bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 784: Andrographolide altered inflammation pathways and cytokine expression in prostatecancer
Authors: Rosario Mitzy J. Santiago , Carde Gabriela Erazo , Vázquez María Sánchez , Cardona Valerie , Ferrer Magaly Martínez 
Published: June 2022

Abstract
Prostate cancer is the most diagnosed cancer in men in the USA. Andrographolide (AG) is a labdane diterpenoid compound isolated from the medicinal plant Andrographis paniculata. Previous studies in our laboratory showed that Andrographolide decreased prostate tumor size in mice, induced expression of DNA repair genes associated with double-strand break repair and altered mitochondrial function. The objective of this study is to determine the role of AG in inflammation in prostate cancer. Microarray analysis of tumors treated with Andrographolide 10 mg/kg and their vehicle were conducted. Tumors were developed using a xenograft model in which the prostates of SCID mice were injected with 22RV1, and mice were treated three times per week with Andrographolide 10 mg/kg. Tumor tissues were collected and snap frozen. Gene expression was identified and analyzed using the Affymetrix GeneChip® Human Gene 2.0 array. Using Ingenuity Pathway Analysis (IPA) we found that Andrographolide 10 mg/kg altered genes associated with inflammatory response such as ATM, DHFR, HIF-1-α, CDKAL1, DHFR, NOX1, C5, CCL4, COG6, SUPT20H, CA5B, TTC3. To determine changes of cytokine expression in PC3 prostate cancer cells treated with 25 μM Andrographolide, we used the Abcam Cytokine Antibody Array test®. PC3 prostate cancer cells treated with Andrographolide showed altered expression of cytokines such as IL-2, TNF-α, TNF-β, EGF, IGF-1, ENA-78, GM-CSF, GRO, GRO-α, I-309, and Angiogenin. These results showed that AG may alter the tumor microenvironment promoting the secretion of diverse cytokines that may inhibit tumor development. Understanding these biological pathways and networks is essential to determine possible targets of Andrographolide in prostate cancer.
Citation Format: Mitzy J. Santiago Rosario, Gabriela Erazo Carde, María Sánchez Vázquez, Valerie Cardona, Magaly Martínez Ferrer. Andrographolide altered inflammation pathways and cytokine expression in prostatecancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 784.
Abstract 787: RE1-silencing transcription factor (REST) controls neuroendocrine gene programs in pancreatic ductal adenocarcinoma
Authors: MacPherson Kevin Alexander , Joly Meghan M. , Allen-Petersen Brittany , Pelz Carl , Thoma Mary C. , Torkenczy Kristof , Adey Andrew , Liefwalker Daniel , Worth Patrick J. , Sears Rosalie C. 
Published: June 2022

Abstract
Neuroendocrine (NE) differentiation features contribute to intratumoral heterogeneity and aggressive biology in a subset of pancreatic ductal adenocarcinoma (PDAC) tumors associated with poor disease outcome. We recently showed that treating pancreatic cancer cells with gemcitabine, a standard-of-care chemotherapy for PDAC, increases expression of NE markers, suggesting that ductal to neuroendocrine lineage plasticity could play a role in drug resistance. NE features in prostate cancer have been previously associated with loss of the neuronal gene repressor RE1-Silencing Transcription Factor (REST); in the present study, we explore a potential role of REST in regulating NE differentiation in PDAC. Our experiments show that loss of REST in PDAC cells increases NE gene expression, gemcitabine resistance, and colony formation. RNA sequencing data from gemcitabine-treated PDAC cells were enriched for REST target genes, suggesting gemcitabine relieves REST-mediated repression. Chromatin immunoprecipitation experiments corroborated this by demonstrating that gemcitabine reduces REST binding to the NE genes SYP and SNAP25. In addition, single cell ATAC sequencing also uncovered a heterogeneous response to gemcitabine treatment, revealing two gemcitabine-driven cell states with differing REST motif accessibility. Our study indicates that REST controls NE gene programs in PDAC and that loss of REST promotes gemcitabine resistance and oncogenic growth. Mirroring the heterogeneity of PDAC tumors, a subset of PDAC cells treated with gemcitabine have reduced REST motif accessibility, which may reflect a therapy resistant NE-like subpopulation.
Citation Format: Kevin Alexander MacPherson, Meghan M. Joly, Brittany Allen-Petersen, Carl Pelz, Mary C. Thoma, Kristof Torkenczy, Andrew Adey, Daniel Liefwalker, Patrick J. Worth, Rosalie C. Sears. RE1-silencing transcription factor (REST) controls neuroendocrine gene programs in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 787.
Abstract 788: Prrx1 regulates acinar cell plasticity in Kras-driven pancreatic acinar-to-ductal metaplasia
Authors: Li Alina L. , Sugiura Kensuke , Suzuki Kensuke , Pitarresi Jason R. , Chiarella Anna M. , Efe Gizem , Chandwani Rohit , Rustgi Anil K. 
Published: June 2022

