bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B31: Disruption of Folliculin interacting protein-1 modulates Myc-driven metabolism, increasing cell death following metabolic stress
Authors: Ramirez Julita A. , Tsang Mark , Park Heon , Margineantu Daciana , Gu Haiwei , Raftery Daniel , Hockenbery David M. , Iritani Brian M. 
Published: May 2016

Abstract
Folliculin interacting protein-1 (Fnip1) is a cytoplasmic protein originally discovered through its interaction with Folliculin (Flcn), a tumor suppressor mutated in the rare fibrofolliculoma disorder Birt-Hogg Dubé syndrome. Fnip1 and Flcn both interact with the master metabolic regulator AMP kinase (AMPK). Our previous studies have shown that Fnip1 is required for the development of B-cells past the late pre-B stage (Park et al Immunity 2012) and for the development invariant natural killer T (iNKT) cells in the thymus (Park et al PNAS 2014). Fnip1 deficiency also prevented the development of B cell lymphoma in Eµ-Myc transgenic mice. Fnip1 deficient immune cells exhibited hyperactivation of mTORC1 concurrent with increased activation of AMPK. In this study, we examined the potential efficacy of Fnip1 disruption in cancer by disrupting Fnip1 in primary mouse and human B cell lines overexpressing the Myc oncogene. We show that constitutive depletion of Fnip1 in primary pre-B cells, conditional knockdown of Fnip1 in primary mouse mature B cells using the Cre-loxP system, or siRNA-mediated depletion of endogenous FNIP1 from a human B cell line expressing a conditional Myc allele, increase oxidative phosphorylation and Myc-induced glycolysis, which support cell division. Disruption of Fnip1 increases death of primary murine pre-B Eµ-Myc cells and human B cell lines in response to nutrient deprivation and chemotherapeutic drugs in vitro. Mass spectrometric analysis of a human B cell line depleted of Fnip1 reveals significant alterations in metabolites involved in glutaminolysis, glycolysis, antioxidant and serine biosynthesis pathways. These results suggest that inhibition of Fnip1 may provide a novel strategy to increase death of lymphoma cells in response to cytotoxic and metabolic stress.
Citation Format: Julita A. Ramirez, Mark Tsang, Heon Park, Daciana Margineantu, Haiwei Gu, Daniel Raftery, David M. Hockenbery, Brian M. Iritani. Disruption of Folliculin interacting protein-1 modulates Myc-driven metabolism, increasing cell death following metabolic stress. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr B31.
Abstract B33: Assessing the role of DGAT activity on lipid homeostasis and cancer cell survival
Authors: Ackerman Daniel , Qiu Bo , Xie Hong , Kamphorst Jurre , Simon M. Celeste 
Published: May 2016

