bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B25: Engrailed-1 promotes pancreatic cancer progression via antagonizing COMPASS activity
Authors: Hwang Chang-il , Roe Jae-Seok , Lee Eun Jung , Tonelli Claudia , Somervile Tim D.D. , Yao Melissa , Milazzo Joseph P. , Tiriac Hervé , Park Youngkyu , Vakoc Christopher , Tuveson David 
Published: March 2020

Abstract
Pancreatic ductal adenocarcinoma (PDA) is the most deadly disease in human malignancies. Using pancreatic organoid models, we have shown that enhancer reprogramming allows pancreatic cancer cells to acquire aggressive characteristics during disease progression. Recently we found that organoid cultures (mM) derived from metastatic lesions of KPC mice (Kras+/LSL-G12D; Trp53+/LSL-R172H; Pdx1-Cre) can survive in the reduced condition, unlike the paired primary tumor-derived organoid cultures (mT). We implicate Engrailed-1 (EN1), a neurodevelopmental transcription factor (TF), in this process as a prosurvival factor. We show that EN1 is indispensable for organoid survival in the reduced condition, highly expressed in mM compared to mT organoid cultures, and associated with poor prognosis. Gain- and loss-of-function experiments further show that EN1 is responsible for the aggressiveness of pancreatic cancer cells in vitro (anchorage-independent growth, migration, and invasion) and in vivo. On the other hand, subcutaneous tumors derived from EN1 expressing mT organoids exhibit squamous-like differentiation compared to control. In line with this, squamous-type PDA patients tend to express EN1 compared to other subtypes of PDA. Furthermore, EN1 perturbation renders the changes of squamous-PDA identity and KDM6A deficiency signatures. Mechanistically, EN1 can physically interact with KDM6A and repress H3K4me3 occupancy in a subset of genes without affecting H3K27me3 and H3K27ac occupancies, suggesting that the regulation of COMPASS (Complex Proteins Associated with Set1) activity by EN1 might be critical in this process. Finally, by combining EN1 with FOXA1, previously shown to be responsible for enhancer activation in PDA organoids, we were able to fully reprogram pancreatic cancer cells into highly aggressive pancreatic cancer cells. In sum, we report that EN1 confers the aggressiveness of pancreatic cancer cells via regulation of COMPASS activity and contributes to squamous-type identity and PDA progression.
Citation Format: Chang-il Hwang, Jae-Seok Roe, Eun Jung Lee, Claudia Tonelli, Tim D.D. Somervile, Melissa Yao, Joseph P. Milazzo, Hervé Tiriac, Youngkyu Park, Christopher Vakoc, David Tuveson. Engrailed-1 promotes pancreatic cancer progression via antagonizing COMPASS activity [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 B25.
Abstract B29: Outcomes of DNA repair-deficient pancreatic cancers: KU Cancer Center experience
Authors: Kasi Anup , Bajwa Suhaib , Al-Jumayli Mohammed , Saeed Anwaar , Godwin Andrew 
Published: March 2020