Abstract
Introduction: Acinar cells in the adult pancreas demonstrate cellular plasticity and undergo de-differentiation to a progenitor-like cell type with ductal characteristics after injury. This process, termed acinar-to-ductal metaplasia (ADM), is an important feature facilitating pancreas regeneration after injury. In the absence of oncogenic mutations, the ADM lesions resolve and reform the acinar compartment (adaptive ADM). However, in the presence of oncogenic Kras mutations (oncogenic ADM), acinar cells undergo neoplastic transformation after ADM and evolve to pancreatic intraepithelial neoplasia (PanIN), a well-known precursor of pancreatic ductal adenocarcinoma (PDAC). We have characterized the role of Paired-Related Homeobox1 (PRRX1) in adaptive ADM. We demonstrated through our novel conditional Prrx1 knock-out mouse model that loss of Prrx1 abrogated ADM formation. Here we explore the relationship between Prrx1 and mutant Kras on promoting ADM and a pro-ADM microenvironment.
Methods: We generated novel Pdx1-Cre;LSLKrasG12D/+;Prrx1fl/fl;Rosa26YFP/YFP (KCY Prrx1 KO) mice, in which mutant Kras is efficiently expressed and Prrx1 is deleted in a pancreas-specific manner. KCY Prrx1 WT and KO mice were sacrificed at 3 months and 5 months for histological analysis. Immunofluorescence (IF) staining for CK19, characterized for the rate of ADM formation and evaluated for F4/80 and SMA. Quantification of ADM regions, F4/80 and SMA was performed through automated cell-counting of immunofluorescence staining (IF). Dissociated acinar cell culture in collagen was utilized for the evaluation of ADM under ex vivo conditions.
Results: IF staining revealed that KCY Prrx1 KO mice had fewer ADM lesions compared to Prrx1 WT mice at 3 months. This difference became dramatically apparent at the 5 month timepoint. Additionally, lower areas of fibrosis were identified via H&E staining in KCY Prrx1 KO mice, which was accompanied with lower F4/80 and SMA positivity at both 3 months and 5 months. Ex vivo cultures also demonstrated significant reduction in ADM formation in the context of oncogenic Kras and loss of Prrx1.
Conclusions: PRRX1 can influence ADM formation in both a cell-intrinsic and cell-extrinsic manner in the presence of oncogenic KRAS. Our preliminary data suggest Prrx1 facilitates PDAC progression through PanIN formation. We will continue to investigate the mechanisms driving Prrx1-dependent ADM formation.
Citation Format: Alina L. Li, Kensuke Sugiura, Kensuke Suzuki, Jason R. Pitarresi, Anna M. Chiarella, Gizem Efe, Rohit Chandwani, Anil K. Rustgi. Prrx1 regulates acinar cell plasticity in Kras-driven pancreatic acinar-to-ductal metaplasia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 788.
Abstract 789: Elucidating transcriptional dynamics in neuroendocrine differentiation of advanced prostate cancer
Authors: Chen Chia-Chun , Song Kai , Tran Wendy , Obusan Matthew , Sugimoto Tyler , Sheu Katherine , Cheng Donghui , Varuzhanyan Grigor , Wang Liang , Ta Lisa , Mao Zhiyuan , Bangayan Nathanael , Park Jung-Wook , Graerber Thomas , Witte Owen 
Published: June 2022

Abstract
Small cell carcinomas of the lung, bladder, and prostate share similar transcription patterns and drug sensitivities. Due to their high cellular plasticity, these cancers often escape treatment through a trans-differentiation from adenocarcinoma to the neuroendocrine state. We previously developed a pan small cell cancer in vitro/in vivo model named PARCB that can recapitulate this transition from primary patient tissues. To understand which transcription factors may be important in this transition, we conducted bulk and single cell RNA sequencing over time. We identified a developmental trajectory that is shared among all samples and is defined by stage-specific transcription factors. We plan to interrogate the role that these transcription factors play in the PARCB transformation assay. We performed ATAC sequencing to investigate how these transcription factors regulate these transitional states. Our study will provide a basic understanding of the transcriptional changes that occur during neuroendocrine differentiation and provide new potential therapeutic targets for small cell cancers.
Citation Format: Chia-Chun Chen, Kai Song, Wendy Tran, Matthew Obusan, Tyler Sugimoto, Katherine Sheu, Donghui Cheng, Grigor Varuzhanyan, Liang Wang, Lisa Ta, Zhiyuan Mao, Nathanael Bangayan, Jung-Wook Park, Thomas Graerber, Owen Witte. Elucidating transcriptional dynamics in neuroendocrine differentiation of advanced prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 789.
Abstract 816: Cyclin c suppresses pancreatic intraepithelial neoplasm progression and neuroendocrine neoplasm development in a murine Kras model
Authors: Cai Kathy Q. , Hanley Sara E. , Klein-Szanto Andres , Campbell Kerry S. , Strich Randy 
Published: June 2022

