bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B049: Pancreatic beta cell stress pathways drive pancreatic ductal adenocarcinoma development in obesity
Authors: Garcia Cathy C. , Venkat Aarthi , Tong Alex , Agabiti Sherry , Lawres Lauren , Cardone Rebecca , Kibbey Richard , Krishnaswamy Smita , Muzumdar Mandar D 
Published: January 2024

Abstract
Epidemiologic studies have shown that obesity is a risk factor for more than a dozen cancers, including pancreatic ductal adenocarcinoma (PDAC). As PDAC is one of the leading causes of cancer-related death and obesity rates are rapidly increasing worldwide, it is imperative that we understand the mechanisms by which obesity promotes PDAC progression. To address this gap in knowledge, our lab combined a well-established genetic model for obesity (O: Lepob/ob) with a Kras-driven pancreatic cancer model (KC: Pdx1-Cre; KrasLSL-G12D/+) that mimics human PDAC progression. Resultant KCO mice had a drastic increase in tumor development compared to their lean counterparts, whereas induced weight loss intercepted tumor progression, showing that the tumor-promoting effects of obesity can be reversed. Bulk RNA sequencing of tumors from these mice revealed aberrantly increased expression of multiple peptide hormones expressed in insulin-producing beta (b) cells of pancreatic islets, including cholecystokinin (CCK) and amylin (Iapp). Strikingly, transgenic expression of CCK and Iapp in b-cells was sufficient to promote Kras-driven pancreatic tumorigenesis in non-obese mice. Single-cell RNA sequencing of b cells showed a trajectory of changes in gene expression with increasing obesity from wildtype to high-fat diet-fed to Lepob/ob mice. Further in silico analysis combining archetypal (AANet) with pseudotime (TrajectoryNet) methods demonstrated that b cells misexpressing hormones (CCK and Iapp) arose from a specific subtype of preexisting b cells, specifically virgin b cells, a rare, immature, regenerative population. Preliminary in vivo lineage tracing analyses in MIP-CreERT;LSL-TdTomato;Lepob/ob mice support these findings. Finally, we investigated the transcriptional networks that lead to aberrant CCK and Iapp expression in b cells. By combining Grainger causality analysis with known gene-gene relationships in the Transcriptional Regulatory Relationship Unraveled by Sentence-based Text mining (TRRUST) v2 database, we discovered a stress-induced mitogen-activated protein kinase (MAPK8)-cJun pathway that promotes pro-tumorigenic hormone expression in b cells. These combined experimental and computational methods nominate novel b cell targets to subvert the development of PDAC, an exocrine tumor.
Citation Format: Cathy C. Garcia, Aarthi Venkat, Alex Tong, Sherry Agabiti, Lauren Lawres, Rebecca Cardone, Richard Kibbey, Smita Krishnaswamy, Mandar D Muzumdar. Pancreatic beta cell stress pathways drive pancreatic ductal adenocarcinoma development in obesity [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B049.
