bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C044: PI5P4Kα regulates cell fitness through iron homeostasis in pancreatic cancer
Authors: Arora Gurpreet Kaur , Loughran Ryan , Ly Kyanh , Galapate Cheska Marie , Llorente Alicia , Anderson Taylor R , Pauli Chantal , Scott David A , Altman Yoav , Commisso Cosimo , Emerling Brooke M 
Published: September 2024

Abstract
PI5P4Ks (Phosphatidylinositol 5-phosphate 4-kinases) are a family of lipid kinases that phosphorylate phosphatidylinositol 5-monophosphate (PI-5-P) at the 4-position to generate distinct pools of phosphatidylinositol 4,5-bisphosphate (PI-4,5-P2) largely on intracellular membranes. These lipid species are involved in cellular and metabolic stress responses, signaling and organelle communication. PI5P4Ks have been implicated in multiple cancers, with compelling evidence showing synthetic lethality when PI5P4Ks are inhibited in TP53-mutant cancer cells. Pancreatic ductal adenocarcinoma (PDAC) is characterized by extensive metabolic rewiring but despite the critical roles of PI5P4Ks in cellular metabolism, their role in PDAC remains completely unexplored. We have found that depletion of PI5P4Kα selectively induces apoptotic cell death in PDAC cells. To gain insights into the metabolic mechanisms underlying this apoptotic cell death, we quantified polar metabolites using gas chromatography- mass spectrometry (GC/MS) and found significant reductions in the ratio of monounsaturated to saturated fatty acids, lactate and TCA metabolites. Orthogonal rescue assays demonstrated that exogenous supplementation with fatty acids, pyruvate or lactate fail to rescue the observed apoptosis in PI5P4Kα-knockdown cells; however, TCA cycle metabolites did reverse the extent of apoptosis. Interestingly, we identify that these altered metabolic read-outs and the effects on cell fitness are dependent on iron. Consistent with these findings, intracellular iron levels are reduced upon PI5P4Kα inhibition, and this is directly linked to PI5P4Kα depletion disturbing the intracellular labile iron pools via iron import. Using a heterotopic xenograft mouse model, we demonstrate that PI5P4Kα knockdown leads to the abrogation of PDAC tumor growth due to increased intratumoral cell death. Validating the physiological relevance of PI5P4Kα in human PDAC, we find that PIP4K2A, the gene that encodes PI5P4Kα, is upregulated in human PDAC specimens relative to normal pancreas, and that PIP4K2A gene expression is strongly correlated with iron uptake related gene signatures. This study highlights the critical role of PI5P4Kα in PDAC and suggests that PI5P4Kα inhibition has therapeutic potential in pancreatic cancer.
Citation Format: Gurpreet Kaur Arora, Ryan Loughran, Kyanh Ly, Cheska Marie Galapate, Alicia Llorente, Taylor R Anderson, Chantal Pauli, David A Scott, Yoav Altman, Cosimo Commisso, Brooke M Emerling. PI5P4Kα regulates cell fitness through iron homeostasis in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C044.
Abstract C045: Targeting metabolic heterogeneity in pancreatic ductal adenocarcinoma
Authors: Morningstar Taryn , Anaraki Cecily , Scipioni Lorenzo , Tedeschi Giulia , Digman Michelle , Edinger Aimee , Jorgensen Claus , Fishel Melissa , Halbrook Christopher J 
Published: September 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death in the US. This poor prognosis is related to the complex tumor microenvironment and tumor heterogeneity that drives resistance to chemotherapy. Here the heterogeneity of the stromal, immune, and malignant epithelial cell populations enables signaling and metabolic crosstalk mechanisms that drive immune suppression and resistance to therapy. Recently, our group unveiled that multiple distinct metabolic subclasses of cancer cells coexist within individual PDAC tumors. Among these, two PDAC clonal populations can engage in metabolic symbiosis that supports mitochondrial metabolism. One subtype has a constitutively high integrated stress response (ISR), enabling resistance to mitochondrial inhibitors. Further, these cells release asparagine that supports the mitochondrial metabolism of the other subtype that are more sensitive to mitochondrial inhibition. Given these observations, we are developing approaches to disrupt this metabolic symbiosis. Clonal PDAC cells with constitutively active ISR exhibit increased sensitivity to inhibition of the redox activity of Redox factor 1/Apurinic-apyrimidinic endonuclease 1 (Ref-1). Importantly, this can be leveraged to disrupt the support of the mitochondrial metabolism of clonal symbiotic pairs. Moreover, polyclonal PDAC cell lines representative of the heterogeneity seen in PDAC patients show a highly synergistic response to the combination of Ref-1 redox inhibitors with mitochondrial inhibitors. These data suggest this treatment combination will be synergistic in polyclonal tumors that exist in most PDAC patients. Overall, these data have the potential to lead to new avenues to directly target heterogenous populations of cancer cells to treat pancreatic cancer- an urgent clinical need.
