tbuckley/cabot-search huggingface dataset:
Abstract 441: GOT1 regulates anaplerotic glutamine metabolism under chronic acidosis stress in pancreatic cancer
Authors: Jaime Abrego, Venugopal Gunda, Enza Vernucci, Surendra Shukla, Ryan J. King, Aneesha Dasgupta, Nina Chaika, Pankaj Kumar Singh
Journal: Cancer Research (2017)

Abstract Epithelial-cell derived tumors exhibit the Warburg effect that is characterized by an increased rate of glycolysis and lactate release, as well as, reduced oxidative metabolism. It is known that these metabolic alterations of cancer cells result in a tumor microenvironment with a lower pH than that of the plasma. However, little is known regarding the physiology and metabolism of cancer cells enduring chronic acidosis. Here, we cultured pancreatic cancer cells in chronic acidosis, i.e. pH 6.9 to 7.0, and observed a shift from glycolytic metabolism to oxidative metabolism that also results in reduced cell growth and increased intracellular ROS levels. We identified that this is due to an increase in glutamine uptake and increased expression of the transaminase enzyme GOT1 that enhances glutamine metabolism. Survival in low pH is reduced upon depletion of GOT1 due to further increased intracellular ROS levels. Thus, GOT1 plays an important role in energy metabolism and ROS balance in chronic acidosis stress. Our studies suggest the therapeutic potential of targeting anaplerotic glutamine metabolism in pancreatic cancer. Citation Format: Jaime Abrego, Venugopal Gunda, Enza Vernucci, Surendra Shukla, Ryan J. King, Aneesha Dasgupta, Nina Chaika, Pankaj Kumar Singh. GOT1 regulates anaplerotic glutamine metabolism under chronic acidosis stress in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 441. doi:10.1158/1538-7445.AM2017-441
Abstract 4888: Human PGBD5 DNA transposase promotes site-specific oncogenic mutations in rhabdoid tumors
Authors: Anton G. Henssen, Richard Koche, Jiali Zhuang, Eileen Jiang, Casie Reed, Amy Eisenberg, Eric Still, Elias Rodríguez-Fos, Santiago Gonzalez, Montserrat Puiggròs, Andrew N. Blackford, Christopher E. Mason, Elisa de Stanchina, Mithat Gönen, Anne-Katrin Emde, Minita Shah, Kanika Arora, Catherine Reeves, Nicholas D. Socci, Elizabeth Perlman, Cristina R. Antonescu, Charles W. Roberts, Hanno Steen, Elizabeth Mullen, Stephen P. Jackson, David Torrents, Zhiping Weng, Scott A. Armstrong, Alex Kentsis
Journal: Cancer Research (2017)

Abstract Genomic rearrangements are a hallmark of childhood solid tumors, but their mutational causes remain poorly understood. Here, we identify the piggyBac transposable element derived 5 (PGBD5) gene as an enzymatically active human DNA transposase expressed in the majority of rhabdoid tumors, a lethal childhood cancer. Using assembly-based whole-genome DNA sequencing, we observed previously unknown somatic genomic rearrangements in primary human rhabdoid tumors. These rearrangements were characterized by deletions and inversions involving PGBD5-specific signal (PSS) sequences at their breakpoints, with some recurrently targeting tumor suppressor genes, leading to their inactivation. PGBD5 was found to be physically associated with human genomic PSS sequences that were also sufficient to mediate PGBD5-induced DNA rearrangements in rhabdoid tumor cells. We found that ectopic expression of PGBD5 in primary human cells was sufficient to promote penetrant cell transformation in vitro and in immunodeficient mice in vivo. This activity required specific catalytic residues in the PGBD5 transposase domain, as well as end-joining DNA repair, and induced distinct structural rearrangements, involving PSS-associated breakpoints, similar to those found in primary human rhabdoid tumors. Thus, PGBD5 defines a distinct class of oncogenic mutators and induces site-specific somatic DNA rearrangements in human cancer. Citation Format: Anton G. Henssen, Richard Koche, Jiali Zhuang, Eileen Jiang, Casie Reed, Amy Eisenberg, Eric Still, Elias Rodríguez-Fos, Santiago Gonzalez, Montserrat Puiggròs, Andrew N. Blackford, Christopher E. Mason, Elisa de Stanchina, Mithat Gönen, Anne-Katrin Emde, Minita Shah, Kanika Arora, Catherine Reeves, Nicholas D. Socci, Elizabeth Perlman, Cristina R. Antonescu, Charles W. Roberts, Hanno Steen, Elizabeth Mullen, Stephen P. Jackson, David Torrents, Zhiping Weng, Scott A. Armstrong, Alex Kentsis. Human PGBD5 DNA transposase promotes site-specific oncogenic mutations in rhabdoid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4888. doi:10.1158/1538-7445.AM2017-4888
Abstract 4920: Inflammation and estrogen receptor beta modulate bacterial diversity of the gut
Authors: Ahmed F. Ibrahim, Quentin Thomas, Ashish Saxena, Cecilia Williams
Journal: Cancer Research (2017)

