bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A004: Repetitive elements and viral mimicry co-evolve in pancreatic cancer
Authors: Sun Siyu 
Published: November 2022

Abstract
Overexpression of repetitive DNA is an emerging hallmark of human cancers and several repeats, such as SINE elements and satellite, transcribe immunostimulatory RNA that mimic features associated with viral infection. However, the extent to which specific repeat families affect tumor evolution and the immune microenvironment in a pro-or anti-tumorigenic manner remains poorly understood. We present an integrated, evolutionary multi-omic analysis pf repeat evolution in multiregion-sampled human metastatic and primary pancreatic cancers for the first time. We found that LINE-1 (L1) somatic insertion location coincides with tumor evolution. Moreover, we found L1 activity is negatively correlated with immunogenic SINE element expression. Two orthogonal metrics were used in quantifying immunogenicity of SINE elements: IFN signature and capability of forming dsRNA, where both methods revealed that evolutionary young SINE elements have stronger correlation with IFN signatures and are more likely to form dsRNAs. Moreover, the anti-correlation between L1 activity and SINE expression is validated through both immunohistological analysis of human samples and pancreatic cancer cell lines. In the end, we proposed that the model of hypoactive L1 is beneficial for tumors by suppression of immunogenic SINE elements through either their direct reverse transcription or accelerating their degradation. Our analysis therefore sheds light on the evolutionary role of dark matter repeats in a tumor’s adaptation to immunogenic vulnerabilities.
Citation Format: Siyu Sun. Repetitive elements and viral mimicry co-evolve in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A004.
Abstract A015: Rationale for the use of pulsed rather than continual dosing of the novel Focal Adhesion Kinase inhibitor AMP945 in pancreatic cancer
Authors: Lambert John , Devine Mark , Bishop Anthony 
Published: November 2022

Abstract
Amplia Therapeutics Limited is developing AMP945, a highly selective inhibitor of Focal adhesion kinase (FAK) for the treatment of pancreatic cancer in combination with standard of care gemcitabine and nab-paclitaxel.1 FAK has been associated with the activity of myofibroblasts and collagen deposition and remodeling in PDAC. In preclinical studies, AMP945 displays potent anti-fibrotic activity in vitro and in vivo. In mouse models of PDAC, pulsed dosing of AMP945 added to gemcitabine and nab-paclitaxel inhibited collagen deposition and cross-linking and potentiated the effect of chemotherapy leading to increased survival.2A Phase 1 trial of AMP945 has been completed in which AMP945 showed excellent safety, tolerability, and pharmacokinetic properties as well as pharmacodynamic evidence of target engagement. Amplia’s recently initiated Phase 1b/2a clinical trial AMP945-PC-2013 (ACCENT) will assess a pulse dosing regimen of AMP945 in combination with gemcitabine and nab-paclitaxel as first-line therapy in patients with advanced pancreatic cancer. In ACCENT, patients will undergo a one-week oral loading dose of AMP945 and will be pulse dosed for four days prior to IV administration of gemcitabine and nab-paclitaxel, given according to a standard treatment schedule. Once daily oral dosing has anticipated benefits in terms of limitation of risk of acquired resistance, minimal potential for drug-drug interactions, adherence to therapy, and allows patients to self-administer AMP945 with the aim of potentiating response to standard of care chemotherapy. This abstract presentation will report on AMP945’s development status and the clinical rationale and status of the ACCENT trial. 1. Von Hoff et al., N Engl J Med 2013; 369:1691-1703 2. Murphy KJ et al. Sci Adv. 2021 Oct;7(40):eabh0363. 3. https://clinicaltrials.gov/ct2/show/NCT05355298
Citation Format: John Lambert, Mark Devine, Anthony Bishop. Rationale for the use of pulsed rather than continual dosing of the novel Focal Adhesion Kinase inhibitor AMP945 in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A015.
Abstract A075: NCOA4-mediated ferritinophagy is a pancreatic cancer dependency via maintenance of iron bioavailability for iron-sulfur cluster proteins
Authors: Santana-Codina Naiara , Zhang Huan , del Rey Maria Quiles , Kapner Kevin S. , Gikandi Ajami , Malcolm Callum , Poupault Clara , Kuljanin Miljan , John Kristen , Biancur Douglas E. , Chen Brandon , Das Nupur , Lowder Kristen , Hennessey Connor J. , Huang Wesley , Yang Annan , Shah Yatrik M. , Nowak Jonathan A. , Aguirre Andrew J. , Mancias Joseph D. 
Published: November 2022