Abstract
Cyclin c is a component of the Cdk8 kinase module that plays both a positive and negative role in transcription. In addition, cellular damage induces cyclin c re-localization to the mitochondria where it stimulates fission and recruits Bax in preparation for apoptotic initiation. Previous studies revealed that cyclin c suppresses thyroid hyperplasia in a Pten knockout mouse model. In the present study, a role for cyclin c in suppressing pancreatic cancer progression was investigated in the Pdx1-Cre LSL-KrasG12D murine pancreatic cancer model. Within eight weeks, a 6-8 fold increase in the appearance of pancreatic intraepithelial neoplasia (PanIN) and acinar ductal metaplasia (ADM) lesions was observed in the KrasG12D+Ccnc-/- animals compared to KrasG12D alone. Surprisingly, high-grade neuroendocrine neoplasms (NEN) were also observed. These aggressive NEN showed mixed morphology with areas of acinar-like differentiation. High grade NEN exhibited pronounced proliferative index (Ki67), high EZH2 expression, and elevated Notch1, suggesting a connection between aberrant Notch signaling and NEN formation. Our previous studies identified a positive role for cyclin c in autophagy gene transcription. Similarly, cell lines derived from a KrasG12D+Ccnc-/- pancreas exhibited a reduction in autophagy compared to KrasG12D+Ccnc+/+ cells. Autophagic deficiency induces pancreatic cell stress and is associated with apoptosis. Consistent with this model, high caspase 3 expression was observed in early KrasG12D+Ccnc-/- NEN but not in KrasG12D+Ccnc+/+ tissues. Taken together, these results demonstrate a role for cyclin c in suppressing both progression of early PanIN and the development of high-grade NEN and suggest a model that cyclin c loss suppresses autophagy and increases apoptosis.
Acknowledgements: Support was provided by NCI CCSG grant CA06927 for the FCCC Histopathology and Cell Culture Facilities, the PA Department of Health CURE fund (KSC), the Boye Foundation (RS), and the New Jersey Health Foundation (RS).
Citation Format: Kathy Q. Cai, Sara E. Hanley, Andres Klein-Szanto, Kerry S. Campbell, Randy Strich. Cyclin c suppresses pancreatic intraepithelial neoplasm progression and neuroendocrine neoplasm development in a murine Kras model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 816.
Abstract 821: Dissecting the role of Stag2 in lung adenocarcinoma
Authors: Ashkin Emily L. , Cai Hongchen , Tang Yuning J. , Li Chuan , Chew Su Kit , Hung King , Belk Julia , Karmakar Saswati , Hebert Jess , Yousefi Maryam , Swanton Charles , Petrov Dmitri A. , Winslow Monte 
Published: June 2022

