, the phenotype of macrophages and myeloid cells infiltrating pancreatic carcinoma is, for the most part, highly suppressive of effective adaptive antitumor immunity. Therefore, rather than directly targeting T cells in isolation, immunotherapeutic strategies addressing toleorogenic innate immune cell populations hold greater promise. New potential avenues for immunotherapy include activating or blockade of select innate immune receptors on tumor-associated macrophages to reprogram their suppressive phenotype, targeting the microbiome to modulate the intratumoral inflammatory environment toward a more favorable phenotype, or deleting select subsets of tolerogenic T cells such as delta1 cells. These type of approaches have the potential to enable efficacy for more traditional immunotherapies that target checkpoint or costimulatory receptors, and these strategies can also potentiate the effects of systemic chemotherapy or radiation therapy.
Citation Format: George Miller. Targeting Innate immunity in pancreatic carcinoma [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 I02.
Abstract I04: Regulatory T-cell depletion causes compensatory immune suppression and accelerates pancreatic carcinogenesis
Authors: Zhang Yaqing , Lazarus Jenny , Steele Nina , Lee Ho-Joon , Yan Wei , Halbrook Cristopher J. , Menjivar Rosa , Kemp Samantha B. , Sirihoracai Veerin , Carpenter Eileen S. , Nevison Anna C. , Vinta Alekya , Anderson Michelle A. , Crawford Howard C. , Lyssiotis Costas A. , Frankel Timothy L. , Bednar Filip , Magliano Marina Pasca di 
Published: March 2020

Abstract
In human patients and in mouse models, immunosuppressive regulatory T cells (Tregs) accumulate in pancreatic cancer. Tregs are considered a potential therapeutic target with the goal to reverse immunosuppression in a number of malignancies, including pancreatic cancer. Using a genetically engineered mouse model of pancreatic cancer, we determined that—unlike in other malignancies—Treg depletion failed to relieve immunosuppression. Contradicting the current paradigm, depletion of Tregs led to accelerated tumor progression. We show that Tregs are a key source of TGFb ligands both in human samples and in mouse models. Accordingly, their depletion reprograms the fibroblast population, exemplified by loss of smooth muscle actin expression and an increase in the myeloid-recruiting chemokines Ccl3, Ccl6, and Ccl8. Our findings point to a dual role of Tregs in pancreatic cancer, with their immune-suppressive function being balanced by their induction of a SMA-high (tumor-restraining) fibroblast phenotype. Further, our data point to a compensatory immunosuppression mechanism that confers resistance to Treg depletion in pancreatic cancer. Finally, blockade of the common CCL3/6/8 receptor CCR1 combined with Treg-depletion successfully inhibited tumorigenesis, a finding with potential therapeutic implications.
Citation Format: Yaqing Zhang, Jenny Lazarus, Nina Steele, Ho-Joon Lee, Wei Yan, Cristopher J. Halbrook, Rosa Menjivar, Samantha B. Kemp, Veerin Sirihoracai, Eileen S. Carpenter, Anna C. Nevison, Alekya Vinta, Michelle A. Anderson, Howard C. Crawford, Costas A. Lyssiotis, Timothy L. Frankel, Filip Bednar, Marina Pasca di Magliano. Regulatory T-cell depletion causes compensatory immune suppression and accelerates pancreatic carcinogenesis [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 I04.
Abstract I05: Heterocellular interactions in the tumor microenvironment
Authors: Jorgensen Claus 
Published: March 2020

Abstract
Pancreatic ductal adenocarcinoma (PDA) is characterized by a heterocellular microenvironment, exhibiting tumor-promoting as well as tumor-restrictive effects. Tumor cells coerce host cells, such as fibroblasts and myeloid cells, to remodel the stroma, which results in altered stiffness, cell-cell signaling, and modified tumor cell function. The rules governing tumor-stromal interactions are currently not clearly defined. To demark and characterize the cellular components of the tumor microenvironment we devised protein-based marker panels for single-cell analysis by cytometry by time of flight (CyTOF), specifically aimed at defining populations of cancer-associated fibroblast (CAFs). Importantly, we employed cell surface markers, enabling isolation and functional characterization of identified stromal populations. Using these panels, we interrogated tumors from the pdx1-cre; LSL-KrasG12D/+; LSL-Trp53R172H/+ (KPC) genetic engineered model of pancreatic cancer. We observe previously defined CAF populations expressing markers for myofibroblastic CAFs (myCAF); inflammatory CAFs (iCAF) and antigen presenting CAFs (apCAF). In addition to these CAF populations, we observe that differential expression of the auxiliary receptor for the TGFβ receptor complex, endoglin (CD105), demarks two distinct fibroblast populations that are present in murine and human PDA. In addition, we observe CD105-positive (CD105+) and -negative (CD105-) fibroblasts in normal healthy pancreas, liver, and lung, indicating that the presence of these CAFs in tumors is likely due to local expansion. Isolated fibroblasts preserve differential expression of CD105+ and CD105- throughout extended in vitro culture, co-culture, and treatment with regulators of fibroblast function, indicating that CD105 may act as a bona fide lineage marker. We find that while both CD105+/- lineages are able to adapt a general myCAF or iCAF polarization, they show distinct regulation of specific genes. Using a syngeneic subcutaneous co-transplant model, we demonstrate that CD105+ fibroblasts are tumor-promoting, while CD105- fibroblasts are highly tumor-restrictive. Interestingly, both mechanisms are mediated by differential regulation of CD8 T cell-dependent adaptive immunity. Together these data define two novel, functionally distinct fibroblast populations in PDA with pro- or antitumorigenic effects.
Citation Format: Claus Jorgensen. Heterocellular interactions in the tumor microenvironment [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 I05.
Abstract I06: Clonal evolution and progression of pancreatic cancer precursor lesions
Authors: Wood Laura D. 
Published: March 2020