Citation Format: Taryn Morningstar, Cecily Anaraki, Lorenzo Scipioni, Giulia Tedeschi, Michelle Digman, Aimee Edinger, Claus Jorgensen, Melissa Fishel, Christopher J Halbrook. Targeting metabolic heterogeneity in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C045.
Abstract C047: Autophagy-mediated proline-supply is important for cell survival in pancreatic cancers
Authors: Kim Ji hyeon , Cheong Heesun 
Published: September 2024

Abstract
Oncogenic KRAS mutations present in 90–95% of pancreatic cancer patients. KRAS mutation in pancreatic cancer increased the dependency on glutamine and consumption of proline. Proline is a non-essential amino acid but it is important for the synthesis of proteins such as collagen, and also for precursors of antioxidant molecules. Several enzymes such as P5CS(ALDH18A1),PYCR1 and PYCR2 are involving proline synthesis. The effects of proline synthesis enzymes on pancreatic cancer cells are relatively less studied than that of enzymes catalyzing proline. Here, we examined the impact of proline synthesis enzymes on pancreatic cancer cell survival and proliferation. We first examined that exogenous proline promotes cell survival under low glutamine conditions in various pancreatic cancer cells. Exogenous proline supplementation increased some pancreatic cell survival even when glutamine was not sufficiently available, whereas proline supplement is dispensible for certain cell types of pancreatic cancer. Next, to investigate the importance of proline synthesis enzymes in cell survival, we measured the cell proliferation of pancreatic cancer with knock-down the proline synthesis enzymes. The knockdown of ALDH18A1 and PYCR1,2, which are proline biosynthesis enzyme genes, reduced cell survival in pancreatic cancer cells, suggesting that in PDAC cells, the enzymes that synthesize proline from glutamine are crucial for cancer cell survival and growth. To test the effect of proline-sysnthesis enzymes on autophagy, we measured autophagy flux in the cell harboring GFP-RFP-LC3 or GFP-LC3 as a reporter. Knockdown of proline synthesis enzymes, particularly ALDH18A1 or PYCR1 led to an increase in autophagy levels, indicating that proline-independent cells can bypass proline synthesis by autophagy induction in the absence of proline synthesis genes. Furthermore gemcitabine-resistant cells showed reduced levels of proline synthesis enzymes. In pancreatic cancer cell lines, proline promotes cancer cell survival, generated by both biosynthesis from glutamine and starvation-induced autophagy, which also critically important for supporting cellular drug resistance. Taken together, these results indicate that proline synthesis is mechanistically associated with autophagy induced by glutamine-starvation, which is pivotal for supplying proline in pancreatic cancer cells.
Citation Format: Ji hyeon Kim, Heesun Cheong. Autophagy-mediated proline-supply is important for cell survival in pancreatic cancers [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C047.
