tbuckley/cabot-search huggingface dataset:
Abstract 2814: Effect of kif14 overexpression on tumor formation in mice in a lifespan study
Authors: Natalie Pitt, Kamakshi Sishtla, Mehdi Shadmand, Rania Sulaiman, Anthony L. Sinn, Keith Condon, George E. Sandusky, Timothy W. Corson
Journal: Cancer Research (2017)

Abstract KIF14 is a mitotic kinesin and microtubule-associated molecular motor that plays an essential role in the last stages of cytokinesis. In multiple cancer types, KIF14, overexpression in tumors correlates with stage, aggressiveness, and poor patient outcomes. There is considerable interest in KIF14 as a possible oncogene, since the KIF14 locus is in a common region of genomic gain in multiple cancers. In this study, wild type BDF-1 mice and a strain constitutively overexpressing Kif14, known as Kif14-Tg mice, were evaluated at the end of their natural lifespan, specifically for the occurrence of tumors. There were approximately fifty mice per genotype, and eighty of these mice have died. These mice were necropsied and the following tissues were collected: kidney, liver, lung, spleen, seminal vesicles, ovary, mammary gland, bone marrow, pituitary gland, eye, and brain. Any gross nodules were also collected. These tissues were then fixed in 10% neutral buffered formalin, processed, sectioned, and stained with hematoxylin and eosin. Although there was no significant difference in mouse weights through the lifespan or in the survival curve between the Kif14-Tg and their wild type littermates, a significant increase in follicular lymphoma and diffuse large B cell lymphoma was seen in Kif14-Tg mice compared to the wild type mice. Thirty-three mice developed either a follicular lymphoma or a diffuse large B cell lymphoma, and twenty-four of those mice were Kif14-Tg mice. These were the two most common tumors in Kif14-Tg mice. Other lesions and tumors that were seen in both strains included thymic lymphoma, sarcomas, myeloid dysplasia, and other carcinomas. Nontumorous lesions were seen in both strains of mice including hydronephrosis and telangiectasia in multiple organs. Ballooning degeneration of the lens of the eyes was observed in five mice from the strain Kif14-Tg. Our finding of increased follicular lymphoma and diffuse large B cell lymphoma proves the first evidence that Kif14 can promote tumor formation in a wild-type background. This is the first evidence that Kif14 may have a role in lymphoma, but complements our earlier finding that Kif14 overexpression can accelerate tumor formation in a mouse model of retinoblastoma. Together, these outcomes further support Kif14’s potential as an oncogene. Citation Format: Natalie Pitt, Kamakshi Sishtla, Mehdi Shadmand, Rania Sulaiman, Anthony L. Sinn, Keith Condon, George E. Sandusky, Timothy W. Corson. Effect of kif14 overexpression on tumor formation in mice in a lifespan study [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 2814. doi:10.1158/1538-7445.AM2017-2814
Abstract 4845: Induction of aldolase C expression by NME1 may mediate metastasis suppressor activity in malignant melanoma
Authors: Nidhi Pamidimukkala, Katie Leonard, Joseph McCorkle, Qingbei Zhang, Anup Mahurkar, Amol Shetty, David Kaetzel
Journal: Cancer Research (2017)

