bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1832: Ligand-dependent Wnt signaling directs metabolic adaptations to promote pancreatic tumorigenesis
Authors: Aguilera Kristina Y. , Riahi Rana , Saadat Edris A. , Lay Anna R. , Le Thuc , Cabebe Anthony , Donahue Timothy R. , Radu Caius , Dawson David W. 
Published: August 2019

Abstract
Wnt/β-catenin signaling plays important roles in pancreatic adenocarcinoma (PDA) tumor initiation and progression via broad-ranging effects on proliferation, differentiation, survival, and stemness. Although Wnt has been shown to promote glycolysis in colon cancer, its role in regulating metabolism in PDA has not been explored in any detail. For this study, the AsPC-1 cell line was selected as an exemplar of ligand-dependent autocrine Wnt signaling in PDA. AsPC-1 harbors an inactivating mutation in RNF43 that confers Wnt growth-dependency and response to LGK974, a PORCN inhibitor that blocks Wnt ligand secretion and signaling. Global transcriptomic, proteomic, and metabolomic analysis revealed several metabolites and putative mediators of metabolism that are directly or indirectly linked to autocrine Wnt signaling in AsPC-1. In contrast to colon cancer, pharmacologic inhibition of Wnt by LGK974 in AsPC-1 led to the accumulation of pyruvate and lactate, as well as reduced tricarboxylic acid cycle metabolites and decreased mitochondrial membrane potential as measured by tetramethylrhodamine assay. These metabolic changes were accompanied by cell cycle arrest and downregulation of transcriptional programs involved in cell cycle progression, DNA replication, and nucleotide metabolism. Pyruvate analogs dichloroacetate and oxamate, that respectively target pyruvate dehydrogenase kinase and lactate dehydrogenase, restored mitochondrial membrane potential in the context of LGK974. Importantly, LGK974 results were phenocopied by siRNA-mediated knockdown of WNT7B. Thus, inhibition of mitochondrial oxidative phosphorylation by LGK974 in RNF43-mutant PDA appears mechanistically linked to its inhibition of canonical Wnt signaling, an adaptation and potential metabolic vulnerability that could be leveraged to therapeutic advantage via combinatorial strategies. Altogether, these results suggest tissue context and differing mechanisms of Wnt pathway activation or signal strength may profoundly influence its role in regulating cancer metabolism.
Citation Format: Kristina Y. Aguilera, Rana Riahi, Edris A. Saadat, Anna R. Lay, Thuc Le, Anthony Cabebe, Timothy R. Donahue, Caius Radu, David W. Dawson. Ligand-dependent Wnt signaling directs metabolic adaptations to promote pancreatic tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1832.
Abstract 1844: xCT promotes tumor formation in airway epithelial cells by activation MYC and WNT pathways
Authors: Ji Xiangming 
Published: August 2019

Abstract
INTRODUCTION: Many tumors increase uptake and dependence on nutrients such as glucose, cysteine or glutamine. These basic observations on cancer cell metabolism have opened multiple new diagnostic and therapeutic avenues in cancer. Recent studies demonstrated that smoking can induce the expression of xCT (SLC7A11) in normal epithelial cells and cancer cells, suggesting that overexpression of xCT may support lung tumor progression. These basic observations on cancer cell metabolism have opened multiple new diagnostic and therapeutic avenues in cancer. Here, we investigated the function of SLC7A11 (xCT), a cystine/glutamate anti-porter, in the pathogenesis of lung cancer. Recently, we found xCT to be strongly overexpressed at the cell surface of lung cancers and began to investigate the mechanisms by which xCT may contribute to lung cancer progression.
METHODS: We overexpressed the xCT in mutiple non-tumorgenic cell lines. These cell lines included 16HBE, BEAS2B, HBEC_KTR_P53_C7, and HEK293. We further investigated the role of xCT in cell proliferation, conly formation, and tumor formation in nude mice. Finally, we used RNAseq analysis to indentify the molecular mechanims associated with xCT expression in HEK293 cells.