Abstract B051: Investigating lipid homeostasis in pancreatic ductal adenocarcinoma under tumor-like stress
Authors: Han Xu , Burrows Michelle , Kim Laura , Mesaros Clementina , Tobias John , Keith Brian , Simon Celeste 
Published: January 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a 5-year survival rate of only 10%. One hallmark of PDAC’s tumor microenvironment is dense desmoplasia, due to abnormal accumulation of extracellular matrix and proliferative fibroblasts. During tumorigenesis, pancreatic stellate cells (PSCs) obtain myofibroblast-like signatures and contribute to the fibrotic environment of PDAC. Desmoplasia-induced hypovascularity severely limits oxygen and nutrient delivery. Our laboratory revealed that hypoxia is prominent even at the pancreatic intraepithelial neoplasia (PanIN) stage, a dominant precursor lesion of PDAC. Hypoxia inhibits oxygen-dependent metabolic processes. For example, unsaturated lipid biosynthesis relies on oxygen to maintain desaturase enzymatic activities. Hypoxia also stimulates lipid uptake. Previous studies demonstrated that RAS-transformed cells preferentially import unsaturated lysophosphatidylcholines (LPCs) from culture media. However, in a nutrient-limited fibrotic environment, the potential source of lipids is unclear. Interestingly, a lipidomic study of a PSC secretome displayed a significant amount of LPCs, suggesting that PSCs are the potential lipid source in the PDAC microenvironment. Our data indicate that exogenous unsaturated lipids sustain PDAC cell viability under hypoxia and nutrient deficiency. Moreover, we find PDAC cell survival under tumor-like stress is enhanced in PSC conditioned medium, but not in delipidated conditioned medium. Strikingly, we show that cancer-associated fibroblasts do not experience hypoxic stress as much as adjacent malignant epithelium cells in vivo, suggesting cancer-associated fibroblasts provide unsaturated (and other) lipids to PDAC cells. Based on our lipidomic mass spectra of PSC conditioned medium, we determined that LPCs are actively utilized by PDAC cells for phosphatidylcholine and triglyceride regeneration. By inhibiting LPC to PC conversion with the drug TSI-01, which targets LPCAT (acyltransferase), unsaturated LPC no longer sustains cancer cell survival and ER stress is reactivated. In this study, we demonstrated metabolic crosstalk between fibroblasts and PDAC cells under stress conditions. Our findings revealed a novel metabolic inhibitor to disrupt the metabolic crosstalk between PSC and pancreatic cancer cells which might benefit developing combinatorial therapy of PDAC.
Citation Format: Xu Han, Michelle Burrows, Laura Kim, Clementina Mesaros, John Tobias, Brian Keith, Celeste Simon. Investigating lipid homeostasis in pancreatic ductal adenocarcinoma under tumor-like stress [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B051.
Abstract B064: Redefining phenotypic heterogeneity of pancreatic ductal adenocarcinoma: A bottom-up approach
Authors: Hilmi Marc , Delecourt Flore , Rafenne Jerôme , Bourega Taib , Dusetti Nelson , Iovanna Juan , Blum Yuna , Richard Magali , Neuzillet Cindy , Couvelard Anne , De Mestier Louis , Rebours Vinciane , Nicolle Rémy , Cros Jérôme 
Published: January 2024

Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) tumor inter-patient heterogeneity has been well described with two major subtypes (classical and basal-like). An important intra-patient heterogeneity has not yet been extensively studied due to the lack of standardized and easily accessible high throughput methods compatible with clinical routine. Material and Methods: To build an immunohistochemical (IHC) tool capable of differentiating classical and basal-like tumors, relevant antibodies were selected using a multi-step process. The successive stages of an in-silico selection from the bulk transcriptome of 309 PDACs and 30 patient-derived xenografts followed by the validation on tissue microarrays in a cohort of PDAC (n=50) were conducted. We used our final IHC panel on whole slides of serial histology sections in 95 resected PDACs. After image registration, we performed a tile-based-analysis in tumoral and pre-neoplastic areas and a k-means clustering to identify relevant marker combinations. Results: Our final selection of the IHC panel included GATA6, CLN18, TFF1, MUC16, S100A2, KRT17, PanBasal. Among the 44,042 tumor tiles analyzed, 4 different phenotypes were identified: 1 classical (CLN18+, TFF1+, GATA6+), 1 intermediate (KRT17+) and 2 basal-like (MUC16+ vs S100A2+) with specific biological properties. A minor basal contingent drastically reduced overall survival (OS) in the multivariate analysis (HR=2.36, p=0.01). In contrast, the presence of the intermediate and classical clusters did not impact OS. However, among patients with PDAC expressing the classical cluster, a tremendous difference of OS was observed according to the co-occurence of a basal cluster (HR=0.34, p=0.003). These prognostic associations have been validated in an independent cohort of 150 patients with PDAC on tissue microarrays. By analyzing preneoplastic lesions, we showed the evolution process of pancreatic carcinogenesis going from a classical toward a basal through an early intermediate phenotype. Conclusion: Our restricted panel of antibodies could help pathologists to predict the high degree of PDAC heterogeneity, ultimately leading to an improvement of patient management.