Abstract Although the metastasis suppressor activity of NME1 has been demonstrated in a number of settings of human cancer, the underlying molecular mechanisms are not well understood. NME1 has two known enzymatic activities, nucleoside diphosphate kinase (NDPK) and a 3’ to 5’ exonuclease. To determine the relative contribution either of these activities has on the metastasis suppressor function of NME1, our lab previously generated site directed mutants to abrogate one or both of the enzymatic activities (Ma et al., 2004). These studies showed that disrupting the 3’ to 5’ exonuclease activity with the point substitutions glutamate5-to-alanine (E5A) and lysine12-to-glutamine (K12Q) also significantly compromised the metastasis suppressor function of NME1 (Zhang et al., 2011). To identify genes that are regulated by NME1 and potentially modulate its metastasis suppressor activity, we compared the gene expression profile induced by forced expression of wild-type NME to those obtained with the E5A and K12Q mutants. Using the human Exon 1.0 Affymetrix microarray , we identified 13 genes whose expression was modulated by wild-type NME1 expression, but not by the suppressor-deficient mutants, which were designated as metastasis suppressor signature (MSS) genes. We are currently refining the list to genes that have the highest clinical relevance through observing expression profiles of the MSS genes in clinical datasets. Preliminary results of unsupervised hierarchal clustering of GEO melanoma dataset GSE8401 showed that expression of the MSS gene, aldolase C (ALDOC), was significantly lower in a subset of metastatic melanoma lesions compared to primary melanomas. Western blot and qPCR analysis confirm that NME1 induces expression of ALDOC in both WM793 and M14 melanoma cell lines, and that induction of ALDOC is dose-responsive to NME1 expression as observed in the WM1158 metastatic melanoma cell line. Further, NME1 induction of ALDOC is specific compared to the ALDOA and ALDOB isoforms. Recent studies have indicated aldolase isoforms can modulate motile and invasive phenotypes of cancer cells (Li et al., 2015 &amp; Hu et al., 2016), suggesting regulation of ALDOC expression may represent a key mechanism underlying the metastasis suppressor function of NME1. Current work is focused on measuring the impact of NME1-induced expression of ALDOC on the metastatic potential of melanoma cells in culture and in vivo. Citation Format: Nidhi Pamidimukkala, Katie Leonard, Joseph McCorkle, Qingbei Zhang, Anup Mahurkar, Amol Shetty, David Kaetzel. Induction of aldolase C expression by NME1 may mediate metastasis suppressor activity in malignant melanoma [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 4845. doi:10.1158/1538-7445.AM2017-4845
Abstract 5762: PR55-alpha associated PP2A promotes pancreatic tumorigenesis
Authors: Ying Yan, Ashley L. Hein, Parthasarathy Seshacharyulu, Satyanarayana Rachagani, Yuri M. Sheinin, Michel M. Ouellette, Moorthy P. Ponnusamy, Surinder K. Batra
Journal: Cancer Research (2017)

Abstract PP2A holoenzyme consists of a catalytic subunit, a scaffold subunit, and a regulatory subunit. Loss of function analysis using PP2A catalytic inhibitors or inhibition via tumor viral proteins suggest PP2A as a putative tumor suppressor. However, PP2A has also been shown to facilitate the activation of oncogenic signaling pathways when associated with specific regulatory subunits. In this study, we investigated the possible oncogenic role of PP2A in pancreatic cancer. We found a striking increase in the expression of PR55α, a PP2A regulatory subunit, in pancreatic cancer cells compared to normal pancreatic epithelial cells. Consistently, PR55α expression was markedly elevated in pancreatic ductal adenocarcinoma tissues compared to adjacent normal pancreatic tissues (P&amp;lt;0.0001) and correlated with poor survival of pancreatic cancer patients (P&amp;lt;0.0003). RNAi-mediated depletion of PR55α in pancreatic cancer cells resulted in diminished phosphorylation of both AKT and ERK1/2 and decreased protein levels of β-catenin. Accordingly, pancreatic cancer cells with reduced PR55α expression exhibited significantly impaired properties of transformation, including attenuated cell growth, clonogenicity, mobility, and anchorage-independent growth. Moreover, orthotopic implantation of PR55α-depleted pancreatic cancer cells into nude mice showed a marked reduction in tumorigenicity (P&amp;lt;0.001) and distant metastases. These results suggest that PR55α promotes pancreatic cancer development by sustaining hyperactivity of multiple oncogenic signaling pathways, including AKT, ERK and Wnt. Citation Format: Ying Yan, Ashley L. Hein, Parthasarathy Seshacharyulu, Satyanarayana Rachagani, Yuri M. Sheinin, Michel M. Ouellette, Moorthy P. Ponnusamy, Surinder K. Batra. PR55-alpha associated PP2A promotes pancreatic tumorigenesis [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 5762. doi:10.1158/1538-7445.AM2017-5762
Abstract 4934: Brain metastatic microenvironment reshapes cancer cell metabolism through epigenetic up-regulation of glutamate decarboxylase 1
Authors: Patricia M. Schnepp, Dennis D. Lee, Ian H. Guldner, Treasa O'Tighearnaigh, Bhavana Palakurthi, Kaitlyn E. Eckert, Tiffany A. Toni, Brandon L. Ashfeld, Siyuan Zhang
Journal: Cancer Research (2017)