Abstract
Pancreatic ductal adenocarcinomas (PDAC) depend on autophagy for survival; however, the metabolic substrates that autophagy provides to drive PDAC progression are unclear. Ferritin, the cellular iron storage complex, is targeted for lysosomal degradation (ferritinophagy) by the selective autophagy adaptor Nuclear receptor coactivator 4 (NCOA4), resulting in release of iron for cellular utilization. Using patient-derived and genetically engineered murine models of PDAC we now demonstrate that ferritinophagy is upregulated in PDAC to sustain iron availability thereby promoting tumor progression. Mass spectrometry-based quantitative proteomics reveals that ferritinophagy fuels iron-sulfur cluster protein synthesis to support mitochondrial homeostasis. Targeting NCOA4 leads to tumor growth delay and prolonged survival but with development of compensatory iron acquisition pathways. Finally, enhanced ferritinophagy accelerates PDAC tumorigenesis, and an elevated ferritinophagy expression signature predicts for poor prognosis in PDAC patients. Together, our data reveal that maintenance of iron homeostasis is a critical function of PDAC autophagy, and we define NCOA4-mediated ferritinophagy as a therapeutic target in PDAC.
Citation Format: Naiara Santana-Codina, Huan Zhang, Maria Quiles del Rey, Kevin S. Kapner, Ajami Gikandi, Callum Malcolm, Clara Poupault, Miljan Kuljanin, Kristen John, Douglas E. Biancur, Brandon Chen, Nupur Das, Kristen Lowder, Connor J. Hennessey, Wesley Huang, Annan Yang, Yatrik M. Shah, Jonathan A. Nowak, Andrew J. Aguirre, Joseph D. Mancias. NCOA4-mediated ferritinophagy is a pancreatic cancer dependency via maintenance of iron bioavailability for iron-sulfur cluster proteins [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A075.
Abstract A077: PancreaCult™ Organoid Medium Kits support the robust establishment and expansion of human pancreatic duct organoids
Authors: Quiskamp Nina , Tsai Angela , Pan Joanna , Hasan Misha , Chang George , Tai Isabella T. , Eaves Allen C. , Louis Sharon A. , Conder Ryan K. 
Published: November 2022

Abstract
Organoid culture is a novel in vitro culture method that promotes the growth of primary and PSC-derived cells in three-dimensional culture to generate structures that recapitulate tissue morphology. We have developed PancreaCult™ Organoid Medium Kits (Human), which combine PancreaCult™ Organoid Initiation Medium (OIM) and serum-free PancreaCult™ Organoid Growth Medium (OGM) into a robust and standardized workflow for the establishment and expansion of pancreatic duct organoids. To establish organoids, fresh or cryopreserved islet-depleted exocrine tissue was seeded in Corning® Matrigel® domes and cultured in PancreaCult™ OIM. After 3 days, the medium was changed to PancreaCult™ OGM and the organoids were passaged and maintained in this medium thereafter, and passaged as fragments every 4 - 7 days. Organoids were successfully established from all 5 donors with a 2- to 6-fold expansion in cell numbers every 7 - 14 days. Real-time PCR and immunocytochemistry demonstrated that these organoids express pancreatic duct markers (PDX1, SOX9, KRT19, CFTR, CA2, and MUC1), as well as proliferation and stem cell markers, Ki-67 and LGR5, respectively. Pancreatic duct organoids could be maintained for at least 10 passages (n = 3) and cryopreserved as fragments that could be used for rapid re-establishment of cultures at later time points. Organoids could also be dissociated and re-seeded in Prostaglandin E2-free PancreaCult™ OGM supplemented with ROCK inhibitor, Y-27632 and 10% FBS on Transwell® inserts to create 2D monolayers. In addition to normal pancreatic duct cultures, PancreaCult™ OGM supported the efficient long-term expansion of 4 pre-established pancreatic ductal adenocarcinoma (PDAC) organoid lines and maintained the mutational profile of the parent line after 5 passages, as determined through whole exome sequencing of 29 cancer-associated genes. Through the optional removal of epidermal growth factor (EGF), PancreaCult™ OGM can be modified to suppress normal cell growth to select for tumor cells with activating KRAS mutations. Our results demonstrate that PancreaCult™ Organoid Medium Kits provide a robust and flexible in vitro culture system for the establishment and expansion of normal pancreatic duct cells, as well as the long-term expansion of PDAC organoids.
Citation Format: Nina Quiskamp, Angela Tsai, Joanna Pan, Misha Hasan, George Chang, Isabella T. Tai, Allen C. Eaves, Sharon A. Louis, Ryan K. Conder. PancreaCult™ Organoid Medium Kits support the robust establishment and expansion of human pancreatic duct organoids [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A077.
Abstract B009: Multi-omics analysis of glutathione S-transferase P1 (GSTP1) knockdown model suggests role in pancreatic ductal adenocarcinoma (PDAC) cell metabolism
Authors: Duttenhefner Jenna , Reindl Katie M. 
Published: November 2022