RESULTS: Our results shows that xCT overexpression transformed the normal airway epithelium cell lines (HBEC3_KTR_P53_C7). The overexpression of xCT in HBEC_KTR_P53C7 induced colony formation in soft agar and promoted cell proliferation. In addition, we found overexpression of xCT reprogrammed multiple metabolic pathways such as glycolysis, glutaminolysis, and pentose phosphate pathway. In addition, we found overexpression of xCT could transform non-tumorigenic cell line HBEC_KTR_P53_C7 to tumor-formation cell line. Our RNAseq data indicated that this transformation is enriched in MYC and WNT pathway.
CONCLUSION: Our results demonstrate that xCT is highly expressed in a subset of NSCLCs. The induction of xCT in transformed aiway epithelial cells causes tumor formation in nude mice. The mechanism of malignant transformation involves the Warburg effect. Further investigation into the mechanisms of transformation may help in answering fundamental questions pertaining to how glutamate/cystine exchange contributes to lung cancer development and progression and also in establishing xCT as a potential novel therapeutic target in lung cancer.
Key words: Non-small cell lung cancer, amino acid transporters, metabolic reprogramming
Note: This abstract was not presented at the meeting.
Citation Format: Xiangming Ji. xCT promotes tumor formation in airway epithelial cells by activation MYC and WNT pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1844.
Abstract 1848: The role of PDK1 in metabolic reprogramming of mesenchymal glioblastoma
Authors: Jain Neha , Guda Maheedhara , Labak Collin , Smith Chase , Park Simon , Tsung Andrew , Velpula Kiran 
Published: August 2019

Abstract
Despite multimodal therapy and ever-improving surgical technique, glioblastoma (GBM) maintains its poor prognosis due to the chemotherapeutic resistance it builds over time, eventually rendering existing agents ineffective. A well-characterized phenomenon that takes place particularly in mesenchymal GBM tissue is the Warburg Effect, characterized by a shift from oxidative phosphorylation to glycolysis as a primary means to derive energy. Pyruvate Dehydrogenase Kinase 1 (PDK1) is one upregulated molecule in this shift toward anaerobic metabolism that is known for phosphorylating pyruvate dehydrogenase, the “gate keeper” of the TCA cycle. We sought to characterize further the role of PDK1 in terms of its metabolic role and any extra-metabolic functions it may serve. By silencing PDK1 and considering changes in downstream expression, we hope to understand what other factors serve as contributors to metabolic alterations seen in GBM. Elucidating the mechanism of this crucial shift more thoroughly, especially without the prominently cited role of PDK1, can begin to expose new targets for interrupting tumor maintenance and proliferation by affecting its metabolism. In this study we used differential expression of two vectors in which PDK1 was silenced, shPDK1 and SCBT-PDK1. GSEA analysis was done and analyzed to identify classes of genes or proteins that are over-represented and to identify significantly enriched or depleted groups of targets whose expression was vastly changed by silencing of PDK1. Using GSEA heat map data, gene targets whose expression was noted to be consistently changed with silencing of PKD1 targets were identified. Datamining and immunoblot analyses were then conducted to evaluate for expression of these genes in correlating GBM specimens. Ultimately, we further characterize PDK1’s global role in GBM and evaluate non-metabolic effects of PDK1 that may still affect survival and proliferation of GBM tumors.
Citation Format: Neha Jain, Maheedhara Guda, Collin Labak, Chase Smith, Simon Park, Andrew Tsung, Kiran Velpula. The role of PDK1 in metabolic reprogramming of mesenchymal glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1848.