Abstract
Background: DNA repair-defective pancreatic cancers are a subset that could be exploited therapeutically. BRCA 1 and 2 deficient pancreatic cancers have shown improved survival outcomes with platinum-based chemotherapy and/or PARP inhibitors. However, survival outcomes of pancreatic cancers harboring other DNA repair defects are not well understood.
Methods: We retrospectively evaluated survival outcomes of 60 metastatic pancreatic cancer patients who had their tumors profiled by standard-of-care next-generation sequencing. Patients with deficient DNA repair genes such as BRCA1 (n=2), BRCA2 (n=12), ATM (n=7), PALB2 (n=1), NBN (n=1), and BRIP1 (n=1) were grouped into DNA repair-deficient group. The remaining patients were grouped into DNA repair-proficient group. Comparative survival analysis between the two groups was performed using Kaplan-Meir methods.
Results: Demographic/baseline data for the DNA repair-deficient group (n=22) vs. the proficient group (n=38) are compared as follows: 12 vs. 20 males, 10 vs. 18 females, 20 vs. 33 with ECOG scores 0-1, 1 vs. 4 with a ECOG score 2+, 12 vs. 19 with tumors in the head, 7 vs. 6 with tumors in the body, 4 vs. 12 with tumors in the tail, 4 vs. 10 with a CA 19-9 of &lt;34, 12 vs. 24 with a CA 19-9 of &gt;34, 7 vs. 19 received initial gemcitabine-based therapy, and 15 vs. 19 received initial FOLFIRINOX chemotherapy. Survival analysis in DNA repair-deficient vs. proficient group revealed comparable median PFS of 7 months (95%CI 5-32 months) vs. 7 months (95% CI 4-30 months) [HR 0.97, p=0.9] but a longer median OS of 18 months vs. 12 months [HR 0.51, p=0.07]. Among DNA repair-deficient group, median OS was 12 months for patients who received first-line platinum-based chemo (n=15) vs. 5 months for first-line non-platinum chemo (n=7) [HR 0.57, p=0.39].
Conclusion: In addition to BRCA1/2 deficiency, pancreatic cancers that harbor other DNA repair defects also show trend towards improved OS when compared to DNA repair-proficient cancers. Treatment with first-line platinum-based chemo favored better OS in DNA repair-deficient cancers. Though median PFS appears comparable, the upper limit of 95% CI for PFS is higher for the DNA repair-deficient cancers. These findings did not meet statistical significance given our small sample size and need to be validated in a larger cohort. We currently have an ongoing clinical trial to investigate DNA repair defects in addition to BRCA1/2 in pancreatic cancers (NCT03553004).
Citation Format: Anup Kasi, Suhaib Bajwa, Mohammed Al-Jumayli, Anwaar Saeed, Andrew Godwin. Outcomes of DNA repair-deficient pancreatic cancers: KU Cancer Center experience [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 B29.
Abstract B37: The complex immune-microenvironment heterogeneity in pancreatic cancer
Authors: Grevers Frederieke , Latifi Diba , Koning Willem de , Eijck Casper H.J. van , Mustafa Dana A. 
Published: March 2020

Abstract
Introduction: Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy, resulting in more than 3,000 deaths per year in The Netherlands. The tumor microenvironment (TME) contributes largely to the treatment failure of the disease. TME consists of the stromal compartment, extracellular matrix, and tumor-infiltrative lymphocytes (TILs). Types and numbers of TILs are associated with clinical outcome, i.e., highCD8+: FOXP3 ratio is linked to a favorable prognosis. However, the intratumor immune variation in pancreatic cancer has not been studied so far. This study aims at investigating the differences of the immune infiltration within various areas of the same pancreatic cancer samples (intratumor variation) and comparing to healthy controls (extratumor variation). Such differences may be used for microenvironment remodeling, which may open new therapeutic approaches for PDAC patients.
Materials and Methods: Formalin-fixed, paraffin-embedded (FFPE) samples of 26 PDAC patients and 8 healthy controls were selected. RNA was isolated separately from the tumor core and from the adjacent normal-like pancreatic tissue of the same sample. Immune profiling was carried out using the PanCancer Immune Profiling Panel of Nanostring technology. Subsequently, the gene expression data were analyzed using nSolver basic software and the advanced module.
Results: The immune infiltration in the core of PDAC samples was different from that in the adjacent normal-like areas of the same patients. Tumor samples exhibited the lowest CD8+, Th1, neutrophil, and Natural Killer cell infiltration as compared to normal-like areas. In addition, the normal-like areas of PDAC samples showed a different immune profile as compared to the healthy controls. B lymphocytes were significantly higher in healthy controls compared to normal-like PDAC samples.
Discussion and Conclusion: Our results present the variation in the immune microenvironment between the normal-like pancreatic tissue and the healthy pancreas, indicating that changes at the immune levels precede morphologic changes, tumorigenesis, and tumor cell infiltration. Additionally, specific changes in TILs occur in a gradient fashion from adjacent normal-like tissue to the tumor core. Understanding the differences of the immune microenvironment in the same tissue samples will enable developing an accurate microenvironment remodeling therapeutic approaches to treat PCDA patients.
Citation Format: Frederieke Grevers, Diba Latifi, Willem de Koning, Casper H.J. van Eijck, Dana A. Mustafa. The complex immune-microenvironment heterogeneity 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 B37.
Abstract B38: Calcium signaling induces a partial EMT in pancreatic ductal adenocarcinoma
Authors: Norgard Robert J. , Maddipati Ravikanth , Aiello Nicole M. , Balli David , Pitarresi Jason R. , Rosario-Berrios Derick N. , Li Jinyang , Yuan Salina , Yamazoe Taiji , Sela Yogev , Merrell Allyson J. , Wengyn Maximilian D. , Sun Kathryn , Rustgi Anil K. , Stanger Ben Z. 
Published: March 2020