Abstract
Lung cancer is the most common cause of cancer-related deaths worldwide. Cancers are driven by genomic alterations that activate tumor-promoting oncogenes and inactivate tumor suppressor genes. While some of the most common driver genes have been extensively characterized, many tumor suppressor genes are less well studied. A better understanding of the mechanisms by which different tumor suppressor genes constrain tumorigenesis has the potential to uncover unappreciated biological processes that influence carcinogenesis. Recently, we performed an in vivo screen within a genetically engineered mouse model of oncogenic KRAS-driven lung cancer and found that STAG2 inactivation dramatically increases tumor growth. While STAG2 is mutated in ~4% of human lung adenocarcinomas, 20% of lung adenocarcinomas are low or negative for STAG2 protein. STAG2 is a subunit of one of the two major cohesin complexes, which are present in all cell types and have been implicated in many different cellular processes. STAG2 has not previously been recognized as a critical tumor suppressor in lung cancer and the mechanism through which its inactivation drives lung tumor growth is unknown. Immunohistochemistry, low-pass whole genome sequencing, and analysis of canonical target genes suggest that STAG2 inactivation is not associated with mechanisms previously implicated in other cancer types including chromosomal instability, increased DNA damage, or the activation of MEK/ERK or cGAS/STING signaling. Interesting, we have found that Stag2 is the only cohesin subunit that functions as a tumor suppressor in lung cancer in vivo. Chromatin accessibility profiling and gene expression analyses on Stag2-proficient and -deficient mouse lung adenocarcinoma cells have unveiled potential mediators and effects of STAG2 function. Ongoing genomic analyses of human and mouse lung cancers will demystify the relationship between major cohesin complexes, uncover the impact of STAG2 inactivation on cohesin binding genome wide, and investigate the role of Stag2 inactivation on the tumor microenvironment. We anticipate that our study will uncover the mechanisms of STAG2-mediated tumor suppression in lung cancer and provide novel insights into lung tumorigenesis.
Citation Format: Emily L. Ashkin, Hongchen Cai, Yuning J. Tang, Chuan Li, Su Kit Chew, King Hung, Julia Belk, Saswati Karmakar, Jess Hebert, Maryam Yousefi, Charles Swanton, Dmitri A. Petrov, Monte Winslow. Dissecting the role of Stag2 in lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 821.
Abstract 835: Estrogen receptor expression and ER dependent breast tumor growth are dependent on translation initiation factor EIF4A
Authors: Boyer Jacob A. , Dorso Madeline A. , Amor Corina , Reiter Jason , Xu Jianing , de Stanchina Elisa , Wendel Hans-Guido , Chandarlapaty Sarat , Rosen Neal 
Published: June 2022

Abstract
The majority of human breast cancers are dependent on Estrogen Receptor Alpha (ER) and sensitive to its inhibition. In advanced, ER+ dependent breast cancers, resistance usually develops and is associated with insensitivity of the estrogen receptor to inhibition. Mutations that activate PI3K signaling occur in over 40% of ER-driven breast cancers. The PI3K pathway regulates cap-dependent protein translation by controlling mTOR complex I (mTORC1). Inhibitors of PI3K/mTOR are effective in this setting when given with anti-estrogens, but induce ER activity and expression. We now show that despite reducing global cap-dependent translation, PI3K/mTOR inhibition does not reduce ER translation or expression. Translation of ER instead depends on the translation initiation factor, EIF4A. Inhibitors of EIF4A significantly reduce the expression of WT and mutant ER, with attendant blockage of breast cancer model growth in vivo, including models driven by estrogen-independent ER fusions that are unaffected by estrogen receptor antagonists. The utility of EIF4A inhibition can be enhanced when combined with Fulvestrant, a degrader of ER. Combining inhibition of ER translation and induction of ER degradation causes synergistic deep and durable inhibition of ER expression and tumor growth. Inhibition of ER translation represents a new potent strategy for treating ER-dependent breast cancers with acquired resistance to current therapies.
Citation Format: Jacob A. Boyer, Madeline A. Dorso, Corina Amor, Jason Reiter, Jianing Xu, Elisa de Stanchina, Hans-Guido Wendel, Sarat Chandarlapaty, Neal Rosen. Estrogen receptor expression and ER dependent breast tumor growth are dependent on translation initiation factor EIF4A [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 835.
Abstract 836: CRACD/CRAD, a tumor suppressor for gastric cancer development
Authors: Zou Gengyi , Huang Yuanjian , Ko Kyung Pil , Zhang Shengzhe , Kim Bong Jun , Zhang Jie , Jun Sohee , Jung Youn-Sang , Zheng Biyun , Park Jae-Il 
Published: June 2022