Abstract 186: Androgen deprivation promotes neuroendocrine differentiation and angiogenesis through CREB-EZH2-TSP1 pathway in prostate cancers
Authors: Zhang Yan , Zheng Dayong , Zhou Ting , Hulsurkar Mohit , Ittmann Michael , Shao Long , Gleave Martin , Li Wenliang 
Published: August 2019

Abstract
The incidence of aggressive neuroendocrine prostate cancers (NEPC) related to androgen-deprivation therapy (ADT) is rising. NEPC is still poorly understood, such as its neuroendocrine differentiation (NED) and angiogenic phenotypes. Here we reveal that NED and angiogenesis are molecularly connected through EZH2 (enhancer of zeste homolog 2). NED and angiogenesis are both regulated by ADT-activated CREB (cAMP response element-binding protein) that in turn enhances EZH2 activity. We also uncover anti-angiogenic factor TSP1 (thrombospondin-1, THBS1) as a direct target of EZH2 epigenetic repression. TSP1 is downregulated in advanced prostate cancer patient samples and negatively correlates with NE markers and EZH2. Furthermore, castration activates the CREB/EZH2 axis, concordantly affecting TSP1, angiogenesis and NE phenotypes in tumor xenografts. Notably, repressing CREB inhibits the CREB/EZH2 axis, tumor growth, NED and angiogenesis in vivo. Taken together, we elucidate a new critical pathway, consisting of CREB/EZH2/TSP1, underlying ADT-enhanced NED and angiogenesis during prostate cancer progression.
Citation Format: Yan Zhang, Dayong Zheng, Ting Zhou, Mohit Hulsurkar, Michael Ittmann, Long Shao, Martin Gleave, Wenliang Li. Androgen deprivation promotes neuroendocrine differentiation and angiogenesis through CREB-EZH2-TSP1 pathway in prostate cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 186.
Abstract 1885: CRISPR/Cas9 engineered immortalized breast epithelial MCF10A reporter line for EMT studies and anti-cancer drug discovery
Authors: Shu Weiguo , Kumari Sangeeta , Douglas Diana , Rodriguez Luis G. , Newman Robert 
Published: August 2019

Abstract
Metastasis is responsible for most cancer-related deaths. One model for the mechanism of metastasis involves epithelial-to-mesenchymal transition (EMT), a process characterized by the decrease in cell adhesion and increase in cell motility. Cells undergoing EMT often display downregulation of epithelial markers (such as, E-cadherin) and upregulation of mesenchymal markers (such as, Vimentin). Besides metastasis, EMT has also been reported to be associated with other pathological conditions, such as acquired therapeutic drug resistance. Given the roles that EMT may play in these various pathological processes, it is of increasing interest as a target for anti-cancer treatment and drug discovery. In vitro reporter models have proven to be a valuable tool for dissecting the signaling pathways that regulate the EMT process and for screening compounds targeting EMT. In previously developed EMT reporter cell lines, the reporter gene was driven by a truncated EMT marker gene promoter. Therefore, the establishment of a more physiologically relevant reporter cell models is critical for advancing our knowledge of EMT. E-cadherin, a hallmark of epithelial cells, has been implicated in the onset of metastatic dissemination. Utilizing CRISPR/Cas9 knock-in technology, we have generated an E-cadherin (ECAD)-emerald green fluorescent protein (EmGFP) reporter model using immortalized breast epithelial MCF10A cells. In the reporter cells, EmGFP gene was tagged at the C-terminus of E-cadherin, allowing for real-time monitoring of EMT progression in live cells. The targeted knock-in of ECAD-EmGFP allele was verified at the genomic DNA, transcript (mRNA), and protein levels. Bio-functional evaluation of the reporter cell line revealed that treatment of ECAD-EmGFP reporter cells with TGFβ led to EMT induction, as demonstrated by a reduction in E-cadherin-GFP expression and increase in vimentin and fibronectin expressions. Additional functional characterization revealed that the reporter cells possessed an enhanced migration capacity upon EMT induction with TGF-β. In summary, this MCF10A-Ecad-EmGFP reporter cell line can serve as a physiologically relevant in vitro cell model for studying EMT cancer biology and anti-EMT drug discovery.
