bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B058: The lincRNA Neat1 controls SWI/SNF occupancy to retain ductal cell identity in the pancreas
Authors: Berry Emily , Soares Zamira Guerra , Twardowski Jennifer , Wang Wenjia , Hezel Aram , Mello Stephano S. 
Published: November 2022

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer deaths in the US and among the most fatal. Cancer originating from the ductal compartment often leads to the emergence of the highly aggressive basal subtype of PDAC. Defining the cellular and molecular origins of basal subtype PDAC would greatly improve our ability to devise strategies to treat patients with this aggressive form of PDAC. Towards this end, we have discovered that loss of the long intergenic non-coding RNA (lincRNA) Neat1 promotes ductal cell plasticity, dramatically inducing the formation of duct-derived preneoplastic lesions known as intraductal papillary mucinous neoplasms (IPMNs), and increasing the likelihood of basal subtype PDAC. Neat1 deficiency has a profound impact on chromatin organization and on the distribution of the SWI/SNF chromatin remodeling complex at the chromatin, suggesting that Neat1 maintains ductal cell identity via impacting SWI/SNF function. Probing for Brg1, a core component of the SWI/SNF complex, we demonstrated that Neat1 loss leads to decreased SWI/SNF binding at enhancer regions. This idea is further supported by the phenotypic similarities between mice deficient for Neat1 and Arid1a. We thus hypothesize that Neat1 and SWI/SNF are critical for the maintenance of ductal cell identity in the pancreas via controlling SWI/SNF-dependent enhancer activity and that loss of Neat1 increases ductal cell transformation and thus facilitates IPMN formation and progression to basal subtype PDAC. These studies will reveal both the biological role and mechanistic underpinnings of the lincRNA Neat1 in relationship with the SWI/SNF chromatin remodeling complexes. Our data suggest that Neat1 or SWI/SNF loss-of-function predisposes pancreatic ductal cells towards the most aggressive subtype of PDAC, laying critical groundwork for development of new diagnostic tools and therapeutic targets.
Citation Format: Emily Berry, Zamira Guerra Soares, Jennifer Twardowski, Wenjia Wang, Aram Hezel, Stephano S. Mello. The lincRNA Neat1 controls SWI/SNF occupancy to retain ductal cell identity in the pancreas [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B058.
Abstract B059: RNA exosome component EXOSC4 amplified in multiple cancer types is required for the pancreatic cancer cell survival via the regulation of BIK and SESN2 mRNA
Authors: Taniue Kenzui , Mizukami Yusuke , Akimitsu Nobuyoshi 
Published: November 2022

Abstract
RNA decay plays a crucial role in the post-transcriptional regulation of gene expression. The RNA exosome is a multi-subunit ribonuclease complex that is evolutionally conserved and the major cellular machinery for the surveillance, processing, degradation, and turnover of diverse RNAs essential for cell viability. The RNA exosome is composed of a catalytically inactive barrel structure of nine core subunits (known as EXO9) that achieves its catalytic activity via the interaction with the exoribonuclease exosome component 10 (EXOSC10), the exo/endo-ribonuclease DIS3, and the two DIS3-like proteins (the exoribonucleases DIS3L and DIS3L2). Moreover, exosome activity is regulated by associated co-factors and RNA-binding adaptor proteins that recruit the exosome to its many targets. Here we performed integrated genomic and clinicopathological analyses of 27 RNA exosome components across 32 tumor types using The Cancer Genome Atlas PanCancer Atlas Studies’ datasets. We discovered that the EXOSC4 gene, which encodes a barrel component of the RNA exosome, was amplified across multiple cancer types. We further found that EXOSC4 alteration is associated with a poor prognosis in pancreatic cancer patients. Moreover, we demonstrated that EXOSC4 is required for the survival of pancreatic cancer cells. EXOSC4 also repressed BIK expression and destabilized SESN2 mRNA by promoting its degradation. Furthermore, knockdown of BIK and SESN2 could partially rescue pancreatic cells from the reduction in cell viability caused by EXOSC4 knockdown. Our study provides evidence for EXOSC4-mediated regulation of BIK and SESN2 mRNA in the survival of pancreatic tumor cells.
Citation Format: Kenzui Taniue, Yusuke Mizukami, Nobuyoshi Akimitsu. RNA exosome component EXOSC4 amplified in multiple cancer types is required for the pancreatic cancer cell survival via the regulation of BIK and SESN2 mRNA [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B059.
Abstract B073: C-terminal Binding Protein (CtBP): a critical regulator of ErbB2/3 signaling in PDAC
Authors: Chougoni Kranthi Kumar , Park Haemin , Damle Priyadarshan K. , Dcona Martin Michael , Szomju Barbara , Dozmorov Mikhail G. , Idowu Michael , Grossman Steven R. 
Published: November 2022

Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains among the most lethal of human cancers with a 5-year survival of ~10%, underscoring the need to identify new therapeutic vulnerabilities. Previously, we reported high expression of transcriptional co-regulators C-terminal binding proteins (CtBP) 1 and 2 in human PDAC, however their precise role in PDAC formation or progression remains unclear. Here we have studied PDAC tumor dependency on CtBPs for growth and metastasis, using an orthotopic syngeneic pancreatic tumor mouse model employing a mouse PDAC cell line (CKP) derived from a pancreatic tumor that formed in a mouse expressing mutated K-Ras in the setting of p53 deletion. CRISPR-based homozygous deletion of Ctbp2 in the parental mouse PDAC cell line (CKP CtBP2 KO) dramatically decreased orthotopic PDAC tumor growth, drastically reduced metastatic potential, and significantly prolonged survival. Interrogating differential gene expression of the orthotopic PDAC tumors from Ctbp2 WT vs Ctbp2 KO cohorts, we identified significant downregulation of the EGFR-superfamily receptor ErbB3 in Ctbp2 KO tumors, and further determined that CtBP2 regulates expression of both the ErbB2 and 3 EGFR superfamily genes in PDAC cells. We therefore hypothesized that CtBP regulation of physiologic ErbB2/3 signaling contributes, in part, to PDAC growth and metastasis. Indeed, we observed that Ctbp2 KO cells exhibited near complete loss of ErbB2/3 expression and exhibited severely attenuated activation of phospho-Akt after neuregulin stimulation of ErbB2/3, and furthermore, human PDAC cells also demonstrated CtBP dependence of ErbB3 expression. Our results suggest that a subset of PDAC tumors are dependent on physiologic ErbB2/3 signaling and could be targeted by pharmacologic inhibitors of ErbB2 and/or ErbB3. Providing proof of concept, the ErbB2-targeted multikinase inhibitor lapatinib effectively killed the ErbB3 expressing CKP PDAC cells, while CKP CtBP2 KO cells, where ErbB3 expression was extinguished, were resistant to lapatinib. Taken together, our data suggests that ErB2/3 targeted therapeutics can effectively target a critical PDAC dependency on physiologic ErbB2/3 signaling which is the result of CtBP’s oncogenic transcriptional program that drives PDAC tumor progression.
Citation Format: Kranthi Kumar Chougoni, Haemin Park, Priyadarshan K. Damle, Martin Michael Dcona, Barbara Szomju, Mikhail G. Dozmorov, Michael Idowu, Steven R. Grossman. C-terminal Binding Protein (CtBP): a critical regulator of ErbB2/3 signaling in PDAC [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B073.
Abstract B082: Autoimmune conditions and pancreatic cancer risk in older American adults
Authors: Yuan Fancheng , Pfeiffer Ruth M. , Julian-Serrano Sachelly , Arjani Simran , Barrett Michael J. , Koshiol Jill , Stolzenberg-Solomon Rachael Z. 
Published: November 2022