Abstract
Metastasis and chemoresistance—the two main reasons for the high mortality of cancer—are associated with a form of cellular plasticity known as epithelial-to-mesenchymal transition (EMT). Cancer cells undergoing EMT become invasive, facilitating metastasis, and undergo a shift in their vulnerability to antineoplastic drugs. In recent work, it has been shown that EMT does not involve a single mechanism but rather a diversity of programs, yielding a continuum of cell phenotypes along the epithelial-mesenchymal spectrum. We previously developed a lineage-traced model of pancreatic ductal adenocarcinoma (PDA) to study EMT in the context of stochastically-arising tumors. As expected, epithelial-mesenchymal plasticity in some tumors involves transcriptional repression of the epithelial state, resulting in a “classical EMT” (C-EMT) phenotype. Surprisingly, however, epithelial-mesenchymal plasticity in the majority of tumors involves post-transcriptional repression of the epithelial state, resulting in a “partial EMT” (P-EMT) phenotype. These two plasticity programs are associated with other aspects of tumor biology as well, including distinct modes of cellular invasion. Here, we identify calcium signaling in pancreatic cancer cells as a regulator of the P-EMT phenotype. Prolonged calcium flux induces PDA cells to remove E-cadherin (ECAD) and other epithelial proteins from the surface and relocalize it intracellularly. This loss of the epithelial phenotype occurs without changes in the abundance of mRNAs for these proteins, reminiscent of the P-EMT phenotype observed in tumors in vivo. In addition, inhibition of the calcium-signaling protein calmodulin blunts this EMT-inducing effect. These results implicate calcium signaling as a mediator of partial EMT phenotypes.
Citation Format: Robert J. Norgard, Ravikanth Maddipati, Nicole M. Aiello, David Balli, Jason R. Pitarresi, Derick N. Rosario-Berrios, Jinyang Li, Salina Yuan, Taiji Yamazoe, Yogev Sela, Allyson J. Merrell, Maximilian D. Wengyn, Kathryn Sun, Anil K. Rustgi, Ben Z. Stanger. Calcium signaling induces a partial EMT in 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 B38.
Abstract B42: Patient stratification and precision medicine in pancreatic cancer: GemciTest, an innovative in vitro diagnostic for the decision-making process of pancreatic cancer treatment
Authors: Ritter Didier , Piquemal David , Noguier Florian , Pierrat Fabien , Bruno Roman 
Published: March 2020

Abstract
Pancreatic cancer is currently the 4th leading cause of death by cancer in Europe. If no action is taken, it is set to be 2nd by 2021. For nearly 80% of patients, diagnosis occurs at an advanced stage, too late (metastatic pancreatic adenocarcinoma; mPDAC), making them nonelective for surgery. The high mortality rate (less than 5% of patients alive at 5 years), is partly due to the difficulty to diagnose and to the lack of patients’ stratification for effective treatments. Despite advances in treatment and outcomes, the capability of biomarkers to improve treatment is potentially greater than in any other area of current medical research. Based on a multicenter, randomized, retrospective clinical phase III evaluation (ClinicalTrials.gov: NCT00789633), Acobiom identified an 11-gene blood signature and developed the GemciTest, an IVD associated with gemcitabine treatment in mPDAC. This blood signature evaluates both progression-free survival (PFS) and overall survival (OS) rates, and identifies the patients who are likely to benefit from 1st-line gemcitabine treatment. Briefly, the IVD allows to identify 37% of patients having a median overall survival of 15 months with 1-year survival rate superior to 65%. The GemciTest, a quantitative real-time PCR assay, is currently a prototype in an operational environment through a Clinician Peer Network in EU and US. In this context, Acobiom is always looking for new partnerships (public or private), the right way to open opportunities to develop the GemciTest solution for mPDAC patients (bench-to-bedside), and to assist physicians in routine patient care.
Citation Format: Didier Ritter, David Piquemal, Florian Noguier, Fabien Pierrat, Roman Bruno. Patient stratification and precision medicine in pancreatic cancer: GemciTest, an innovative in vitro diagnostic for the decision-making process of pancreatic cancer treatment [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 B42.
Abstract B45: IL35/STAT3 axis as regulator of tolerance and T-cell exclusion in pancreatic cancer
Authors: Mirlekar Bhalchandra , Michaud Daniel , Pylayeva-Gupta Yuliya 
Published: March 2020