Citation Format: Marc Hilmi, Flore Delecourt, Jerôme Rafenne, Taib Bourega, Nelson Dusetti, Juan Iovanna, Yuna Blum, Magali Richard, Cindy Neuzillet, Anne Couvelard, Louis De Mestier, Vinciane Rebours, Rémy Nicolle, Jérôme Cros. Redefining phenotypic heterogeneity of pancreatic ductal adenocarcinoma: A bottom-up approach [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B064.
Abstract B069: Double-stranded RNA derived from tandem repeat sequences induces mesenchymal transition in pancreatic cancer cells by regulating alternative splicing
Authors: Kishikawa Takahiro , Iwata Takuma , Otsuka Motoyuki , Fujishiro Mitsuhiro 
Published: January 2024

Abstract
Human satellite II (HSATII) composed of tandem repeats in pericentromeric regions in the human genome is aberrantly transcribed in epithelial cancers, particularly pancreatic cancer. Dysregulation of the repetitive elements in cancer tissues can facilitate incidental double-stranded RNA formation. However, it remains controversial whether double-stranded RNAs play tumor-promoting or tumor-suppressing roles during cancer progression. Therefore, we focused on the formation of double-stranded HSATII (dsHSATII) RNA and explored its molecular functions. The overexpression of dsHSATII RNA promoted mesenchymal-like morphological changes and enhanced the invasiveness of pancreatic cancer cells. We identified an RNA-binding protein, STRBP, which preferentially binds to dsHSATII RNA rather than single-stranded HSATII RNA. Depletion of STRBP induced the mesenchymal transition and enhanced the invasiveness. Conversely, the epithelial–mesenchymal transition (EMT) of dsHSATII-expressing cells was rescued by STRBP overexpression. Mechanistically, STRBP is involved in the alternative splicing of genes associated with the EMT events, which was interfered by the overexpression of dsHSATII RNA. Finally, we confirmed that isoform switching of CLSTN1, one of the target genes of STRBP-associated alternative splicing, induced EMT-like morphological changes. These findings reveal a novel cell-autonomous function of dsHSATII RNA in enhancing malignant potential, providing a better understanding of the biological significance of aberrant expression of satellite arrays in malignant tumors.
Citation Format: Takahiro Kishikawa, Takuma Iwata, Motoyuki Otsuka, Mitsuhiro Fujishiro. Double-stranded RNA derived from tandem repeat sequences induces mesenchymal transition in pancreatic cancer cells by regulating alternative splicing [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B069.
Abstract B104: Epigenetic small molecule library screen to discover compounds that inhibit and reverse pancreatic acinar to ductal metaplasia
Authors: Perkins Corey M. , Atanasova Kalina R. , Ratnayake Ranjala , Jiang Jinmai , Chen Qi-Yin , Schmittgen Thomas D. , Luesch Hendrik 
Published: January 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) development is believed to be preluded by the event of acinar to ductal metaplasia (ADM), the transdifferentiation of acinar cells into a duct-like state. It is widely accepted that either acinar or ductal cells bearing mutant Kras drive the development of PDAC. We have previously shown that we can inhibit and reverse ADM in a 3D organoid assay using primary pancreatic tissue from p48Cre/+LSL-KRASG12D/+ mice using the histone deacetylase inhibitor (HDACi), Trichostatin A (Da Silva, 2022). We further employed our 3D organoid model to perform a phenotypic and molecular screening of 144 epigenetic compounds. We identified class I HDACi, FK228, and the histone methyltransferase inhibitor, Chaetocin, as the top hits of reversing ADM without inducing cytotoxicity as assessed by calcein AM staining. Largazole homodomer, a novel HDACi derived from marine cyanobacteria, was also identified as both an inhibitor and reversal agent of ADM. These three compounds demonstrated phenotypic and molecular reversal of duct-like structures back into their acinar state, in addition to relative mRNA upregulation of acinar markers (Amy2a, Cela1, Cpa2) and downregulation of ductal markers (Krt19, Krt7, Sox9). Bulk-RNA sequencing combined with pathway analysis demonstrated pronounced inhibition of cancer signaling pathways during ADM reversal, such as TGFβ1, Vegf, TNF, IL-6, and STAT3. Moreover, RNA sequencing showed significant upregulation and downregulation of acinar and ductal/PDAC markers, respectively. Thus, a novel phenotypic small molecular screen based on organoid morphology was developed to discover compounds that inhibit and reverse pancreatic ADM in a mouse model with mutant Kras.