Abstract Background: Chronic inflammation is a risk factor of colorectal cancer (CRC), and the microbiota of the gut is important in both colitis and carcinogenesis. Estrogen receptor beta (ERβ) is the predominant nuclear receptor in the colon, and is downregulated in CRC. Here, we explore the role of colitis and ERβ signaling with respect to the microbiota diversity. Methods: Intestinal ERβ-/- mice were generated using the Cre-loxP system. WT and knockout mice were treated with AOM/DSS inducing colitis (at 9 weeks) and CRC (at 16 weeks). After 9 and 16 weeks, stool pellets were collected from treated and untreated mice (n=39), and DNA was extracted. Library preparation and 16S rRNA-sequencing was performed using the illumina Miseq platform with specific primers targeting the V3-V4 regions, and QIIME software was used to analyze microbiota diversity. Sequencing results were validated by qPCR Results: High-throughput 16S rRNA gene sequencing demonstrated that treatment induced significant differentiation of both alpha (p=0.01) and beta (p=0.01) microbiota diversity. Alpha diversity indicators implied a significant reduction of microbiota richness and evenness after treatment. qPCR confirmed that 9-weeks treatment increased OTUs affiliated with Bifidobacteria (p=0.03), Bacteroidetes (p=0.04), Lactobacilli (p=0.0014), Cyanobacteria (p=0.0023) and Gammaproteobacteria (p=0.05) in WT mice. After 16 weeks treatment, 16s rRNA sequencing show enrichment of Tenercutes, Proteobacteria and Cyanobacteria in all tumor-bearing mice (treated WT and ERβ-/-), while Verrucomicrobia increased in untreated mice (No tumors). Further treated ERβ-/- but not WT mice displayed significant reduction of Gammaproteobaceria (p=0.0083). Conclusion: Our data demonstrate a clear effect of colitis-induced treatment on the microbiota, and that ERβ attenuates this response. Lactobacilli and Bifidobacteria has, for example, been shown to attenuate inflammatory response. We note an increase in Lactobacilli and Bifidobacteia after treatment in WT mice, but not in ERβ-/- mice. This can result in increased colitis in ERβ-/- mice and help explain the increased expression of pro-inflammatory cytokines we note in treated ERβ-/- mice. Citation Format: Ahmed F. Ibrahim, Quentin Thomas, Ashish Saxena, Cecilia Williams. Inflammation and estrogen receptor beta modulate bacterial diversity of the gut [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4920. doi:10.1158/1538-7445.AM2017-4920
Abstract 781: Functional consequence of the p53 codon 72 polymorphism in colorectal cancer
Authors: Venkat R. Katkoori, Upender Manne, Harvey Bumpers
Journal: Cancer Research (2017)