Abstract C049: Computational Methods for Central and Lipid Metabolism Networks Analysis to Reveals Flux Change in PDAC
Authors: Cao Sha , Zhu Haiqi , Wang Yijie , Fishel Melissa , Zhang Chi 
Published: September 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is among the most challenging cancers to treat due to its aggressive nature and the difficulties in early detection. The disease progresses rapidly from stage T1 to T4, leaving a narrow window for effective intervention. This swift progression is closely tied to significant metabolic alterations, and current studies have highlighted specific metabolic changes. This includes elevated glutamine metabolism and altered aspartate and alpha-ketoglutarate production to support uncontrolled tumor growth; and elevated lysophosphatidylcholines secretion by cancer-associated fibroblasts to support tumor progression. These insights underscore the need for a holistic understanding of PDAC metabolism. Hence, there is an urgent need for a comprehensive and high-resolution analysis of PDAC's metabolic landscape remains unexplored. To computationally characterize the PDAC metabolism and fully leverage the large-scale transcriptomics with matched or unmatched metabolomics data, we developed an algorithm based on the Michaelis-Menten equation to estimate distribution-wise variations in mass-carrying metabolic networks using gene expression and metabolomics data. We start by manually curating a PDAC-specific metabolic network that focuses on central metabolism, glutamine-glutamate metabolism, and lipid metabolism. We then gathered comprehensive kinetic parameters, predicted enzyme activity from transcriptomics data, and conducted metabolomic profiling to determine metabolic compound concentrations. By applying Monte Carlo sampling methods, we achieved an overall balance of metabolic flux, enabling us to model reaction rates accurately and predict metabolic shifts. This approach holds potential to provide a comprehensive perspective on the rewired metabolism in PDAC, inspiring the development of metabolic targets or diet interventions for therapeutic treatment.
Citation Format: Sha Cao, Haiqi Zhu, Yijie Wang, Melissa Fishel, Chi Zhang. Computational Methods for Central and Lipid Metabolism Networks Analysis to Reveals Flux Change in PDAC [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C049.
Abstract C050: Vitamin B6 restriction impairs pancreatic cancer progression
Authors: He Chunbo , Mehla Kamiya 
Published: September 2024

Abstract
Introduction: Cancer cells utilize altered metabolism to sustain their rapid growth, and understanding how these metabolic changes aid in tumor development could enhance current treatment approaches. Vitamins are essential micronutrients necessary in small quantities to support the proper functioning and metabolism of our organs and systems. Despite the recognized importance of vitamins in maintaining overall health, there is no direct evidence linking vitamin metabolism to pancreatic ductal adenocarcinoma (PDAC). Methods: PDAC animal models, organoid models, 3D-culture models, and LC-MS/MS-based metabolomic analysis were used to explore the role of vitamin B6 (VB6) in pancreatic cancer. Results: Our data showed that 1) Patients with PDAC exhibit lower levels of circulating vitamin B6 compared to healthy individuals of the same age. Additionally, vitamin B6 levels are reduced in the interstitial fluid of KPC (KrasG12D/+; p53R172H/+; Pdx1-Cretg/+) tumors and in the blood of mice with KPC tumors compared to healthy mice of the same age; 2) PDAC cells metabolize VB6 more rapidly than non-cancerous pancreatic epithelial cells; 3) VB6 restriction impairs PDAC cell proliferation in vitro and PDAC tumor growth in vivo; 4) VB6 depletion decreases key metabolites of the one-carbon pathway necessary for PDAC cell growth; 5) Inhibiting the one- carbon pathway mimics the effects of a vitamin B6 deficiency on PDAC cell proliferation. And knocking down VB6-dependent enzymes SHMT1/2 negates the pro-growth impact of VB6. Conclusion: Our research suggests that VB6 plays a key role in regulating various metabolic processes essential for the growth of PDAC cells. By focusing on inhibiting VB6-dependent enzymatic reactions, we may uncover new therapeutic strategies for treating PDAC.
Citation Format: Chunbo He, Kamiya Mehla. Vitamin B6 restriction impairs pancreatic cancer progression [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C050.