Citation Format: Corey M. Perkins, Kalina R. Atanasova, Ranjala Ratnayake, Jinmai Jiang, Qi-Yin Chen, Thomas D. Schmittgen, Hendrik Luesch. Epigenetic small molecule library screen to discover compounds that inhibit and reverse pancreatic acinar to ductal metaplasia [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B104.
Abstract B109: Reinforcing risk prediction for intraductal papillary mucinous neoplasms of the pancreas with AI-optimized nucleotide-to-amino acid analyses
Authors: Nguyen Nam , Teer Jamie K. , Park Margaret A. , McDonald Patricia , Fleming Jason B. , Permuth Jennifer B. , Chen Kwang-Cheng , Karolak Aleksandra 
Published: January 2024

Abstract
Intraductal papillary mucinous neoplasms (IPMNs) often precede invasive pancreatic ductal adenocarcinoma, with each IPMN tumor carrying a 10-25% risk of progressing to cancer within 10 years of detection. The objective of this work is to employ AI-augmented analyses of single mutations occurring at specific tri-nucleotide sequences or codons and identify markers associated with the progression of cysts to pancreatic cancer. Despite being precursors of pancreatic cancer there is a lack of validated intervention targets for precision prevention for IPMNs. Currently cancer prevention for patients with IPMN is centered on surgery using a risk-tailored approach; the clinical ability to stratify risk of cancer progression of individual IPMN tumors is poor and essentially no effective non-surgical interventions exist. To advance the precision cancer prevention for IPMNs we develop an intelligent, machine learning (ML) derived framework addressing the challenge of IPMN stratification from samples with limited data space, e.g., somatic mutations. Our study incorporates the text-based statistical and ML analyses of the mutational profiles of patients’ genomes followed by an integration of codon sequence derived mutational features for biomarkers validation. Given the potential of genome spatial organization to understand mutagenesis and genomic instability, we also map the DNA sequence information onto the local spatial genome organization to elucidate intrinsic features and molecular mechanisms that potentially lead to mutations. Results of this study show that information extracted from mutational profiles with the proposed methods significantly improves performance of the ML models in stratification of IPMNs and biomarker identification. We also present how utilization of these ML tools for mutational data, spatial genome organization, and functional analyses from tumor samples, can aid understanding of the underlying mechanisms of mutations in IPMNs and pancreatic cancer.
Citation Format: Nam Nguyen, Jamie K. Teer, Margaret A. Park, Patricia McDonald, Jason B. Fleming, Jennifer B. Permuth, Kwang-Cheng Chen, Aleksandra Karolak. Reinforcing risk prediction for intraductal papillary mucinous neoplasms of the pancreas with AI-optimized nucleotide-to-amino acid analyses [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B109.
Abstract B112: Single-cell profiling of neoplastic cell populations in a KRAS-initiated zebrafish pancreatic cancer model
Authors: Matar Somer M. , Goodale Britton C. , Liu Xiaoying , Katanga Annie , Gallien Nicole F. , Blazquez Sandra , Alonso-Curbelo Direna , Leach Steven D. 