Abstract
Pancreatic cancer arises from noninvasive precursor lesions that are curable if detected and treated early enough. These precursor lesions include microscopic pancreatic intraepithelial neoplasia (PanIN) and cystic intraductal papillary mucinous neoplasm (IPMN). Interrogation of these lesions can provide critical insights into the earliest stages of pancreatic tumorigenesis and provide a rational foundation for early detection approaches. We have performed comprehensive genomic analyses of PanINs, IPMNs, and associated invasive carcinomas, highlighting several unique features of initiation and progression of pancreatic neoplasms. We show that early-stage precursor lesions contain multiple independent clones, each with distinct mutations, indicating their polyclonal origin. In addition, we identify convergent evolution of tumor suppressor gene loss at later stages of tumorigenesis, as well as subclonal complexity of driver gene mutations and mutations in specific genes limited to invasive cancers. Taken together, these data challenge the traditional monoclonal origin of pancreatic tumors, highlight distinct evolutionary features of precancerous lesions, and transform our understanding of the clonal evolution of pancreatic neoplasia.
Citation Format: Laura D. Wood. Clonal evolution and progression of pancreatic cancer precursor lesions [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 I06.
Abstract I10: Immune cell signaling in human and mouse pancreas cancer
Authors: Habtezion Aida 
Published: March 2020

Abstract
Acute pancreatitis (AP) is the most common gastrointestinal disorder leading to hospital admission in the United States. Patients who present with recurrent acute pancreatitis are at a very high risk of developing chronic pancreatitis (CP). Patients with CP experience intractable, difficult to treat abdominal pain and the disease is associated with pancreatic acinar cell loss and fibrosis, and can result in exocrine and endocrine insufficiency. CP is also a risk factor for developing pancreatic ductal adenocarcinoma (PDAC). In AP, initial injury signals likely start at the acinar cell level, where injured acinii produce proinflammatory cytokines and chemokines leading to the recruitment of inflammatory leukocytes into the pancreas. One of the initially recruited leukocytes includes neutrophils, which play pathogenic role locally within the pancreas and in distant organs such as the lung. Soon after, inflammatory monocytes follow into the pancreas and differentiate into macrophages with pro-inflammatory properties and exacerbate the pancreatic injury. Earlier and recent studies show that T cells and macrophages are the predominant immune cell infiltrates in CP. Macrophages in CP are found in close proximity to key pro-fibrogenic pancreatic stellate cells. Experimental studies suggest an interaction between the stellate cells and macrophages to promote fibrosis in CP. In contrast to AP, macrophages in CP display alternate activation consistent with immunosuppressive environment associated with CP. Immune cells also play a critical and differential role of anti- and pro-tumor functions in PDAC. For example, immune signals such as IL-22/IL-22R axis are involved in AP, CP, and PDAC but play differential role between the diseases. To get insight into the inflammatory processes involved, we use multiplex based assays to profile immune cells isolated from the pancreas as well as in situ to determine functional and geographic localization.
Citation Format: Aida Habtezion. Immune cell signaling in human and mouse pancreas 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 I10.
Abstract I13: Modulating the immune response with epigenetic agents
Authors: Azad Nilofer S. 
Published: March 2020

Abstract
Epigenetic modulation offers the potential of altering key tumor-immune interactions to allow for more effective therapeutic targeting. Epigenetic abnormalities in cancer in the tumor-immune response will be discussed, as well as data that support the reversibility of these lesions with epigenetic modulators. Preclinical and emerging clinical data in solid tumors will be surveyed, with an eye towards how these data support the rationale of epigenetic-immunotherapy combinations in pancreatic cancer.
Citation Format: Nilofer S. Azad. Modulating the immune response with epigenetic agents [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 I13.
Abstract I15: Deciphering the origins of PDAC development
Authors: Flowers Brittany , Xu Hang , Hanson Kathryn , Curtis Christina , Vogel Hannes , Wood Laura D. , Attardi Laura D. 
Published: March 2020

Abstract
The TP53 gene, encoding the p53 transcription factor, is mutated in the majority of human pancreatic cancers, underscoring its critical role as a barrier to PDAC development. Despite this essential function, however, the cellular and molecular pathways through which p53 acts in pancreatic cancer suppression have remained elusive. To gain a better understanding of the programs through which p53 suppresses PDAC development, which will provide key insight into how the disease develops, we have taken combined mouse genetic and genomic approaches. First, we have sought to understand whether p53 acts in acinar and/or ductal cells to restrain PDAC development. For these studies we have used adult mice to more accurately mimic the development of PDAC in humans. Second, we have sought to systematically deconstruct the role of p53 loss-of-function and gain-of-function mutations in driving cancer from these different cells of origin. In addition, we have characterized the trajectory of cancer development in these models through histologic analysis of lesions at different time points and through lineage tracing. This comprehensive analysis of large adult mouse cohorts has helped to define the role for p53 in restraining spontaneous PDAC development, an essential first step for understanding p53 programs involved in tumor suppression. To gain insight into the programs that become dysregulated during pancreatic cancer development, we have performed transcriptomic analysis on tumors arising from different compartments and driven by different genetic lesions. These studies have revealed the molecular profiles of tumors arising from acinar versus ductal cells as well those driven by different types of p53 mutations. Through comparison to human pancreatic cancer data, our studies will reveal the paths to PDAC development in humans and the underlying origins of different subtypes of this disease.
Citation Format: Brittany Flowers, Hang Xu, Kathryn Hanson, Christina Curtis, Hannes Vogel, Laura D. Wood, Laura D. Attardi. Deciphering the origins of PDAC development [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 I15.