Citation Format: Weiguo Shu, Sangeeta Kumari, Diana Douglas, Luis G. Rodriguez, Robert Newman. CRISPR/Cas9 engineered immortalized breast epithelial MCF10A reporter line for EMT studies and anti-cancer drug discovery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1885.
Abstract 1890: Calcitonin receptor is required for T-antigen-induced prostate carcinogenesis
Authors: Aldahish Afaf , Thakkar Arvind , Shah Girish V. 
Published: August 2019

Abstract
Calcitonin & calcitonin receptor axis (CT-CTR) expression is increased in prostate cancer & its levels positively correlate with Gleason grade of prostate cancer. Moreover, activation of CT-CTR autocrine axis promotes several processes with tumor progression such as, tumor growth, invasion, angiogenesis, chemoresistance & metastasis. However, the role of CT-CTR axis in carcinogenesis process has not been investigated. To examine the role of CT-CTR axis in prostate carcinogenesis we examined the impact of CTR deficiency on T-antigen-induced prostate tumorigeneses in transgenic mice. We achieved this by cross-breading CTR-knockout mice with LPB-Tag mice (the transgenic mice that uses long Probasin promotor for prostate-specific expression of Tag T-antigen). The cross-breeding of these two transgenic mice yielded four different groups of mice with the following genotypes 1. Control (which lacked both transgenes), 2. CTRKO (only CTRKO transgene), 3. LPB-Tag (contained LPB-Tag transgene), & 4. CTRKO-LPB-Tag (expressed Both CTRKO & LPB-Tag transgenes). The growth of these mice were monitored until they reached the age of 90 days. The mice were sacrificed, the prostates were collected, fixed & evaluated by histology & immunohistochemistry. The results suggest that the mice of all groups developed normally with the exception of LPB-Tag group which displayed slower growth & the presence of prostatic tumors at the time of necropsy. Although all LPB-Tag mice displayed all prostate tumors, as expected wild type & CTRKO mice did not display change in the size or mass of prostates. Subsequently, H&E histology as well as Ki67 staining confirmed that all LPB-Tag mice displayed well-developed prostatic adenocarcinoma, all CTRKO-LPB-Tag displayed no presence of tumor with the exception of occasional presence of HGPIN. Since our earlier studies have shown that CTR induced epithelial-to-mesenchymal transition (EMT) in prostate cancer cell lines, we also examined the expression of two epithelial markers, ZO-1 & E-cadherin, & two mesenchymal markers, fibronectin & vimentin. The results suggest that prostates of the three groups ( WT, CTRKO, LPB-Tag-CTRKO) displayed higher epithelial markers expression with a remarkably lower expression of mesenchymal markers when compared with those of LPB-Tag group. This was further substantiated by the expression of EMT markers such as snail & N-cadherin. In conclusion, this study shows that the CTR deficiency inhibits prostate carcinogenesis in LPB-Tag mice without reducing T-antigen expression or causing any other apparent harmful side effects. This work was supported by NIH grant CA096534.
Citation Format: Afaf Aldahish, Arvind Thakkar, Girish V. Shah. Calcitonin receptor is required for T-antigen-induced prostate carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1890.
Abstract 191: Extracellular signaling linked to PI3K/AKT triggers the formation of vasculogenic mimcry in ovarian cancer
Authors: Valdivia Andres , Mingo Gabriel , Aldana Varina , Sandoval Alejandra , Corvalan Alejandro , Nualart Francisco , Owen Gareth I. 
Published: August 2019

Abstract
Introduction: The presence of an endothelial cell-free perfusion pathway, known as Vasculogenic Mimicry (VM), strongly correlates with reduced patient survival, however the mechanisms by which a tumor can create a self-generated irrigation system remain unknown. Currently there is no mechanism of VM formation reported in fluid conducting tubular structures. Herein, using a standardized in vitro model, we sought to understand the pathways required for VM formation.