Abstract
GSTP1 belongs to a large family of detoxification enzymes essential for cellular homeostasis in healthy cells. GSTP1 is overexpressed in many cancers and is associated with poor survival in PDAC patients. Studies in glioblastoma and breast cancer have suggested crucial roles of GST family members in metabolism through increased lactate dehydrogenase A and increased GAPDH activity, respectively. The mechanisms underlying the action of GSTP1 in PDAC metabolism and cell proliferation are not well studied. To begin characterizing the diverse functions of GSTP1 in cancer cells, we knocked down GSTP1 expression in three different PDAC cell lines. We revealed unique changes in the global transcriptomic, proteomic, and metabolomic signatures associated with GSTP1 knockdown compared to control cells through multi-omics techniques, real-time ATP production assays, and comprehensive hydrophilic metabolite and phospholipid panels. Through preliminary transcriptomic and proteomic analyses, we found 461 genes and 57 proteins differentially expressed in our GSTP1 knockdown MIA PaCa-2 cells. Among these, 41 were similarly upregulated or downregulated at the mRNA and protein levels. Pathway analysis of these changes revealed profound effects on energy production and lipid metabolism in GSTP1 knockdown cells. Hydrophilic metabolite and phospholipid panels and real-time ATP production assays supported our findings. Our results indicate that GSTP1 knockdown may directly influence mitochondrial dysfunction and lipid peroxidation pathways through associated reductions in ALDH7A1, GLUT3, and SLC7A11 levels. Continued research to further elucidate precise mechanisms and understand GSTP1’s role in driving cancer cell metabolism will aid in establishing GSTP1 targeting as a therapeutic opportunity for PDAC treatment.
Citation Format: Jenna Duttenhefner, Katie M. Reindl. Multi-omics analysis of glutathione S-transferase P1 (GSTP1) knockdown model suggests role in pancreatic ductal adenocarcinoma (PDAC) cell metabolism [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B009.
Abstract B011: Identifying druggable lipid synthesis targets as novel therapeutics for pancreatic cancer
Authors: Kubota Casie S. , Ishida Chiaki T. , Myers Stephanie , Espenshade Peter J. 
Published: November 2022