Published: January 2024

Abstract
While the majority of human pancreatic cancers are classified as ductal adenocarcinomas, the cell of origin of these tumors remains uncertain and many tumors are comprised of dedifferentiated cell types, making it imperative to understand the full spectrum of neoplastic differentiation and how it is regulated. We have developed a new zebrafish model of pancreatic cancer driven by tissue-specific expression of UAS:mK02-KRASG12D under the regulation of a Ptf1a:Gal4/VP16 transcriptional driver. Transgenic zebrafish generate mixed tumors comprised histologically of mixed acinar and ductal elements, providing the opportunity to interrogate specific transcriptional and epigenetic modifiers responsible for regulating neoplastic pancreatic cellular differentiation. Single-cell RNA sequencing of these tumors has confirmed neoplastic cell populations expressing exclusively acinar and ductal markers, as well as distinct clusters expressing markers of both cell lineages. Screening a panel of 21 unique chromatin modifiers and chromatin readers for differential expression in these distinct cell clusters reveals hdac9b to be upregulated in the progenitor-like ductal population. Gain- and loss-of-function genetic studies will be used to determine the functional role of hdac9b in generating distinct neoplastic cell differentiation states. We are also generating pseudo-time trajectory inferences to further determine the directionality of differentiation states in these cells. By generating new insights into regulation of distinct differentiation states in pancreatic cancer, we hope that new strategies for therapeutic manipulation of neoplastic cell differentiation will emerge.
Citation Format: Somer M. Matar, Britton C. Goodale, Xiaoying Liu, Annie Katanga, Nicole F. Gallien, Sandra Blazquez, Direna Alonso-Curbelo, Steven D. Leach. Single-cell profiling of neoplastic cell populations in a KRAS-initiated zebrafish pancreatic cancer model [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B112.
Abstract C043: Spatial proteomic immune profiling of pancreatic ductal adenocarcinoma and the tumor microenvironment
Authors: Yeung Jason , Bai Yunhao , Yeo Yao Yu , Qiu Huaying , Zhu Bokai , Heij Lara R. , Shah Enas Abu , Nolan Garry P. , Sivakumar Shivan , Jiang Sizun 
Published: January 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with poor prognosis and treatment options. Technological challenges in dissecting the immune constituents of the PDAC tumor microenvironment (TME) has limited our understanding of the complex disease mechanisms in vivo, which may in part explain the lack of novel therapeutics for this recalcitrant disease. Here, we performed spatial proteomics using the multiplexed ion beam imaging (MIBI) approach to quantify 36 spatial signatures in tissues from a cohort of twelve treatment naïve PDAC patients. We applied a deep learning segmentation algorithm to better resolve expression levels at the single cell resolution, and robustly stratify phenotypes through an iterative process of clustering and annotation, with expert visual validation. The combination of phenotypic quantification, functional marker evaluation within the cell types identified, as well as machine-learning based topic modeling to understand cellular neighborhoods, can better explain the cellular and functional components within the intricate PDAC TME. Our analysis revealed markedly lower B and effector T cell infiltration in the treatment-naive TME of patients who eventually relapsed to date following adjuvant chemotherapy. We additionally observed the enrichment of myeloid cell populations, including tumor-associated macrophages and neutrophils, associated with PDAC tumorigenesis and worse prognosis. A deeper analysis of our functional protein expression exhibited the enrichment of GATA3 in regulatory T cells in relapsed patients, a marker which has been associated with increased accumulation and infiltration of Tregs at inflammatory sites. Our study demonstrates the importance of a targeted dissection of the spatially orchestrated immune responses and dysregulation associated with PDAC, and exemplifies how a deeper understanding of the immune and tumor components and functional aspects in situ can help improve our understanding for patients with this disease.
Citation Format: Jason Yeung, Yunhao Bai, Yao Yu Yeo, Huaying Qiu, Bokai Zhu, Lara R. Heij, Enas Abu Shah, Garry P. Nolan, Shivan Sivakumar, Sizun Jiang. Spatial proteomic immune profiling of pancreatic ductal adenocarcinoma and the tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C043.