Methods: We utilized confocal microscopy and Imaris reconstruction to demonstrate that cancer cells can create an internal tubular network in cultured cancer cell lines, cancer spheres and primary cancer cultures of ovarian cancer. Matrigel and 3D matrices containing specific protein components allowed the deciphering of the extracellular matrix proteins involved in VM formation. Intercellular pathways were resolved using chemical inhibitors.
Results: VM only occurs when cells are grown in 3D culture and only 30% of primary cancer cultures undergo this process. The presence of laminin 1 is sufficient to trigger the formation of tubular structures and this may involve the alpha2beta1 integrin and metalloproteases. Downstream FAK and PI3K/AKT intercellular pathways are required to form functional tubular networks. Microarray data elucidated the presence of the mRNA transcripts that were increased in cells that undergo VM.
Discussion: We demonstrate that Laminin 1, a component of the extracellular matrix (ECM), can promote the process of VM, which further involves the downstream signaling of the potentially druggable targets of the PI3K pathway. As VM is associated with reduced patient survival, elucidation of the mechanisms of formation may deliver new cancer therapies.
Funding: FONDECYT 1180241, CONICYT FONDAP 15130011, IMII P09/016F
Citation Format: Andres Valdivia, Gabriel Mingo, Varina Aldana, Alejandra Sandoval, Alejandro Corvalan, Francisco Nualart, Gareth I. Owen. Extracellular signaling linked to PI3K/AKT triggers the formation of vasculogenic mimcry in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 191.
Abstract 1910: Regulation of ovarian tumor microenvironment dynamics by compressive stress
Authors: Asem Marwa , Young Allison Young , ClaureDeLaZerda Alejandro , Ravosa Matthew , Stack Sharon 
Published: August 2019

Abstract
Ovarian cancer (OvCa) is the most fatal gynecologic malignancy and the fifth leading cause of overall cancer death among American women with a low (27%) 5-year survival rate, as 75% of women are diagnosed with disseminated intra-peritoneal (IP) metastasis. OvCa cells detach from the primary tumor and shed into the peritoneal cavity, adhere to the peritoneal mesothelial cell (MC) monolayer, intercalate within this layer, and invade into the submesothelial matrix, where they proliferate and form secondary lesions.
More than one third of OvCa patients develop ascites that correlates with relapse and poor prognosis. The accumulated ascites can reach volumes up to 5 liters, causing a striking elevation in intraperitoneal pressure (IPP) from normally sub-atmospheric ~5 mmHg to as high as 27 mmHg, impacting the tumor microenvironment including host and tumor cells. The pressure created by accumulated ascites alters the force environment in the peritoneal cavity, causing strain and compressive forces on peritoneal structures. Yet, the mechanism through which ascites-induced IPP influences OvCa progression is poorly understood. The aim of this study is to understand how ascites-induced IPP promotes OvCa progression.
To model the compressive force present in vivo due to accumulated tense ascites (~27 mmHg), we evaluated the effects of compressive force on primary human and murine MC monolayers and murine peritoneal explants using the Flexcell Compression System. Strikingly, compressed MC and peritoneal explants exhibited phenotypic alterations and formed abundant Tunneling Nanotubes (TNT), which are cell membrane extensions that modulate transfer of organelles between cells under stress. Furthermore, compression of OvCa cells adherent to murine peritoneal explants show intense formation of TNT between OvCa cells and peritoneal MC. Remarkably, TNT formed under compression displayed membrane distension and modulated the transfer of mitochondria from MC to OvCa cells. Moreover, collected peritoneal explants from OvCa murine model with intense ascites showed TNT formation and changes in the peritoneal sub-mesothelial collagen ultrastructure.
This study reveals a novel response of OvCa cells and the tumor microenvironment to mechanical compression, uncovering a new mechanism by which OvCa metastatic success may be regulated.
Note: This abstract was not presented at the meeting.
Citation Format: Marwa Asem, Allison Young Young, Alejandro ClaureDeLaZerda, Matthew Ravosa, Sharon Stack. Regulation of ovarian tumor microenvironment dynamics by compressive stress [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1910.