Abstract C052: Repurposing Statins to Target Gemcitabine Resistance in Pancreatic Cancer
Authors: Calderon Sabrina , Beutel Alica K. , Nghiem Ethan , Singh Rima , Yousefian Natalie , Anaraki Cecily , Gulay Kevin , Juarez Dennis , Kleger Alexander , Seufferlein Thomas , Muir Alexander , Jang Cholsoon , Tiriac Herve , Fruman David , Halbrook Christopher 
Published: September 2024

Abstract
Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy with a devastating prognosis. Gemcitabine, a pyrimidine anti-metabolite, is a cornerstone in PDA therapy, but resistance remains a major hurdle in clinical care. Metabolic reprogramming is an important driver of chemoresistance. Accordingly, targeting these altered metabolic pathways can improve response to treatment. To investigate metabolic vulnerabilities, we generated models of acquired PDA gemcitabine resistance. Screening common metabolic inhibitors we observed that gemcitabine-resistant cells were exquisitely susceptible to statins, inhibitors of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. This is due to a downregulation of the mevalonate biosynthesis pathway in gemcitabine-resistant cells. Importantly, the statin sensitivity correlates with the extent of the gemcitabine resistance, suggesting this metabolic vulnerability is gradually gained during acquisition of resistance. Rescue experiments showed that statins induce apoptosis by reduced protein geranylation of small GTPases. Finally, we find that pitavastatin inhibits growth of gemcitabine resistant tumors in immune competent models. Collectively, these data suggest that targeting the HMG-CoA reductase is a metabolic vulnerability that is gained in PDA cells upon the acquisition of gemcitabine resistance. The treatment combination of gemcitabine and pitavastatin, two widely used compounds in patients, has potential to translate into an immediate clinical benefit and improve survival in this deadly disease.
Citation Format: Sabrina Calderon, Alica K. Beutel, Ethan Nghiem, Rima Singh, Natalie Yousefian, Cecily Anaraki, Kevin Gulay, Dennis Juarez, Alexander Kleger, Thomas Seufferlein, Alexander Muir, Cholsoon Jang, Herve Tiriac, David Fruman, Christopher Halbrook. Repurposing Statins to Target Gemcitabine Resistance in Pancreatic Cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C052.
Abstract C058: A novel approach to understanding pancreas cancer risk through enhancer- promoter interactions
Authors: Wang Li , Baek Songjoon , Prasad Gauri , Truongvo Thucnhi , Hoskins Jason , Amundadottir Laufey , Arda Efsun 
Published: September 2024

Abstract
Genetic or epigenetic variations in regulatory enhancer elements increase susceptibility to a range of pathologies, including pancreas cancer. Pinpointing genes affecting pancreas cancer risk holds promise for early detection, prevention, and effective therapies. Despite recent advances, linking enhancer elements to target genes and predicting the transcriptional outcome of enhancer dysfunction remain significant challenges. Using 3D chromatin assays, we generated an extensive enhancer interaction dataset for the human pancreas, spanning more than 20 donors and five major cell types, including both the exocrine and endocrine compartments. We employed a network approach to parse chromatin interactions into enhancer-promoter tree models, facilitating quantitative, genome-wide analysis of enhancer connectivity. Using the tree models, we developed a machine learning algorithm capable of estimating the impact of enhancer perturbations on cell-type specific gene expression in the human pancreas. Complementing this computational approach, we streamlined an experimental platform using CRISPR-interference and RNA-FISH coupled with high-throughput imaging to quantitatively measure the effect size of enhancer perturbations in primary human pancreas cells. Our enhancer tree models enabled functional annotation of genetic variants associated with pancreas diseases, revealing novel target genes in specific cell types. For pancreas cancer (PDAC), our data suggests a stronger association of disease susceptibility variants with acinar cells, even though ductal cells historically have been the focus of PDAC. This discovery linked three potentially functional variants associated with PDAC risk to acinar cell enhancers, revealing novel target genes to further investigation. By integrating genomics with mechanistic findings into enhancer function, our work offers a framework for understanding genetic basis of pancreas cancer disease risk.
Citation Format: Li Wang, Songjoon Baek, Gauri Prasad, Thucnhi Truongvo, Jason Hoskins, Laufey Amundadottir, Efsun Arda. A novel approach to understanding pancreas cancer risk through enhancer- promoter interactions [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C058.