Abstract Cancer metabolism has been well documented to influence primary tumor development. Yet, the role of deregulated metabolism in metastasis progression is not well understood. Based on a distinct metabolic transcriptome profile in brain metastases compared to their primary tumor counterparts, we hypothesized that metabolic transcriptome shifting during metastatic evolution is crucial for metastatic success to the brain. Here we show that, despite a global down-regulation of multiple metabolic pathways in the brain metastatic tumors, the expression of the GABA metabolic pathway mediator glutamate decarboxylase 1 (GAD1) is significantly up-regulated. Using cell based co-culture models for different primary and brain metastatic microenvironments and in vivo brain metastasis models, we demonstrate that down-regulation of DNA methyltransferase 1 (DNMT1) induced by the brain microenvironment results in decreased GAD1 promoter methylation and subsequent up-regulation of GAD1 expression in tumor cells. To dynamically visualize the cellular metabolic responses mediated by GAD1, we utilized the Peredox biosensor to monitor the cytosolic NADH:NAD+ equilibrium in tumor cells using time-lapse imaging. By knocking down of GAD1 induced by primary glia cell co-culture, we abolished the capability of tumor cells to utilize extracellular glutamine, leading to an NADH accumulation in the cytosol and a more oxidative cellular status. Lastly, either loss of GAD1 genetically or targeting GABA metabolic pathway by the repurposing of a neurological drug, vigabatrin, results in a significant decrease in brain metastasis incidence. Taken together, our results demonstrated that brain microenvironment-specific metabolic shifting through GAD1 promoter de-methylation drives brain metastasis outgrowth. Citation Format: Patricia M. Schnepp, Dennis D. Lee, Ian H. Guldner, Treasa O'Tighearnaigh, Bhavana Palakurthi, Kaitlyn E. Eckert, Tiffany A. Toni, Brandon L. Ashfeld, Siyuan Zhang. Brain metastatic microenvironment reshapes cancer cell metabolism through epigenetic up-regulation of glutamate decarboxylase 1 [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 4934. doi:10.1158/1538-7445.AM2017-4934
Abstract 3991: Profiling the immune tumor microenvironment in primary and recurrent epithelial ovarian cancer
Authors: Laureen S. Ojalvo, Elizabeth D. Thompson, Tian-Li Wang, Alan K. Meeker, Ie-Ming Shih, Amanda N. Fader, Ashley Cimino-Mathews, Leisha A. Emens
Journal: Cancer Research (2017)

Abstract Clinical trials targeting the immune tumor microenvironment (TME) in epithelial ovarian cancer (EOC) typically have included patients with heavily pre-treated advanced disease and demonstrated only marginal efficacy. A better understanding of how the EOC TME evolves with progression from primary to recurrent disease may inform future immunotherapy trials. Here, we evaluate the immune TME in primary and recurrent EOC using tissue microarrays. Our cohort included matched primary and recurrent tumors from 17 patients, and additional non-matched primary tumors from 20 patients and recurrent tumors from 15 patients. We stained for CD8, FOXP3 (regulatory T cells (Tregs)), CD68 (tumor associated macrophages (TAMs)), programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) by immunohistochemistry to interrogate the immune composition of the TME. Tregs increased in recurrent tumors compared to primary tumors (8.0 vs 14.2/HPF, p=0.0210). Higher TAM density was associated with higher levels of Treg and CD8+ T cell infiltrates in recurrent tumors (p=0.001 and p&amp;lt;0.001, respectively), and with higher Treg but not CD8+ T cell infiltrates in primary tumors (p=0.027 and p=0.200). TAM-dense recurrent tumors had increased PD-L1 on tumor cells and immune cells, whereas TAM-dense primary tumors had increased PD-L1 only on immune cells. Increased Tregs in primary tumors correlated with decreased time to first recurrence (17.0 vs 28.5 months, p=0.022). Conversely, increased Tregs in recurrent tumors correlated with longer overall survival (OS) from recurrence (median not met vs 20.0m, p=0.022). Although TAM density did not affect patient survival, analysis of matched primary and recurrent tumors revealed that patients with increased TAMs at recurrence (n=5) had a longer median OS from recurrence than patients without increased TAMs at recurrence (n=12). Tregs increased at recurrence in the majority of matched tumor pairs (n=12), but there was no correlation with survival. In conclusion, the TME of EOC is immunologically active. TAM-dense recurrent disease had higher CD8+ T cell and Treg infiltrates and PD-L1 expression. In this study, patients with increased cellular recruitment to the TME at recurrence had improved survival. Larger, more detailed studies characterizing the evolution of the TME with progression from primary EOC to recurrence are warranted. Citation Format: Laureen S. Ojalvo, Elizabeth D. Thompson, Tian-Li Wang, Alan K. Meeker, Ie-Ming Shih, Amanda N. Fader, Ashley Cimino-Mathews, Leisha A. Emens. Profiling the immune tumor microenvironment in primary and recurrent epithelial ovarian 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 3991. doi:10.1158/1538-7445.AM2017-3991
Holding Onto Youth
Authors: Alain Dagher, Bratislav Misic
Journal: Cell Metabolism (2017)