Abstract Background: The codon 72 polymorphism in p53 has been implicated in colorectal cancer (CRC) and CRC health disparities. In this study, we determine the functional consequence of this polymorphism in CRC following both in-vitro cell based and in-vivo mouse model studies. Experimental Design: Plasmids (pCMV6) that express different phenotypes of p53 [p53 wild type (wt) at codon 72 (R72wt), R72wt with mutation at codon 273 cysteine (R72273Cys), p53 mutation at codon 72 (P72wt) and P72wt with mutation at codon 273 (P72273Cys)] were constructed. We selected a CRC cell line Caco2, which does not express p53 for in vitro studies. Severe combined immunodeficient mice were inoculated with CRC cells (HT29, SW480, and LS174) to establish tumor xenografts (tumors). Tumor angiogenesis was assessed in tumors by immunostaing for CD31. Sequencing analysis for codon 72 polymorphism of p53 was performed using genomic DNA purified from tumors. Western blot (WB) or immunostaining analyses for proteins of signaling mechanisms were performed to assess the functional consequence of P72 phenotype of p53. Results: Our study demonstrated that P72 tumors had well established vascularity, while R72 tumors had very poor vascularization. Indeed, the mean micro vessel density was higher in P72 tumors than in R72 tumors. WB analyses revealed that P72wt or mutant phenotypes effectively induced the activation of p38 and RAF/MEK/ extracellular signal-regulated kinase (ERK) MAP kinases. Up-regulation of phosphorylated SEK1/MKK4, an upstream kinase of p38 MAPK was associated with P72wt or mutant phenotypes. This activation was accompanied by up-regulation of phosphorylated-MAPKAPK-2, -Hsp27, and -CREB, downstream targets of p38 MAPK. Increased activation of CREB was found to be higher in tumors that exhibit P72 phenotype. Metastatic lesions of CRC expressed more phospho-CREB than non-metastatic lesions. Furthermore, suppression of RAF/MEK/ERK activation was significantly higher in cells that express R72wt phenotype compared to cells that express P72wt or mutant phenotypes. The expression of P72wt or mutant phenotypes displayed decreased expression of E cadherin and/or an increased expression of vimentin, fibrinectin, CD44, thereby promoting CRC metastasis. Conclusions: These findings offer significant novel insights into the mechanism by which P72 contributes to the aggressiveness of CRC. Because P72 is over-expressed in CRC, specifically in African-American patients, these studies suggest a role for P72 in cancer health disparities. This work was supported by NIH/NCI Workforce Diversity Grant R21-CA171251. Citation Format: Venkat R. Katkoori, Upender Manne, Harvey Bumpers. Functional consequence of the p53 codon 72 polymorphism in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 781. doi:10.1158/1538-7445.AM2017-781
Abstract 2024: Reactivating apoptosis in BFL-1/A1 driven cancer with cysteine-reactive stapled peptide inhibitors
Authors: Rachel M. Guerra, Annissa J. Huhn, Edward P. Harvey, Gregory H. Bird, Loren D. Walensky
Journal: Cancer Research (2017)

Abstract BFL-1/A1 is a BCL-2 family protein implicated in the progression and chemoresistance of melanoma, lymphoma, and other cancers, yet it remains undrugged. Anti-apoptotic BCL-2 family proteins block cell death by trapping the critical α-helical BH3 domains of pro-apoptotic members in a surface groove. Cancer cells hijack this survival mechanism by overexpressing a spectrum of anti-apoptotic members, mounting formidable apoptotic blockades that resist chemotherapeutic treatment. Drugging the BH3-binding pockets of anti-apoptotic proteins has become a highest-priority goal, fueled by the clinical success of venetoclax, a selective BCL-2 inhibitor, in reactivating apoptosis in BCL-2-dependent cancers. A natural juxtaposition of two unique cysteines at the binding interface of the NOXA BH3 helix and BFL-1/A1 pocket informed the development of stapled BH3 peptides bearing acrylamide warheads to irreversibly inhibit BFL-1/A1 by covalent targeting. Here, we describe the development and application of cysteine-reactive stapled peptides that, compared to their non-covalent analogs, trigger rapid mitochondrial cytochrome c release, caspase 3/7 activation, and apoptosis induction of BFL-1/A1 driven cancers such as melanoma. Mechanism of action studies demonstrated the exquisite BFL-1/A1 selectivity and mitochondrial localization of the in situ covalent reaction. Given the frequent proximity of native cysteines to regulatory binding surfaces, covalent stapled peptide inhibitors provide a new therapeutic strategy for targeting oncogenic protein interactions. Citation Format: Rachel M. Guerra, Annissa J. Huhn, Edward P. Harvey, Gregory H. Bird, Loren D. Walensky. Reactivating apoptosis in BFL-1/A1 driven cancer with cysteine-reactive stapled peptide inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2024. doi:10.1158/1538-7445.AM2017-2024
Abstract 1925: Modeling physiologic microenvironments in three-dimensional microtumors facilitates brain tumor initiating cell maintenance
Authors: Ashley Gilbert, Kiera Walker, Anh Tran, Yancey Gillespie, Raj Singh, Anita B. Hjelmeland
Journal: Cancer Research (2017)

