bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A059: Targeting pancreatic cancer metabolic dependencies through glutamine antagonism
Authors: Encarnacion-Rosado Joel , Kimmelman Alec C. , Wild Robert 
Published: January 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest types of cancer. A factor that contributes to the poor prognosis of the disease is the complex tumor microenvironment (TME). The PDAC TME is composed of excessive fibrosis and desmoplasia, which creates a harsh environment resulting in hypoxia and altered nutrient availability. To promote survival and proliferation in this environment, PDAC cells can reprogram glutamine (Gln) metabolism. Previous studies have demonstrated that PDAC cells use Gln to support proliferation and redox balance. However, earlier attempts to inhibit Gln metabolism using glutaminase inhibitors resulted in rapid metabolic reprogramming and therapeutic resistance. We hypothesized that a Gln analogue, such as 6-Diazo-5-oxo-L-norleucine (DON), could broadly target Gln metabolism in PDAC and prevent rapid adaptation. Indeed, DON treatment led to a significant decrease in PDAC proliferation and a profound reduction of various metabolites involved in central carbon and nucleotide metabolism, suggesting that DON creates a metabolic crisis. In addition, we observed a significant decrease in tumor growth in various in vivo models (syngeneic, immunodeficient and PDXs) using DRP-104 (sirpiglenastat), a novel pro-drug version of DON that was designed to circumvent DON associated GI toxicity and allow the therapeutic exploration of broad Gln antagonism. Mechanistically, we found that ERK signaling is increased as a compensatory mechanism through the increased activity of receptor tyrosine kinases (RTKs). Combinatorial treatment of DRP-104 and Trametinib (MEK1/2) inhibitor led to a significant increase in survival in a syngeneic model PDAC. Taken together, these pre-clinical results suggest that broadly targeting Gln metabolism could provide a new therapeutic avenue for PDAC and that the combination with an ERK signaling pathway inhibitor could further improve the therapeutic outcome.
Citation Format: Joel Encarnacion-Rosado, Alec C. Kimmelman, Robert Wild. Targeting pancreatic cancer metabolic dependencies through glutamine antagonism [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 A059.
Abstract A095: ZNF274 suppresses the mesenchymal state, thereby causing intrinsic resistance to CDK7 inhibition
Authors: Gianopulos Jessica , Wallace-Povirk Adrianne , Kugel Sita 
Published: January 2024

Abstract
Pancreatic Ductal Adenocarcinoma (PDA) can be characterized by two distinct transcriptional subtypes: classical and basal. The basal PDA subtype is more aggressive and has the worst overall survival. We have previously shown that the histone deacetylase (HDAC) Sirtuin 6 (SIRT6), a marker of the classical PDA subtype, can control sensitivity to CDK7 inhibitors. Interestingly, SIRT6 is part of the KAP1 repressive complex where it functions as an HDAC. This complex functions to maintain heterochromatin at specific regions of the genome by removing marks of open chromatin and installing marks of repressive chromatin with histone methyltransferases (HMT) and DNA methyltransferases (DNMT). The complex relies on a KRAB-Zinc Finger protein to bind DNA directly and modify chromatin at those regions. Since we found that SIRT6 can control sensitivity to CDK7 inhibition, we hypothesized that the KAP1 repressive complex is crucial for maintaining subtype-specific chromatin states and that manipulation of any part of this complex could alter subtype, thereby changing sensitivity to CDK7 inhibition. In a survey of basal and classical PDA cell lines, we found that the KRAB-Zinc Finger ZNF274 showed substantial differential expression, similar to SIRT6, and correlated with overall patient survival. We validated ZNF274 expression in PDA cell lines and organoids by western blot and immunofluorescence and found that classical PDA expressed high levels of ZNF274. Next, we investigated how loss of ZNF274 would affect classical PDA cells and found that knockdown of this protein induced an epithelial-to-mesenchymal (EMT) transition through increased ZEB1 expression. We analyzed protein and RNA expression of more EMT regulators and identified morphological changes representative of EMT. Therefore, this induction of EMT upon loss of ZNF274 could be initiating a subtype switch from classical PDA to basal. To determine if loss of ZNF274 and induction of the mesenchymal state could sensitize cells to CDK7 inhibition as we have previously shown, we performed ZNF274 knockdown in classical PDA and saw a dramatic increase in sensitivity to CDK7 inhibitors. Therefore, we have shown the KAP1 repressive complex to be important in regulating cell state and sensitivity of classical PDA to CDK7 inhibitors which we hope to exploit to improve patient responses to CDK7 inhibition therapy.