Abstract
Pancreatic ductal adenocarcinoma (PDA) is an aggressive malignancy refractory to immunotherapeutic interventions. The mechanisms that drive robust immunosuppression and CD8+ T-cell dysfunction in PDA are not well known. Using the Kras- and p53-driven mouse model of pancreatic cancer, we show that activation of IL35/STAT3 pathways directs reprogramming of suppressive regulatory B-cell lineage and inhibits CD8+ T cells via suppression of gene program that regulates infiltration and effector function. Activation of STAT3 in CD8+ T cells is driven by B cell, but not Treg-specific production of cytokine IL35. Targeting IL35 via cell lineage-specific deletion or therapeutic anti-IL35 blockade converts PDA from CD8+ T cell low to high tumor and confers sensitivity to anti-PD1 immunotherapy. Therapeutic inhibition of STAT signaling in tumor-educated CD8+ T cells improves PDA growth control upon adoptive transfer to tumor-bearing animals. Finally, we identify IL35+ B cell subset in patients with PDA and demonstrate that the presence of IL35+ cells in tumor samples predicts increased occurrence of dysfunctional CD8+ T cells. Together, these data identify IL35/STAT3 signaling as an important mediator of immune tolerance and a direct link to CD8+ T-cell exclusion and immunotherapy resistance in PDA.
Citation Format: Bhalchandra Mirlekar, Daniel Michaud, Yuliya Pylayeva-Gupta. IL35/STAT3 axis as regulator of tolerance and T-cell exclusion 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 B45.
Abstract B51: Examining the differential cellular response of pancreatic cancer cell lines to 12C vs. photon irradiation
Authors: Saha Janapriya , Story Michael D. , Davis Anthony , Sishc Brock J. 
Published: March 2020

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is expected by 2020 to become the second most common cause of cancer-related deaths globally. The 5-year overall survival rate for patients with locally advanced nonresectable (LANR) PDAC is ~12%, likely because of the inherent resistance to conventional radio- and chemotherapy and the fact that the majority of pancreatic cancer patients present with advanced disease. While median overall survival (mOS) for chemoradiotherapy is 15.2 months, mOS determined from a retrospective analysis of patients with LANR PDAC treated with carbon ion therapy (CIRT) and concurrent gemcitabine was 21.5 months. Recently, UTSW initiated a randomized multi-institutional phase III trial (CIPHER) comparing CIRT to intensity-modulated radiation therapy for LANR PDAC. In conjunction with CIPHER, we initiated preclinical studies to exploit genetic vulnerabilities amenable to CIRT vs. IMRT. Eight PDAC cell lines with known genetic backgrounds were exposed to g-rays and 12C ions to determine the range of relative biologic effectiveness of 12C ion exposure. A specific area of interest is the DNA damage response given the vulnerability of tumor cells with slight deficiencies in genes associated with homologous recombination or replication fork maintenance to 12C ion exposure that is not seen with g-rays. Other endpoints being examined include differences in cell signaling that may affect inflammatory and immune responses, alterations to the microenvironment, or other signaling pathways that may identify druggable targets for combination with CIRT.
Citation Format: Janapriya Saha, Michael D. Story, Anthony Davis, Brock J. Sishc. Examining the differential cellular response of pancreatic cancer cell lines to 12C vs. photon irradiation [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 B51.
Abstract B56: Endogenous retrovirus transcript levels are associated with immunogenic signatures in multiple metastatic cancer types
Authors: Topham James T. , Titmuss Emma , Pleasance Erin , Williamson Laura M. , Karasinska Joanna M. , Culibrk Luka , Lee Michael K.C. , Kalloger Steve E. , Mendis Shehara , Moore Richard A. , Mungall Andrew J. , Laskin Janessa , Loree Jonathan M. , Mager Dixie L. , Marra Marco A. , Jones Steven J.M. , Schaeffer David F. , Renouf Daniel J. 
Published: March 2020