Abstract
Pancreatic cancer (PC) is highly fatal, and its incidence is increasing in the United States. Population-based registry studies suggest associations between a few autoimmune conditions and PC risk, albeit based on a relatively small number of cases. We hypothesize that autoimmune conditions are associated with risk of PC. We conducted a population-based, nested case-control study to examine the association between autoimmune conditions and PC risk within the Surveillance, Epidemiology, and End Results Program (SEER)-Medicare population. Incident primary malignant PC cases (n=80,074) were adults &gt; 66 years and diagnosed between 1992 and 2015. Controls (n=320,296) were alive at the time cases were diagnosed and frequency-matched to cases (4:1 ratio) by age, sex, and year of diagnosis. We used multivariable-adjusted, unconditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for 45 autoimmune conditions identified from Medicare claims. Eight autoimmune conditions including ankylosing spondylitis (OR = 1.45; 95% CI: 1.14-1.84), Graves’ disease (OR = 1.18; 95% CI: 1.03-1.34), localized scleroderma (OR = 1.27; 95% CI: 1.06-1.52), pernicious anemia (OR = 1.08; 95% CI: 1.02-1.14), primary sclerosing cholangitis (OR = 1.37; 95% CI: 1.18-1.59), pure red cell aplasia (OR = 1.31; 95% CI: 1.16-1.47), type 1 diabetes (OR = 1.11; 95% CI: 1.07-1.15), and ulcerative colitis (OR = 1.18; 95% CI: 1.07-1.31) were associated with increased PC risk (false discovery rate-adjusted P values &lt; 0.10). In subtype analyses, these conditions were associated with pancreatic ductal adenocarcinoma, whereas only ulcerative colitis was associated with pancreatic neuroendocrine tumors. Our results support the hypothesis that autoimmune conditions may play a role in PC development.
Citation Format: Fancheng Yuan, Ruth M. Pfeiffer, Sachelly Julian-Serrano, Simran Arjani, Michael J. Barrett, Jill Koshiol, Rachael Z. Stolzenberg-Solomon. Autoimmune conditions and pancreatic cancer risk in older American adults [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B082.
Abstract C019: FAK suppresses antigen processing and presentation to promote immune evasion in pancreatic cancer
Authors: Canel Marta , Slawinska Aleksandra , Lonergan David W. , Kallor Ashwin A. , Upstill-Goddard Rosie , Davidson Catherine , von Kriegsheim Alex , Biankin Andrew V. , Bryron Adam , Alfaro Javier , Serrels Alan 
Published: November 2022

Abstract
Immunotherapy for the treatment of Pancreatic Ductal Adenocarcinoma (PDAC) has shown limited efficacy. Poor CD8 T-cell infiltration, low neoantigen load and a highly immunosuppressive tumor microenvironment are key factors that contribute to this lack of response. Here, we identify a novel role for Focal Adhesion Kinase (FAK) in regulating type-II interferon signalling in human and murine PDAC cells and tumors, leading to suppression of antigen processing and presentation pathways critical for T-cell tumor recognition. We find that FAK loss promotes expression of the immunoproteasome and MHC-I, resulting in a significant increase in the diversity of antigens presented by FAK-/- PDAC cells. We show that regulation of the immunoproteasome subunit Psmb8 (β5i) is a critical determinant of this response, optimising the physicochemical properties of the peptide repertoire for high-affinity binding to MHC-I. Expression of the immunoproteasome and MHC-I can be further amplified in a STAT1-dependent manner via co-depletion of FAK and STAT3, leading to extensive CD8 T-cell infiltration into PDAC tumors and further restraint of tumor growth. Regulation of antigen processing and presentation by FAK preferentially occurs in human and murine PDAC cells and tumors of the classical/progenitor molecular subtype, further suggesting that precision medicine approaches based on molecular subtyping should be integrated into current and future clinical testing of FAK targeted therapies for the treatment of pancreatic cancer.
Citation Format: Marta Canel, Aleksandra Slawinska, David W. Lonergan, Ashwin A. Kallor, Rosie Upstill-Goddard, Catherine Davidson, Alex von Kriegsheim, Andrew V. Biankin, Adam Bryron, Javier Alfaro, Alan Serrels. FAK suppresses antigen processing and presentation to promote immune evasion in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C019.
Abstract C049: WT1+ cancer-associated fibroblasts promote pancreatic cancer growth
Authors: Bischoff Allison , Zhang Yaqing , Yan Wei , Brown Kristee , Du Wenting , di Magliano Marina Pasca 
Published: November 2022