Citation Format: Jessica Gianopulos, Adrianne Wallace-Povirk, Sita Kugel. ZNF274 suppresses the mesenchymal state, thereby causing intrinsic resistance to CDK7 inhibition [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 A095.
Abstract A100: KRAS inhibition targets and depends on pro-oncogenic HuR in PDAC cells
Authors: Halamish Hen , Bush Michaela , Smith Alexander , Sears Rosalie , Brody Jonathan 
Published: January 2024

Abstract
The Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation is found in more than 90% of patients with pancreatic ductal adenocarcinomas (PDACs), making it a prime target for therapeutic drug development. HuR (ELAVL1) has been extensively studied in the context of PDAC and also plays a key role in PDAC progression and chemoresistance. In recent years, researchers have shed light on the specific role of the HuR protein in PDAC and its relationship with KRAS signaling. Using in KRASG12D – mutant patient derived models, cell lines derived from GEMM models, and conventional cell lines, we found that HuR CRISPR knock out lines showed more than 80-fold resistance to MRTX1133 (a KRAS inhibitor targeted against G12D mutation) compared to wild type cells. Furthermore, western blot and immunofluorescence studies demonstrated that therapeutic inhibition of KRAS, inhibited HuR protein expression and subcellular localization in as early as 3 hours post-treatment. Furthermore, HuR protein levels decreased post-treatment even under nutrient starvation. Herein, we show that the presence of HuR is necessary for the efficacy of KRAS targeting and Kras inhibition can rapidly degrade HuR protein levels and its active subcellular localization. Mechanistic studies determining the molecular interaction between HuR and KRAS and KRAS related proteins and mRNAs are underway. Taken together with ongoing studies, we are exploring the importance of HuR as a key downstream target of KRAS’ oncogenic activity and if the loss of HuR may be a potent, PDAC therapeutic resistance mechanism. Understanding the interplay between KRAS and HuR could offer a novel strategy to disrupt the oncogenic KRAS signaling cascade and overcome the potential inherent resistance of KRAS-mutant PDACs to promising, KRAS-targeted therapies.
Citation Format: Hen Halamish, Michaela Bush, Alexander Smith, Rosalie Sears, Jonathan Brody. KRAS inhibition targets and depends on pro-oncogenic HuR in PDAC cells [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 A100.
Abstract A102: Secreted frizzled related-protein 2 is prognostic for survival in pancreatic cancer
Authors: Hsu Lillian , Siegel Julie , Nasarre Patrick , Mukherjee Rupak , Gormley Meghan , Richardson Bailey , Morningstar Jordan , Khan Imran , Hilliard Eleanor , O’Bryan John , Helke Krist , Spruill Laura , Dolloff Nathan , Klauber-Demore Nancy 
Published: January 2024

Abstract
INTRODUCTION: Secreted frizzled-related protein 2 (SFRP2) is overexpressed in several tumor types and blocks tumor apoptosis, increases angiogenesis, and promotes T-cell exhaustion. It has also been shown to be associated with fibrosis in non-neoplastic pathologies. We hypothesize SFRP2 is prognostic for survival and associated with PDAC fibrosis and mesenchymal transformation. METHODS: SFRP2 gene expression and protein levels in patients with PDAC were analyzed using NCI’s The Cancer Genome Atlas (TCGA) data and data from resected tumors analyzed for protein levels by western blot. Disease free survival (DFS) and overall survival (OS) were analyzed using Kaplan Meier test. The association of stroma content and SFPR2 RNA expression in human PDAC was studied using Spearman correlation between the ESTIMATE algorithm stromal score and TCGA data. The GEPIA tool was used to compare SFRP2 mRNA levels between PDAC and normal pancreas tissue. Immunohistochemistry (IHC) for SFRP2 in KPC PDAC tumors were correlated with fibrosis stains Picrosirus red and Massone trichome. The role of SFRP2 in mesenchymal transformation was assessed by western blot in fibroblasts. RESULTS: TCGA RNAseq analysis of SFRP2 expression showed highest SFRP2 mRNA levels in pancreatic cancer out of 32 cancer types. GEPIA analysis of PDAC (n=179) and normal pancreas (n=177) mRNA data showed higher levels of SFRP2 mRNA in PDAC compared to normal pancreas (p&lt;.01). High SFRP2 mRNA levels were associated with decreased disease-free survival hazard ratio = 2.6; p=0.0097). PDAC tissue showed higher SFRP2 protein compared to matched normal-adjacent tissue (n=24, p=0.0003). High SFRP2 expression was associated with decreased OS (p=0.0158. The ESTIMATE stromal score correlated with SFRP2 expression in human PDAC (Spearman correlation coefficient 0.81). Fibrosis levels in KPC PDAC tumors correlated with SFRP2 IHC (Spearman correlation coefficient 0.75). Fibroblasts treated with SFRP2 and TGFβ showed higher mesenchymal markers compared to untreated control. CONCLUSIONS: SFRP2 is increased in PDAC, associated with tumor fibrosis, and prognostic for survival. SFRP2 is a novel therapeutic target in PDAC.
Citation Format: Lillian Hsu, Julie Siegel, Patrick Nasarre, Rupak Mukherjee, Meghan Gormley, Bailey Richardson, Jordan Morningstar, Imran Khan, Eleanor Hilliard, John O’Bryan, Krist Helke, Laura Spruill, Nathan Dolloff, Nancy Klauber-Demore. Secreted frizzled related-protein 2 is prognostic for survival in pancreatic cancer [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 A102.
Abstract B013: Effect of aging on pancreatic cancer progression
Authors: Bhullar Deepika , Maganti Swetha , Zhang Yijuan , Galapate Cheska Marie , Murad Rabi , Adams Peter D. , Commisso Cosimo 
Published: January 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly invasive disease mainly seen in older adults. Most pancreatic cancer cases occur in individuals who are over the age of 60, and the risk continues to increase with each decade of life, with the median age at diagnosis for PDAC being around 70 years old. Why age is a significant risk factor in PDAC remains unanswered question. To examine the impact of organismal age on PDAC progression, we used a syngeneic orthotopic mouse model of PDAC in young and old animals. We found that the growth of primary tumors was significantly enhanced in the older mice indicating that organismal age can influence tumor progression. We also found that older mice had increased metastatic tumor burden in the liver, intestines and diaphragm. To gain a comprehensive view of how age might be affecting PDAC progression, we performed transcriptomics on the tumors derived from young or old animals. Strikingly, using gene set enrichment analysis (GSEA), we found that epithelial-mesenchymal transition (EMT) and extracellular matrix (ECM) molecule deposition-related signatures were enriched in the old mice, suggesting that the enhanced metastasis that we observed in old animals could be related to changes in the ECM. Moreover, we also identified various immune cell signatures that were enriched in the old or young mice, suggesting that the immune contexture dramatically changes depending on the age of the organism. These ECM and immune cell signatures were validated histologically. Based on these preliminary data, our working hypothesis is that the tumor stroma in old versus young organisms plays a critical role in PDAC progression, and we are employing various in vitro and in vivo techniques to test this idea.
Citation Format: Deepika Bhullar, Swetha Maganti, Yijuan Zhang, Cheska Marie Galapate, Rabi Murad, Peter D. Adams, Cosimo Commisso. Effect of aging on pancreatic cancer progression [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 B013.