Abstract Development of effective novel anti-tumor treatments will require improved in vitro models that incorporate physiologic microenvironments and maintain intratumoral heterogeneity including tumor initiating cells. Brain tumor initiating cells (BTIC) are a target for cancer therapy because they are highly tumorigenic and contribute to tumor angiogenesis, invasion, and therapeutic resistance. Current leading studies rely on BTIC isolation from patient-derived xenografts followed by propagation as neurospheres. As this process is expensive and time-consuming, we determined whether three-dimensional microtumors were an alternative in vitro method for modeling tumor growth via BITC maintenance and/or enrichment. Brain tumor cells were grown as neurospheres or as microtumors produced using a human-derived biomatrix HuBiogelTM and maintained with physiologically relevant microenvironments. Percentages of BITCs were determined based on cell surface marker expression (CD133), label retention (carboxyfluorescein succinimidyl ester; CFSE), and tumorsphere formation capacity. Our data demonstrate that expansion of brain tumor cells as hypoxic and nutrient restricted microtumors significantly increased the percentage of both CD133+ and CFSE+ cells. We further demonstrate that BTIC-marker positive cells isolated from microtumors maintain neurosphere formation capacity in the in vitro limiting dilution assay and tumorigenic potential in vivo. These data demonstrate that microtumors can be a useful three-dimensional biological model for the study of BTIC maintenance and targeting. Citation Format: Ashley Gilbert, Kiera Walker, Anh Tran, Yancey Gillespie, Raj Singh, Anita B. Hjelmeland. Modeling physiologic microenvironments in three-dimensional microtumors facilitates brain tumor initiating cell maintenance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1925. doi:10.1158/1538-7445.AM2017-1925
Abstract LB-036: Citrullinome analysis identifies the role of PADI4 in regulating RNA processing and tumor immunogenicity
Authors: Chizu Tanikawa, Koichi Matsuda
Journal: Cancer Research (2017)

Abstract Recent proteome analyses have provided a comprehensive overview of various posttranscriptional modifications (PTM); however, PTMs involving protein citrullination remain unclear. Thus, we performed a proteomic analysis of citrullinated proteins and identified more than 100 PADI4 substrates, the majority of which are related to RNA processing and protein translation. Citrullination of RBMX (RNA binding motif protein, X-linked) inhibited the interaction with other hnRNP family members. RNA sequence analyses revealed altered splicing patterns in more than 300 genes in bone marrow cells in Padi4-/- mice. Approximately one-fifth of the PADI4 substrates contained an RG/RGG motif, and citrullination by PADI4 competitively inhibited the methylation of the RGG motif in FET proteins (EWS and TAF15). In addition, PADI4-mediated citrullination inhibited the aggregation of TAF15 proteins, which is a frequently-observed feature in neurodegenerative diseases, such as ALS. An antibody against citrullinated RGG motifs was observed in 11.5% (27 among 234) of serum samples from patients with HCV-related hepatocellular carcinoma, and female patients with high serum antibody exhibited poor prognosis. Our findings imply that PADI4-mediated citrullination plays a key role in RNA processing, protein aggregation and tumor immunogenicity, and suggest that PADI4 activation has potential therapeutic implications for neurodegenerative disease and cancer immunotherapy. Citation Format: Chizu Tanikawa, Koichi Matsuda. Citrullinome analysis identifies the role of PADI4 in regulating RNA processing and tumor immunogenicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-036. doi:10.1158/1538-7445.AM2017-LB-036
Abstract 2892: Oncostatin M elicits cellular plasticity through cooperative STAT3-SMAD3 signaling
Authors: Benjamin L. Bryson, Damian J. Junk, Jacob Smigiel, Neetha Parameswaran, Mary R. Doherty, Courtney A. Bartel, Mark Jackson
Journal: Cancer Research (2017)