Abstract
Pancreatic ductal adenocarcinoma (PDA) is characterized by dense, fibro-inflammatory stroma that is established in early pathogenesis. Cancer-associated fibroblasts (CAFs) make up a significant proportion of the tumor microenvironment and represent a heterogeneous cell population that play both tumor-promoting and tumor-restricting roles. Despite their dramatic expansion in PDA pathogenesis, it is still unclear what cells in the normal pancreas give rise to these CAFs. Lineage-tracing experiments have previously identified pancreatic stellate cells, mesothelial, and tissue-resident fibroblasts as progenitors to subsets of CAFs. In this research, we firstly pulse-labeled cells expressing the mesothelial and fibroblast marker Wilms tumor 1 (WT1) in the normal pancreas of WT1CreERT;R26tdTomato mice and used an orthotopic model of PDA to trace their contribution to the PDA tumor microenvironment. We found WT1+ cells in the normal pancreas expanded to comprise a significant proportion of PDA CAFs according to immunofluorescence. Based upon single-cell RNA-sequencing (scRNA-seq), these WT1+ precursors represent an endogenous pancreatic fibroblast population similar to previously characterized universal adventitial fibroblasts (Pi16+, Dpp4+). To determine the role of WT1 in established PDA, we labeled WT1+ cells following orthotopic tumor implantation into WT1CreERT;R26tdTomato mice, and scRNA-seq analysis revealed that both inflammatory CAFs (iCAFs) and myofibroblastic CAFs (MyCAFs) express WT1. Notably, iCAFs had higher relative expression of WT1+. Additionally, we depleted WT1+ cells with diphtheria toxin from orthotopic tumors established in WT1CreERT;R26tdTomato/iDTR mice. We found depletion of WT1+ cells reduced orthotopic tumor growth, and depleted fibroblasts from the PDA tumor microenvironment. These findings implicate WT1 as a promising lineage tracing marker for a subset of pancreatic fibroblasts and demonstrates a pro-tumorigenic role of WT1+ fibroblasts in PDA.
Citation Format: Allison Bischoff, Yaqing Zhang, Wei Yan, Kristee Brown, Wenting Du, Marina Pasca di Magliano. WT1+ cancer-associated fibroblasts promote pancreatic cancer growth [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C049.
Abstract C067: Understanding the tumor extrinsic role of oncogenic Kras in pancreatic cancer
Authors: Bonilla Monica E. 
Published: November 2022

Abstract
Pancreatic ductal adenocarcinoma (PDA) is a lethal disease with a 5-year survival rate of 10.8%. Most patients present with locally advanced or metastatic disease which is refractory to therapy. Even when surgical resection is possible, relapse is frequent. Thus, there is a need to understand relapse and treatment resistance in pancreatic cancer to develop more effective treatments. Oncogenic KRAS is a driving mutation in PDA. Work in mouse models demonstrated that oncogenic KRAS drives the initiation of pancreatic cancer. Further, our group and others showed that oncogenic KRAS is required for the maintenance of precursor lesions as well as advanced and metastatic disease. We have recently investigated the extrinsic effects of oncogenic KRAS in precursor lesions of pancreatic cancer; we found that oncogenic KRAS drives reprogramming of precursor associated fibroblasts (PAFs or pre-cancer associated fibroblasts; pre-CAFs) to express immunosuppressive cytokines. The extrinsic effects of oncogenic KRAS in advanced disease have so far not been fully elucidated. In brief, we orthotopically transplanted iKRAS cells —derived from a mouse model of inducible and reversible oncogenic KRAS expression— in the pancreas of syngeneic mice. We then administered Doxycycline (DOX) to induce tumor growth. Once tumors had reached the desired size, we split the mice in two cohorts, one that was kept of DOX and one that was taken off DOX. All the animals were sacrificed 3 days later, tumors were dissected and processed for single cell RNA sequencing. We performed bioinformatics analysis on the tumors using the SEURAT pipeline, and mapped cellular composition, changes in gene expression and predicted interactions regulated by oncogenic KRAS. Interestingly, we discovered that several immunosuppressive pathways are alleviated upon KRAS inactivation, and CD8+ T cell infiltration increases. We and others have described resistance to oncogenic KRAS and eventual relapse in the iKRAS mouse model. Further, clinical data from the first KRAS inhibitors tested in clinical trials (G12C mutant-specific inhibitors in lung adenocarcinoma) similarly revealed initial response followed, in most cases, by relapse. We are thus interested in studying the mechanisms of KRAS inhibition resistance and specifically determine whether immunotherapy can be combined with KRAS inactivation to prevent relapse.
Citation Format: Monica E. Bonilla. Understanding the tumor extrinsic role of oncogenic Kras in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C067.
Abstract C073: CRO-67 is a novel therapeutic for pancreatic cancer: Implications for tumor and stromal reprogramming
Authors: Kokkinos John , Sharbeen George , Haghighi Koroush S. , Youkhana Janet , Raina Aparna , Pitiyarachchi Omali , Truong Quach , Wenholz Daniel , Laczka Olivier , Kumar Naresh , Goldstein David , Phillips Phoebe A. 
Published: November 2022

Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies and new therapeutic strategies are urgently required. A key drug delivery barrier and promoter of tumor progression is the fibrotic and heterogeneous microenvironment of PDAC which is mainly orchestrated by stromal cancer-associated fibroblasts (CAFs). Thus, any novel therapeutic strategy should not only target PDAC cells but should also aim to inhibit the pro-tumor properties of the PDAC stroma. However, to accurately evaluate the clinical potential of novel PDAC therapeutics, preclinical models are required that closely mimic the heterogeneity and multicellular architecture of human disease. Aim: We aimed to investigate the therapeutic potential of novel functionalized benzopyrans (CRO-05 & CRO-67) in a patient-derived PDAC tumor explant model. Methods: We collected PDAC tumor samples from patients undergoing resection of their primary tumor. We cultured whole tumor explants (1-2mm diameter) on gelatin sponges. This model accurately maintains the multicellular tumor and stromal architecture of human PDAC [Kokkinos et al, Scientific Reports, 11,1941 (2021)]. Tumor explants were treated every 3 days with the racemic compound CRO-05 or its active enantiomer CRO-67 and explants were fixed in paraformaldehyde at day-12. Therapeutic response was assessed by immunohistochemistry for markers of tumor cells (cytokeratin), CAFs (α-Smooth Muscle Actin), cell-proliferation (Bromodeoxyuridine), and cell-death (TUNEL). Results: Treatment of human PDAC explants with CRO-05 resulted in reduced tumor cell frequency in 3/4 patients and in 4/4 patients, reduced CAF frequency, decreased cell-proliferation, and increased cell-death relative to controls. CRO-67 treatment in explants from 4/5 patients led to reduced tumor cell frequency, and in 5/5 patients, reduced CAF frequency, decreased cell-proliferation, and increased cell-death relative to controls. Conclusions: This work identifies the functionalized benzopyrans CRO-05 and CRO-67 as novel dual-cell therapeutics that potently inhibit both PDAC tumor cells and their surrounding CAFs and provides support for their clinical development as novel PDAC therapeutics.
Citation Format: John Kokkinos, George Sharbeen, Koroush S. Haghighi, Janet Youkhana, Aparna Raina, Omali Pitiyarachchi, Quach Truong, Daniel Wenholz, Olivier Laczka, Naresh Kumar, David Goldstein, Phoebe A. Phillips. CRO-67 is a novel therapeutic for pancreatic cancer: Implications for tumor and stromal reprogramming [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C073.
Abstract C074: Mining the secreted microproteome for novel regulators of PDAC progression
Authors: Martinez Marion , Hergueta Marta , de Embún Pilar Ximénez , Dueso Ana , Torrents David , Macarulla Teresa , Muñoz Javier , Peinado Héctor , Abad María 
Published: November 2022

Abstract
Recent work has unveiled a hidden microproteome composed by thousands of small proteins named microproteins: they are functional short proteins coded by genomic regions previously considered non-coding, and which had been completely ignored, mainly due to their small size (&lt;100 aminoacids). To date, only a small part of the thousands of microproteins present in our cells have been characterized, and they are key players in fundamental processes such as DNA repair, mRNA splicing or cell metabolism. In cancer, they have been shown to regulate most tumor hallmarks, and present a huge potential for the clinic as diagnostic and prognostic biomarkers as well as therapeutic targets. Interestingly, their small size makes them ideal candidates to be shed in tumor-derived exosomes. PDAC-shed exosomes have been shown to prepare the pre-metastatic niche in the liver, and their presence in the bloodstream can be used as a surrogate marker of metastasis. Herein, we have mined the PDAC exosome-secreted microproteome for novel regulators of tumor progression and metastasis. Using proteogenomics in PDAC patient-derived explants, we have identified 439 microproteins secreted in exosomes by pancreatic tumors. We have selected a set of top microprotein candidates for further characterization by in silico analyses (e.g. phylogenetic conservation, predicted protein stability and localisation, mRNA expression in PDAC, etc). We have confirmed their exosome secretion in PDAC cell lines, and preliminary characterisation of these top candidates has shown that they extrinsically promote PDAC cell growth and invasion in vitro. Together, this work advances our knowledge on the underexplored field of secreted microproteins and provides pioneering evidence of their role in tumor cell communication in PDAC. It may further be a source of novel therapeutic targets and PDAC biomarkers for liquid biopsy in the clinic.
Citation Format: Marion Martinez, Marta Hergueta, Pilar Ximénez de Embún, Ana Dueso, David Torrents, Teresa Macarulla, Javier Muñoz, Héctor Peinado, María Abad. Mining the secreted microproteome for novel regulators of PDAC progression [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C074.