Abstract B024: Hypoxia at 3D organoid establishment selects essential subclone within heterogenous pancreatic cancer
Authors: Kumano Koichiro , Nakahashi Hiromitsu , Louphrasitthiphol Pakavarin , Kuroda Yukihito , Miyazaki Yoshihiro , Shimomura Osamu , Hashimoto Shinji , Akashi Yoshimasa , Mathis Bryan James , Kim Jaejeong , Owada Yohei , Oda Tatsuya 
Published: January 2024

Abstract
Hypoxia is a key microenvironment associated with malignant traits, including epithelial-mesenchymal transition (EMT) and chemotherapy resistance. Pancreatic ductal adenocarcinoma (PDAC) is extremely hypoxic due to hypovascularity and abundant stromal proliferation. This severe condition accelerates the emergence of hypoxia-adapted cells, which contaminate PDAC as a heterogeneous population. Thus, analyzing hypoxia-adapted cells should be prioritized in analyzing/developing PDAC therapeutic strategies. Recently, 3D organoid culture has been widely used to simulate various organ cancers, featuring precise control with respect to cellular selection through diverse culture conditions. However, as the technology of single-cell analysis has revealed more details of the heterogeneity, the current 3D organoid culture system was also known to have limitation that the system has some potential selection bias. Although several selection biases have been identified, very few reports have focused on oxygen concentrations as a selection bias, leaving room for intervention. To overcome the potential selection bias, we focused on oxygen concentration during the establishment of 3D organoids. We subjected identical PDAC surgical samples to normoxia (O2 20%) or hypoxia (O2 1%) from primary culture, yielding glandular and solid organoid morphology, respectively. Pancreatic cancer organoids established under hypoxia displayed higher expression of EMT-related proteins, a Moffitt basil-like subtype transcriptome, and higher 5-FU resistance in contrast to established organoids under normoxia. We suggest that hypoxia during organoid establishment efficiently selects for hypoxia-adapted cells possibly responsible for PDAC malignant traits, facilitating a fundamental source for elucidating and developing new treatment strategies against recalcitrant PDAC.
Citation Format: Koichiro Kumano, Hiromitsu Nakahashi, Pakavarin Louphrasitthiphol, Yukihito Kuroda, Yoshihiro Miyazaki, Osamu Shimomura, Shinji Hashimoto, Yoshimasa Akashi, Bryan James Mathis, Jaejeong Kim, Yohei Owada, Tatsuya Oda. Hypoxia at 3D organoid establishment selects essential subclone within heterogenous pancreatic cancer [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 B024.
Abstract B026: αvβ5 Integrin serves as a tumor-specific marker for immunosuppressive regulatory T cells in pancreatic cancer
Authors: Kunisada Yuki , Suzuki Kodai , Miyamura Norio , Eikawa Shingo , de Mendoza Tatiana Hurtado , Mose Evangeline S. , Lu Caisheng , Kuroda Yukihito , Ruoslahti Erkki , Lowy Andrew M. , Sugahara Kazuki N. 
Published: January 2024

Abstract
Regulatory T cells (Tregs) contribute to the immunosuppressive nature of pancreatic ductal adenocarcinoma (PDAC). Systemic depletion of Tregs can enhance anti-tumor T cell immunity, but can also cause unwanted autoimmune complications. A tumor-specific Treg-targeted therapy that effectively and safely enhances anti-tumor immunity for PDAC treatment remains an unmet need. We have recently found that αvβ5 integrin is expressed on Tregs that reside in the PDAC, but not those in the spleen, suggesting that the integrin can serve as a targetable marker for tumor-resident Tregs. Indeed, long-term treatment with the iRGD tumor-penetrating peptide, which effectively targets αvβ5+ cells in PDAC tissue, depleted Tregs in a tumor-specific manner leading to a significant expansion of CD8+ T cells in transgenic and syngeneic PDAC mouse models. αvβ5+ Tregs were induced from both naïve CD4+ T cells and naturally occurring Tregs. T cell receptor stimulation was found to be the common inducer of αvβ5+ Tregs. αvβ5+ Tregs formed a subpopulation of CCR8+ Tregs, which are preferentially found in the tumor tissue of various cancer types. Our most recent data show that the αvβ5 integrin marks a highly immunosuppressive fraction of the CCR8+ Tregs, suggesting that targeting αvβ5+ Tregs can lead to effective depletion of immunosuppressive Tregs in a tumor-specific manner.