Abstract
Lipid metabolic reprogramming is a hallmark of cancer that contributes to tumorigenesis by supporting energy metabolism and the synthesis of signaling molecules, cellular membranes, and protein modifications. Cells modulate lipid metabolic genes through the regulation of sterol regulatory element-binding proteins (SREBPs), which serve as transcriptional activators of genes responsible for fatty acid and cholesterol synthesis and uptake. Despite efforts demonstrating that the SREBP pathway is an attractive chemotherapeutic target, a potent bioavailable inhibitor of the pathway has not yet been discovered. Here, we identify druggable SREBP target genes as potential targets in pancreatic ductal adenocarcinoma (PDAC). Results: To discover candidate genes, we constructed a CRISPR knockout library containing 148 known SREBP target genes. We used a patient-derived PDAC cell line to conduct the knockout screens in vivo (n = 7 tumors) by injecting library-infected cells into the pancreas of nude mice. After 4 weeks of growth, mouse PDAC tumors showed a statistically significant depletion of guide RNAs targeting 8 genes within the mevalonate pathway, which is responsible for synthesizing cholesterol and isoprenoids such as farnesyl-diphosphate and geranyl-diphosphate. One of the most significant hits was HMG-CoA reductase (HMGCR), which catalyzes the formation of mevalonate. We chose to investigate statins, which are a well-characterized class of FDA-approved drugs that inhibit HMGCR. Using flow cytometry, we stained for annexin-V as a marker for apoptosis and found minimal cell death induced by Fluvastatin alone. Given that inhibiting HMGCR would disrupt lipid homeostasis and in turn activate the SREBP pathway, we hypothesized that a combination therapy with an SREBP inhibitor, TMDP, would potentiate statin-induced cell death. We observed minimal cell death with TMDP alone, but striking synergy between Fluvastatin and TMDP, showing a five-fold increase in annexin-V staining after 48 hours. Mevalonate and geranylgeranyl-diphosphate both fully rescued this cell death to basal levels. Conclusions: In vivo CRISPR screening is a powerful tool for the identification of novel therapeutic targets for cancer. We found that the mevalonate pathway plays a significant role in pancreatic tumor growth in vivo and that existing FDA-approved drugs can be used in combination with an SREBP inhibitor to dramatically enhance cell killing in vitro.
Citation Format: Casie S. Kubota, Chiaki T. Ishida, Stephanie Myers, Peter J. Espenshade. Identifying druggable lipid synthesis targets as novel therapeutics for pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B011.
Abstract B015: Systemic reprogramming of fibroblasts and immune cells precedes metastatic spread in pancreatic cancer
Authors: Opsahl Emily L. Lasse , Velez-Delgado Ashley , Donahue Katelyn L. , Kadiyala Padma , Espinoza Carlos , Zhang Yaqing , di Magliano Marina Pasca 
Published: November 2022

Abstract
Oncogenic KRAS (Kras*) is a near-universal driver of pancreatic ductal adenocarcinoma (PDA), and its activity is required for the formation of the PDA precursor lesions, pancreatic intraepithelial neoplasia (PanIN). PanIN formation is accompanied by fibrosis and immune cell infiltration, creating a precursor tumor microenvironment (PME) that is maintained and evolves through the disease progression. In mice bearing overt pancreatic cancer, pancreatic cells secrete specific factors to prime the liver and lung, forming the premetastatic niche. Presently, it remains to be elucidated at what stage of PDA tumorigenesis the premetastatic niche is initiated, as well as the mechanisms underlying this formation. As PDA patients are commonly diagnosed with metastatic disease, it is imperative to understand the mechanism underlying formation of the premetastatic niche, as well as determinants of metastasis outgrowth. To determine whether Kras*-dependent signals are required for the formation of the premetastatic niche, we used an inducible and reversible murine model of pancreas-specific Kras* expression developed by our group known as the iKras* mouse. We expressed Kras* in the pancreatic epithelium of adult mice for 16 weeks and validated the presence of advanced PanIN lesions without overt malignancy. We then performed single cell RNA sequencing (scRNA-seq) on the pancreas, liver, and lung of these mice, with liver and lung being common sites of metastasis for pancreatic cancer. We have previously shown that pancreatic fibroblasts are reprogrammed early during carcinogenesis, a finding that holds true at this later timepoint. Interestingly, we observed parallel changes in gene expression in fibroblasts, macrophages, and T cells in the lungs of PanIN bearing mice. Ongoing studies aim to validate the changes seen in the scRNA-seq and functionally evaluate systemic activation of fibroblasts and immune cells within the premetastatic niche.
Citation Format: Emily L. Lasse Opsahl, Ashley Velez-Delgado, Katelyn L. Donahue, Padma Kadiyala, Carlos Espinoza, Yaqing Zhang, Marina Pasca di Magliano. Systemic reprogramming of fibroblasts and immune cells precedes metastatic spread in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B015.
Abstract B042: Inhibition of CPSF3 attenuates pancreatic cancer cell proliferation through disruption of histone processing
Authors: Alahmari Abdulrahman A. , Chaubey Aditi , Tisdale Arwen , Schwarz Carla , Cornwell Abigail , Maraszek Kathryn , Paterson Emily , Kim Minsuh , Venkat Swati , Gomez Eduardo Cortes , Wang Jianmin , Gurova Katerina , Feigin Michael E. 
Published: November 2022