Abstract Increasing evidence suggests that tumor cell plasticity promotes metastasis and tumor recurrence, resulting in cancer patient mortality. While it is clear that the tumor microenvironment (TME) contributes to tumor cell plasticity, the specific TME factors that actively generate tumor cell plasticity are largely unknown. Here, we identify TME cytokines that promote epithelial-mesenchymal plasticity, and acquisition of cancer stem-cell (CSC) properties. A screen of 27 TME cytokines identified multiple Interleukin-6 family members as inducers of mesenchymal/CSC properties, with Oncostatin M (OSM) being the most potent. Importantly, OSM induced plasticity was mediated by STAT3, but also dependent on TGF-β signaling and downstream SMAD3. Inhibition of functional TGF-β/SMAD signaling by expressing a dominant-negative TGF-β receptor, treating with a TGF-β receptor inhibitor, or suppressing SMAD3 expression using a SMAD3-shRNA prevented the OSM-induced mesenchymal/CSC properties. OSM-activated STAT3 binds to SMAD3 and promotes SMAD3 nuclear localization and binding to the SNAIL promoter, increasing transcription of the SNAIL gene. The epithelial-mesenchymal transition induced by the STAT3/SMAD3 axis results in a highly invasive and metastatic phenotype and the emergence of CSC properties, including therapeutic resistance. Importantly, maintenance of the OSM-induced mesenchymal/CSC state requires sustained exposure to the cytokine, as removal of OSM results in a marked phenotypic reversion. A high-throughput screen for small molecule inhibitors of the OSM-induced mesenchymal/CSC phenotype has been performed and are currently being confirmed. We propose that, targeted blockade of the STAT3/SMAD3 axis in tumor cells may represent a novel therapeutic approach to prevent the plasticity associated with metastasis and tumor recurrence. Citation Format: Benjamin L. Bryson, Damian J. Junk, Jacob Smigiel, Neetha Parameswaran, Mary R. Doherty, Courtney A. Bartel, Mark Jackson. Oncostatin M elicits cellular plasticity through cooperative STAT3-SMAD3 signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2892. doi:10.1158/1538-7445.AM2017-2892
Foamy Virus Backbone Has Insulator Properties Which Remarkably Reduce Its Genotoxicity Potential
Authors: Michael Goodman, Paritha Arumugam, Devin Pillis, Danielle Lynn, Johannes C.M. Van der Loo, Mehdi Keddache, Thomas R. Bauer, Dennis D. Hickstein, David W Russell, Punam Malik
Journal: Blood (2016)
Abstract 5284: Gastric cancer in Alaska Native people: A cancer health disparity
Authors: Holly Martinson, Steven Alberts, Matthew Olnes
Journal: Cancer Research (2017)

Abstract Gastric cancer in the Alaska Native (AN) people occurs at a 3-fold higher incidence and 4-fold higher mortality rate compared to Non-Hispanic Whites (NHW), representing one of the largest cancer disparities in the AN population. We aimed to review the AN gastric cancer burden and identify clinicopathological factors that are associated with cancer outcomes. Patient information was collected from 132 AN gastric cancer patients diagnosed between 2006-2015 at the Alaska Native Medical Center. The Surveillance, Epidemiology and End Result database 18 was used to collect comparison United States NHW gastric cancer patient data. Compared to NHW patients, AN gastric cancer patients have a higher incidence rate, are significantly younger, 60 versus 69 years, and have a poorer 5-year overall survival rate of 10% compared to 22%. AN patients differ from NHW patients in gastric cancer anatomic location, subtype, and higher presence of signet ring cell carcinomas. Forty-one percent of AN patients were positive at the time of diagnosis for Helicobacter pylori, 77% had chronic gastritis, 30% had a family history of a first-degree relative with gastrointestinal cancers, and 82% were current or former tobacco users. Using univariate analysis, diminished overall survival was observed with anatomic site, increasing stage, no treatment, the number of lymph nodes examined during resection, blood type, and chronic gastritis. Multivariable analysis revealed stage and treatment type were independently associated with improved overall survival. AN gastric cancer cases vary in their clinical and epidemiologic features, relative to NHW. Citation Format: Holly Martinson, Steven Alberts, Matthew Olnes. Gastric cancer in Alaska Native people: A cancer health disparity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5284. doi:10.1158/1538-7445.AM2017-5284