Abstract C061: Loss of CaMK2B accelerates tumor formation and enhances metastatic competency in genetically engineered mouse models of PDAC
Authors: Peura Jessica , Bhalerao Nikita , Johnson Calvin , Ogoti Yamini , Keller Faith , Watson Emma , Zhao Zhen , Pitarresi Jason 
Published: September 2024

Abstract
Background Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer- related deaths in the United States and is often not diagnosed until it has already metastasized. Our prior work established that calcium signaling pathways facilitate a pro-metastatic phenotype through the induction of an epithelial-to-mesenchymal transition (EMT) program in PDAC tumor cells, but the downstream signaling molecules mediating this phenotype have remained elusive. MethodsUsing a novel genetically engineered model of pancreatic cancer, we demonstrate that loss of Calcium/calmodulin-dependent kinase-II B (CaMK2B), a downstream effector kinase activated by calcium, enhances cellular plasticity, and increases metastasis. To this end, we generated a genetically engineered mouse model where Camk2b was knocked out in tumor cells in a lineage-labeled Kras- and p53-driven PDAC mouse model (herein KPCY-Camk2bcKO). Results Genetic deletion of Camk2b in the KPCY genetically engineered model accelerated tumor formation and dramatically reduced the overall median survival of KPCY- Camk2b cKO mice (78 days) relative to KPCY controls (136 days). Pathological and immunofluorescence analysis of KPCY-Camk2b cKO animals showed an increased number of poorly differentiated tumor regions and a higher metastatic burden, with &gt;85% of KPCY- Camk2b cKO animals presenting with multi-focal metastases. Further analysis of tumor cells in KPCY-Camk2b cKO mice showed enhanced expression of markers of the highly aggressive squamous PDAC subtypes. Strikingly, Camk2b deletion combined with oncogenic Kras G12D (in the absence of p53 alterations), was sufficient to form lethal metastatic PDAC tumors, while age-matched control Kras G12D tumors with intact Camk2b only progressed to the acinar-to-ductal metaplasia (ADM) or Pancreatic Intraepithelial Neoplasia (PanIN) stage. Collectively, these results establish Camk2b loss as a new oncogenic and pro-metastatic mechanism in PDAC Conclusion This work demonstrates that Camk2b loss enhances tumor cell evolution and plasticity within PDAC to promote metastasis. In this context, we speculate that loss of Camk2b rewires calcium signaling to drive an aggressive subtype of PDAC with increased metastasis.
Citation Format: Jessica Peura, Nikita Bhalerao, Calvin Johnson, Yamini Ogoti, Faith Keller, Emma Watson, Zhen Zhao, Jason Pitarresi. Loss of CaMK2B accelerates tumor formation and enhances metastatic competency in genetically engineered mouse models of PDAC [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C061.
Abstract C063: Inhibition of PRMT5 reduces aggressiveness in basal-like pancreatic ductal adenocarcinoma
Authors: Wang Christina , Soares Zamira Guerra , Esgdaille Dakarai , Mello Stephano Spano 
Published: September 2024

Abstract
The basal-like pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive type of mesenchymal PDAC that resists treatment and has a poor prognosis. Understanding the mechanisms driving basal-like PDAC biology is crucial for unraveling the intricacies of PDAC plasticity and developing effective treatment strategies for this aggressive tumor. Recent studies from our laboratory have shown that protein arginine methyl transferase 5 (PRMT5) significantly contributes to PDAC plasticity and progression towards the basal-like subtype. Specifically, our data show that patients with high levels of PRMT5 expression have a worse outcome, thus arguing that PRMT5 plays a role in PDAC aggressiveness and outcome. Moreover, our experiments indicate that inhibiting PRMT5, either genetically or chemically, in basal-like PDAC cells induces the expression of epithelial markers like GATA6 and E-CADHERIN, suggesting that PRMT5 promotes mesenchymal features in PDAC. Using wound healing and transwell assays, we have demonstrated that pharmacological inhibition of PRMT5 significantly suppresses cell migration and invasion. Additionally, colony formation and cell proliferation are markedly reduced upon PRMT5 inhibition in basal-like PDAC. Collectively, these findings suggest that inhibiting PRMT5 can effectively constrain the aggressive cellular features characteristic of basal-like PDAC, such as cell proliferation, clonogenicity, and migration. Recent research indicates that PRMT5 preferentially methylates splicing factors in various cell types, implying that RNA splicing regulation is crucial to PRMT5’s role in enhancing tumor plasticity and aggressiveness. We are currently investigating whether PRMT5-mediated RNA splicing alterations contribute to the maintenance of the basal-like PDAC phenotype. These studies provide key evidence that PRMT5 is essential for maintaining the aggressive characteristics of basal-like PDAC, highlighting its potential as a therapeutic target for this challenging cancer subtype.
Citation Format: Christina Wang, Zamira Guerra Soares, Dakarai Esgdaille, Stephano Spano Mello. Inhibition of PRMT5 reduces aggressiveness in basal-like pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C063.