Abstract
Treatment regimens of pancreatic ductal adenocarcinoma (PDAC) are limited and minimally effective which potentiates the importance of discovering novel potential drug targets. We discovered widespread dysregulation of alternative polyadenylation (APA) in PDAC patients. APA is a pre-mRNA processing mechanism that generates mRNAs isoforms with distinct 3’ untranslated regions (3’UTRs). These isoforms contribute to the expression and function of mRNAs and proteins. Our recent study revealed that APA alterations in PDAC drive dysregulation of PDAC-promoting genes and present a reliable prognostic marker. APA is controlled by a suite of genes, including cleavage and polyadenylation specificity factor 3 (CPSF3). Because CPSF3 is the endonuclease that catalyzes mRNA cleavage, we here sought to target CPSF3 in PDAC. We show that CPSF3 expression is significantly upregulated and associated with unfavorable prognosis in PDAC patients. Loss of CPSF3 decreases PDAC cell proliferation, clonogenicity and tumor growth. We show that CPSF3 loss causes APA changes of tumor-associated genes and validate the tumor suppressing activity of one APA-altered gene, FHL1. Using JTE-607, a chemical inhibitor of CPSF3, we find that PDAC cells are preferentially sensitive while non-transformed cell lines are resistant to CPSF3 inhibition. Notably, we show that JTE-607 decreases proliferation-dependent histone expression and disrupts nucleosome assembly. Finally, we find that JTE-607 arrests cells in early to mid S-phase of the cell cycle, resembling histone defect-induced cell cycle arrest. Overall, we reveal alternative polyadenylation and histone processing as two distinct mechanisms underlying CPSF3-induced attenuation of cell proliferation and identify CPSF3 as a potential therapeutic target in PDAC.
Citation Format: Abdulrahman A. Alahmari, Aditi Chaubey, Arwen Tisdale, Carla Schwarz, Abigail Cornwell, Kathryn Maraszek, Emily Paterson, Minsuh Kim, Swati Venkat, Eduardo Cortes Gomez, Jianmin Wang, Katerina Gurova, Michael E. Feigin. Inhibition of CPSF3 attenuates pancreatic cancer cell proliferation through disruption of histone processing [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B042.
Abstract B052: Uncovering the lineage of chemosensory cells in the progression of pancreatic cancer
Authors: Salas-Escabillas Daniel , Crawford Howard , Hoffman Megan 
Published: November 2022

Abstract
Pancreatic ductal adenocarcinoma (PDA) is predicted to become the second leading cause of cancer-related death in 2025 and has a 5-year survival rate of only 11%. Progression of the pancreatic disease is in part driven by the transdifferentiation of acinar cells into metaplastic ducts in the pancreas. Metaplastic tuft cells (MTCs) are a specialized subset of the metaplastic epithelium that has the potential to drive tumor progression through communication with the microenvironment and modulate PDA progression. Also known as solitary chemosensory cells, tuft cells were first discovered in rodent luminal surfaces, including the nose, stomach, intestine, and bladder, more than 60 years ago. They are characterized by the “tuft” of microvilli reaching into the lumen and, only recently, have studies started to determine the role of normal tuft cells in different organs. These studies determined that tuft cells have different roles depending on the organ in which they reside. Tuft cells are found in several different organs during normal development; however, studies have shown that tuft cells are not present in a normal pancreas. MTCs are only present in the pancreas in PanINs during PDA progression in both humans and mice. Furthermore, the population of MTCs in the pancreas disappears as PDA progresses into invasive carcinoma when using canonical markers of tuft cells. We know little about the role of MTCs in the pancreas, but prior studies have suggested their role as a progenitor cell during PDA. However, these studies do not exclusively mark MTCs during their genesis in a progressive model of PDA due to a lack of a mouse model as well as the complexity of culturing them ex vivo. We have generated a unique mouse model to drive lineage tracing of MTCs during PDA, and I have preliminary data to suggest that MTCs are not disappearing as PDA progresses but can transdifferentiate into another cell type that is correlated with lower survival in patients.
Citation Format: Daniel Salas-Escabillas, Howard Crawford, Megan Hoffman. Uncovering the lineage of chemosensory cells in the progression of pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B052.