Abstract
Variability in the immunogenic landscape of metastatic cancer lesions has revealed insight into detection of potential immunotherapy-responsive patients, though underlying mechanisms driving such variation are not fully understood. Endogenous retrovirus (ERV)-containing transcripts have recently emerged as a potential source of tumor-associated antigen that are orthogonal to somatic mutation-derived neoantigens. To characterize the intersection between ERV levels and predicted immunogenicity in metastatic cancer, we comprehensively profiled the transcript abundance of 702,533 ERV loci in 199 metastatic tumors from breast, colorectal, and pancreatic cancer patients. In all three cancer types, overall ERV transcript load was associated with upregulation of genes involved in innate antiviral response pathways as well as genes involved in both adaptive and innate immune signaling. In colorectal and pancreatic tumors, samples with concomitant increases in ERV load and antiviral response gene expression, termed viral mimicry tumors, showed high expression of the DNA demethylation gene TET2, a gene previously described to promote transcription of ERV-containing transcripts. Collectively, these data are compatible with the notion that an increased level of ERV-containing transcripts may account for increased immunogenicity in a subset of metastatic tumors and support the relationship between DNA demethylation and ERV load in colorectal and pancreatic tumors.
Citation Format: James T. Topham, Emma Titmuss, Erin Pleasance, Laura M. Williamson, Joanna M. Karasinska, Luka Culibrk, Michael K.C. Lee, Steve E. Kalloger, Shehara Mendis, Richard A. Moore, Andrew J. Mungall, Janessa Laskin, Jonathan M. Loree, Dixie L. Mager, Marco A. Marra, Steven J.M. Jones, David F. Schaeffer, Daniel J. Renouf. Endogenous retrovirus transcript levels are associated with immunogenic signatures in multiple metastatic cancer types [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 B56.
Abstract C12: Lipids signaling contributes to glucose-independent metabolic adaptation in pancreatic ductal adenocarcinoma
Authors: Chen Ziheng , Liu Jintan , Ho I-Lin , Rose Johnathan , Yan Liang , Yao Wantong , Viale Andrea , Carugo Alessandro , Ying Haoqiang , Draetta Giulio 
Published: March 2020

Abstract
Increasing researches verify that mitochondrial oxidase phosphorylation (OXPHOS) plays remarkable roles in cancer initiation, development, and drug resistance. Our previous study identified that preclinic OXPHOS inhibitor IACS-010759 significantly suppressed cancer cell growth in brain cancer and acute myeloid leukemia (AML) in vivo and in vitro with very low compound concentration. In pancreatic ductal adenocarcinoma (PDAC), there were actually different responses to OXPHOS inhibition in glucose-independent conditions. Using patient-derived xenograft (PDX) model, we identified sensitive and resistant groups to IACS-010759, and there were dramatic metabolic changes to feed-back compound resistance. By metabolomics analysis, we found a novel lipids-signaling activation mechanism that is responsible for the adaptive metabolic resistance. Furthermore, combination of OXPHOS inhibitor and specific lipids pathway inhibitor showed significant cancer cell growth suppression in resistant PDAC types. Our findings uncovered a novel adaptive metabolism in drug resistance and provide new thoughts on therapy strategy in PDAC.
Citation Format: Ziheng Chen, Jintan Liu, I-Lin Ho, Johnathan Rose, Liang Yan, Wantong Yao, Andrea Viale, Alessandro Carugo, Haoqiang Ying, Giulio Draetta. Lipids signaling contributes to glucose-independent metabolic adaptation in 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 C12.