Aerobic glycolysis (AG), the synthesis of lactate despite the presence of oxygen, has been implicated in the growth of cancer cells, synaptic development, and brain plasticity. In this issue of Cell Metabolism, Goyal et al. (2017) demonstrate that AG declines with age in the human brain, disappearing almost completely by age 60.
Abstract 4394: Whole-genome, virome, and immuno-genome of liver cancer indicate its genomic feature associated with virus infection and inflammation
Authors: Hidewaki Nakagawa
Journal: Cancer Research (2017)

Abstract Liver cancer is prevalent worldwide, mainly associated with virus infection and chronic inflammation, but its underlying molecular mechanism is quite heterogeneous. We performed virome and immuno-genomic analyses, in addition to whole-genome landscape of somatic alterations and transcriptome in 300 liver cancers. Our whole-genome analysis elucidated point mutations in non-coding regions, structural variations, and virus integrations (HBV and AAV), in addition to coding mutations. We discovered novel recurrently mutated coding and non-coding regions, such as NEAT1/MALAT1 lincRNAs, promoters, CTCF-binding sites, and novel regulatory regions, and known cancer genes (CDKN2A, APC, TERT) and novel cancer genes (ASH1L, NCOR1, MACROD2) that were recurrently affected by SVs. For virome analysis, we performed ultra-deep sequencing after capturing HBV sequences from DNAs of 100 liver cancers or adjacent HBV-infected liver tissues, which demonstrated genome-wide HBV-integrations (1794 sites) in liver cancers and infected liver tissues and eliminated pathological mechanism of viral integration. We also generated immuno-genomic profiles of these liver cancers, including HLA genotypes and mutations, neo-antigen presentation, immune signatures, and TCR repertories, which suggested some distinct immunological features and underlying molecular pathways of liver cancer associated with inflammation. These trans-omics data demonstrated comprehensive and distinct immuno-genomic feature of virus-related liver cancer, as well as its distinct whole-genome profiles, and can help to understand the molecular and microenvironment pathways underlying carcinogenesis and treatment response of liver cancer. Citation Format: Hidewaki Nakagawa. Whole-genome, virome, and immuno-genome of liver cancer indicate its genomic feature associated with virus infection and inflammation [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 4394. doi:10.1158/1538-7445.AM2017-4394
Abstract 1474: Epigenetic silencing of microRNA-137 enhances ASCT2 expression and tumor glutamine metabolism
Authors: Xiao Daibiao, Junli Dong, Zihan Zhao, Ping Ren, Cong Li, Yufeng Hu, Jianguo Shi, Hexiu Su, Zhaojing Wang, Hudan Liu, Bo Li, Peng Gao, Guoliang Qing
Journal: Cancer Research (2017)