Abstract
Gastric cancer (GC) is the third most common cancer and the second most common cause of cancer death in Asia. The highest incidence rates are observed in Eastern Asia. To date, the comprehensive mechanism of GC initiation remains elusive. Here, we discovered CRACD (Capping Protein Inhibiting Regulator of Actin Dynamics/CRAD/KIAA1211) as a tumor suppressor, frequently inactivated in GC. To determine the pathologic roles of CRACD, we employed Cracd knock-out (KO) mice and gastric organoids (GOs). Intriguingly, Cracd KO mice and GOs displayed hyperplastic gastric epithelium. Mechanistically, CRACD is essential for stabilizing the cadherin-catenin-actin (CCA) complex. The loss of CRACD leads to the release and nuclear translocation of β-catenin for Wnt target gene transactivation. Indeed, the genetic ablation of Cracd hyperactivated Wnt/β-catenin signaling with the disruption of the CCA complex. The genes encoding the Receptor Tyrosine Kinase (RTK)-RAS signaling pathway and the TP53 are genetically altered in 60% and 50% of gastric adenocarcinomas, respectively. To define the genetic interaction of Cracd loss with the RTK-RAS and TP53 signaling, we established genetically engineered GOs models carrying Trp53 deletion and KrasG12D activation in combination with Cracd KO (CKP) or Cracd wild type (KP). Compared to KP, CKP GOs exhibited neoplasia, higher mucin deposition, and increased carcinoma embryonic antigen (CEA) expression, pathologically related to the poor prognosis in GC patients. Meanwhile, loss of Cracd significantly accelerated the growth of CKP GOs with increased stemness. Furthermore, the CKP cell line derived from GOs exhibited relatively poor prognosis features of GC than KP cells in the xenograft models, represented by boosted tumor size and weight, poor differentiation, hyperplasia, increased CEA, and mucin secretion. Together, we identified CRACD as a tumor suppressor, of which inactivation contributes to GC initiation and progression, which may be translated into the development of a biomarker-guided regimen for CRACD mutations-associated GC patients.
Citation Format: Gengyi Zou, Yuanjian Huang, Kyung Pil Ko, Shengzhe Zhang, Bong Jun Kim, Jie Zhang, Sohee Jun, Youn-Sang Jung, Biyun Zheng, Jae-Il Park. CRACD/CRAD, a tumor suppressor for gastric cancer development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 836.
Abstract 840: PMEPA1 is an oncogene linked to TGF-β signaling in hepatocellular carcinoma
Authors: Piqué-Gili Marta , Andreu-Oller Carmen , Pinyol Roser , Bárcena-Varela Marina , Esteban-Fabró Roger , Peix Judit , Abril-Fornaguera Jordi , Lindblad Katherine E. , Torres-Martin Miguel , Sia Daniela , Lujambio Amaia , Llovet Josep M. 
Published: June 2022

Abstract
Background: Transforming growth factor β (TGFβ) has a dual role in cancer, including hepatocellular carcinoma (HCC). It acts as a tumor suppressor in early stages of hepatocarcinogenesis, but promotes epithelial-to-mesenchymal transition, angiogenesis and immunosuppression in advanced stages. PMEPA1 (prostate transmembrane protein androgen induced 1), a direct target gene of the TGFβ pathway that negatively regulates TGFβ signaling by interacting with SMAD proteins, has been shown to promote TGFβ oncogenic effects in other cancers and we decided to explore its role in HCC pathogenesis.
Methods: We analyzed transcriptomic, genomic, epigenomic and clinicopathological data of a discovery cohort of 228 HCCs and a validation cohort of 361 HCCs. PMEPA1 levels were quantified by qPCR in the discovery cohort. PMEPA1 overexpression was validated in 6 independent cohorts (n = 916) using microarray and RNAseq data. Genetically engineered mouse models were generated through hydrodynamic tail-vein injection. Equal amounts of plasmids overexpressing PMEPA1, TGFB1 and MYC were injected in mice to evaluate survival. Molecular and histopathological analyses of the murine tumors are currently ongoing.
Results: PMEPA1 was overexpressed in 18% of human HCCs [FC &gt; 2; n = 203/1144], a feature associated with TGFβ signaling (p &lt; 0.05). Overexpression of PMEPA1 was associated with gene body hypermethylation (p &lt; 0.0001). HCCs displaying both TGFβ signaling and high PMEPA1 levels (11% of cases) were significantly enriched in signatures of immune exhaustion, late TGFβ activation, TME response to TGFβ and active stroma (p &lt; 0.05) compared to HCCs with TGFβ signalling alone (8% of cases) or PMEPA1 high levels alone (11% of cases). In vivo, overexpression of MYC+PMEPA1 led to HCC development in 9/16 mice and showed a lower survival when compared to the control arm, overexpression of MYC alone (p = 0.014). On the contrary, only 1/12 mice in the MYC+PMEPA1+TGFβ1 condition developed HCC and none of the MYC+TGFβ1 mice.
Conclusion: PMEPA1 upregulation is linked to TGF-β activation and an aggressive phenotype in human HCC. Overexpression PMEPA1 in combination with MYC in vivo led to HCC development, showing for the first time the oncogenic role of PMEPA1 in this cancer.
Citation Format: Marta Piqué-Gili, Carmen Andreu-Oller, Roser Pinyol, Marina Bárcena-Varela, Roger Esteban-Fabró, Judit Peix, Jordi Abril-Fornaguera, Katherine E. Lindblad, Miguel Torres-Martin, Daniela Sia, Amaia Lujambio, Josep M. Llovet. PMEPA1 is an oncogene linked to TGF-β signaling in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 840.