Citation Format: Yuki Kunisada, Kodai Suzuki, Norio Miyamura, Shingo Eikawa, Tatiana Hurtado de Mendoza, Evangeline S. Mose, Caisheng Lu, Yukihito Kuroda, Erkki Ruoslahti, Andrew M. Lowy, Kazuki N. Sugahara. αvβ5 Integrin serves as a tumor-specific marker for immunosuppressive regulatory T cells in pancreatic cancer [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 B026.
Abstract B030: Spatial coupling of microbes and immune cells shapes the tumor microenvironment in human cancers
Authors: Li Yan , Chang Renee B. , Stone Meredith L. , Xue Yuqing , Coho Heather , Markowitz Kelly , Patel Dhruv , Herrera Veronica M. , Li Joey H. , Delman Devora , Zhang Liti , Choi-Bose Shaanti , Giannone Michael , Lee Jae W. , Beatty Gregory 
Published: January 2024

Abstract
Microbes play a crucial role in the tumor microenvironment, yet the factors governing their presence within tumors remain poorly understood. In this study, we employed advanced in situ spatial-profiling technologies to investigate the relationship between microbial and immune cell heterogeneity in human lung and pancreas cancers. We observed a spatial coupling between microbes and immune cells, which was also replicated in mouse models of pancreatic cancer. Within the tumor, distinct niches characterized by T cell abundance or scarcity exhibited varied microbial diversity and compositions associated with immunologically active and quiescent phenotypes. Interestingly, gut microbiome are similar between mice bearing T cell- enriched or T cell-poor pancreas tumors. Depletion of intra-tumoral bacteria resulted in reduced tumor growth specifically in T cell-poor tumors and altered the phenotype and presence of myeloid and B cells in T cell-enriched tumors, without affecting T cell infiltration. Conversely, depletion of T cells disrupted the immunological state of tumors and led to a decrease in intra-tumoral bacteria. Our findings highlight a tight interplay between microbes and T cells in the tumor microenvironment, where spatially defined immune-microbial communities differentially influence tumor biology.
Citation Format: Yan Li, Renee B. Chang, Meredith L. Stone, Yuqing Xue, Heather Coho, Kelly Markowitz, Dhruv Patel, Veronica M. Herrera, Joey H. Li, Devora Delman, Liti Zhang, Shaanti Choi-Bose, Michael Giannone, Jae W. Lee, Gregory Beatty. Spatial coupling of microbes and immune cells shapes the tumor microenvironment in human cancers [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 B030.
Abstract B035: Investigating the roles of GLI transcription factors in the pancreatic cancer microenvironment
Authors: Medina-Cabrera Paola Isabel , Scales Michael , Steele Nina , Allen Benjamin , di Magliano Marina Pasca 
Published: January 2024

Abstract
Pancreatic ductal adenocarcinoma (PDA) remains a difficult cancer to treat due to an extensive and complex tumor microenvironment. In particular, intercellular signaling between tumor cells, fibroblasts and immune cells is a key contributor to pancreatic tumor growth. One of these signals, the Hedgehog (HH) pathway, is a known feature of PDA. Pancreatic tumor cells secrete HH ligands, which signal in a paracrine fashion to fibroblasts in the tumor microenvironment. Notably, the role of HH signaling is complicated, with reports suggesting both tumor-promoting and tumor-restraining functions in pancreatic cancer. GLI proteins (GLI1-3) are the transcriptional effectors of the HH pathway; their contribution to pancreatic tumor growth is equally complex. This study seeks to investigate the contribution of GLI1-3 in PDA progression. Our lab has demonstrated that Gli1-3 are expressed in pancreatic fibroblasts and that all three Glis functionally contribute to pancreatic cancer progression through effects on immune cell infiltration. To further explore the mechanisms of GLI function, we have generated a novel mouse model carrying endogenous, epitope-tagged Gli alleles (Gli1FLAG/FLAG;Gli2HA/HA;Gli3V5/V5). This model will allow us to define GLI protein processing and localization as well as the identification of target genes to elucidate the contribution of GLI-driven transcriptional programs that regulate tumor immune infiltration in PDA.
Citation Format: Paola Isabel Medina-Cabrera, Michael Scales, Nina Steele, Benjamin Allen, Marina Pasca di Magliano. Investigating the roles of GLI transcription factors in the pancreatic cancer 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 B035.