Abstract Cancer cells amplify the expression of ASC amino acid transporter 2 (ASCT2, also called SLC1A5), a high-affinity glutamine carrier protein, to coordinate metabolic reprogramming and malignant transformation. Yet genetic and/or epigenetic mechanisms underlying the control of ASCT2-mediated glutamine metabolism remain to be clarified. Combined in-silico algorithms with systemic experimental screening, we herein identify the tumor suppressor miR-137 as an essential regulator that targets ASCT2 mRNA and cancer cell glutamine metabolism. Metabolic analysis shows that miR-137 derepression, similar to ASCT2 inactivation, significantly inhibits glutamine consumption and TCA cycle anaplerosis. Mechanistically, methyl-CpG binding protein 2 (MeCP2) and DNA methyltransferases (DNMTs) cooperate to promote active methylation of the miR-137 promoter and its decreased transcription, which conversely enhances ASCT2 expression and glutamine metabolism. As such, expression between miR-137 and ASCT2 is inversely correlated in multiple human cancer types, including colorectal carcinomas, glioblastomas, prostate and pancreatic cancers. These findings thus elucidate a universal mechanism responsible for ASCT2 deregulation in human cancers, revealing a molecular link between miR-137, ASCT2 and tumor metabolism. Citation Format: Xiao Daibiao, Junli Dong, Zihan Zhao, Ping Ren, Cong Li, Yufeng Hu, Jianguo Shi, Hexiu Su, Zhaojing Wang, Hudan Liu, Bo Li, Peng Gao, Guoliang Qing. Epigenetic silencing of microRNA-137 enhances ASCT2 expression and tumor glutamine metabolism [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 1474. doi:10.1158/1538-7445.AM2017-1474
Abstract 4142: Regulation of tumor suppressor decorin by APE1 in head and neck squamous cell carcinoma
Authors: Christina A. Wicker, Timothy L. Scott, Rangaswamy Suganya, Susan M. Arnold, Yolanda M. Brill, Craig M. Horbinski, Dana Napier, Joseph Valentino, Mahesh R. Kudrimoti, Guoqiang Yu, Tadahide Izumi
Journal: Cancer Research (2017)

Abstract Oral cancers have a high rate of recurrence, and a tendency to develop treatment resistance. From 2009 to 2013, Kentucky had a disproportionately higher incidence of invasive oral cancers and resultant higher mortality compared to the national average (SEER &amp; NPCR, Kentucky Cancer Registry). Apurinic/Apyrimidinic endonuclease (APE1) is a key protein in DNA repair, and an important transcriptional regulator. Gene array analysis in pMEFs expressing wild-type APE1 and extremely low levels of APE1 showed an eight-fold reduction of tumor suppressor decorin (DCN), with wild-type APE1. Decorin is a known tumor suppressor and extracellular matrix protein, which can suppress tumor proliferation, migration and angiogenesis. Tumors with decreased decorin are associated with increased mortality. These studies aim to elucidate APE1’s role in decorin regulation in oral cancer and identify biomarkers, which may aid in diagnosis, treatment, or predicting prognosis. Immunohistochemistry studies of head and neck squamous cell carcinoma from Kentuckians were analyzed aided by Aperio’s high resolution scanning capabilities, and software. Analysis showed a significant decrease in decorin in both tumor and carcinoma in situ compared to benign tissue. Whereas, APE1 was significantly increased in tumors. Additionally there was a significant negative correlation between APE1 and decorin total protein in carcinoma in situ. This data supports that increased APE1 may deplete decorin. Superoxide Dismutase 3, which is important in detoxifying extracellular ROS, was also significantly decreased in tumor and in carcinoma in situ. This along with previous research showing increased ROS in the tumor microenvironment and APE1 activation by ROS may explain the origination of decorin suppression. We hypothesize that the overexpression of APE1 in early stages of oral cancer leads to diminished decorin translation, which may drive cancer progression and increase mortality. Better understanding how APE1 influences tumor suppressors may eventually aid in development of therapeutics that would increase patient survival. Citation Format: Christina A. Wicker, Timothy L. Scott, Rangaswamy Suganya, Susan M. Arnold, Yolanda M. Brill, Craig M. Horbinski, Dana Napier, Joseph Valentino, Mahesh R. Kudrimoti, Guoqiang Yu, Tadahide Izumi. Regulation of tumor suppressor decorin by APE1 in head and neck squamous cell carcinoma [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 4142. doi:10.1158/1538-7445.AM2017-4142