Abstract
Studies on the effects of modulating the lipid composition of cells have found that increases in saturated fatty acid levels can lead to ER stress, activation of the unfolded protein response (UPR) and cell death. These effects may occur through saturation of the phospholipid pool and subsequent deterioration of ER membrane function. Changes in the composition of the ER membrane can be sensed by the two UPR stress sensors IRE1 and PERK and lead to activation of UPR targets.
Rapidly proliferating cancer cells frequently exhibit elevated ER stress due to their increased protein translation rate. In addition, the tumor microenvironment is frequently hypoxic and a lack of oxygen can inhibit the activity of the fatty acid desaturase SCD1. This leads to saturation of the fatty acid pool and renders the ER less able to cope with high levels of protein synthesis, making the maintenance of adequate lipid homeostasis of paramount importance to cancer cells within hypoxic tumor domains. Tumor cells adapt to these conditions through a variety of mechanisms, including the uptake of exogenous unsaturated lipid. Both hypoxia and the presence of certain oncogenic drivers have been found to increase lipid uptake, which was found to protect cancer cells against inhibition of SCD1.
Since fatty acids can be converted to triglycerides and stored within lipid droplets, we asked whether cancer cells also cope with saturation of their fatty acid pool by storing excess saturated fatty acids as triglycerides. Clear cell renal cell carcinoma (ccRCC) tumors are very fatty and lipidomic analyses have found high levels of triglycerides in ccRCC compared to normal kidney tissue. We inhibited triglyceride synthesis in A498 ccRCC cells by shRNA –mediated knockdown of DGAT enzymes, which catalyze the final step in the synthesis of triglycerides from fatty acids. We tested whether loss of DGAT activity causes sensitivity to tumor-like stresses and investigated its effect on xenograft tumor growth. Remarkably, while loss of DGAT activity has little effect on cancer cell proliferation under oxygen- and nutrient-rich conditions, loss of DGAT activity has large effects on xenograft tumor growth. We also find that loss of DGAT activity is often accompanied by increases in markers of ER stress. We are currently assessing the lipid composition of these tumors and determining what aspects of the tumor microenvironment sensitize cells to loss of DGAT activity.
Citation Format: Daniel Ackerman, Bo Qiu, Hong Xie, Jurre Kamphorst, M. Celeste Simon. Assessing the role of DGAT activity on lipid homeostasis and cancer cell survival. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr B33.
Abstract B43: The utilization of extracellular proteins as nutrients is suppressed by mTORC1
Authors: Palm Wilhelm , Park Youngkyu , Wright Kevin , Pavlova Natalya N. , Tuveson David A. , Thompson Craig B. 
Published: May 2016

Abstract
To engage in growth and proliferation, cells require a continuous supply of precursors for macromolecular synthesis. Despite being surrounded by diverse nutrients, mammalian cells preferentially metabolize glucose and free amino acids. However, it was recently shown that Ras-induced macropinocytosis of extracellular proteins could reduce a transformed cell's dependence on extracellular amino acids. Here, we show that macropinocytosis and lysosomal catabolism of extracellular proteins can serve as a source of essential amino acids. Lysosomal degradation of internalized proteins can sustain cell survival and induce lysosomal recruitment and activation of mammalian target of rapamycin complex 1 (mTORC1), but fails to elicit significant cell accumulation. Surprisingly, we discovered that unlike its growth-promoting activity under amino acid-replete conditions, mTORC1 activation suppresses proliferation when cells rely on extracellular proteins as an amino acid source. Inhibiting mTORC1 results in increased catabolism of endocytosed proteins and enhances cell proliferation during nutrient-depleted conditions in vitro and within vascularly compromised tumors in vivo. Thus, by preventing consumption of extracellular proteins as nutrients, mTORC1 couples growth to availability of free amino acids. These results may have important implications for the use of mTOR inhibitors as therapeutics.
Citation Format: Wilhelm Palm, Youngkyu Park, Kevin Wright, Natalya N. Pavlova, David A. Tuveson, Craig B. Thompson. The utilization of extracellular proteins as nutrients is suppressed by mTORC1. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr B43.
Abstract IA16: Mapping metabolic drivers of cancer using chemoproteomic and metabolomic platforms
Authors: Nomura Daniel 
Published: May 2016

Abstract
Cancer cells possess fundamentally altered cellular metabolism that not only leads to a re-wiring of cellular biochemistry, but also drives nearly every aspect of cancer cell pathogenicity. While targeting dysregulated metabolism is a promising strategy for cancer treatment, much of cancer metabolism has focused on well-understood metabolic pathways in central carbon metabolism (e.g. glycolytic or glutamine metabolism) underlying cellular transformation and early-stages of cancer, and has largely ignored many of cellular metabolic pathways or those networks involved in cancer progression, despite clear genetic or metabolic evidence of their involvement in cancer. Here, we describe chemoproteomic and metabolomic technologies that we have utilized to identifying unique and novel dysregulated metabolic drivers of cancer. In particular, we have identified several unique nodes within lipid and sialic acid metabolism that are essential in driving cancer pathogenicity.
Citation Format: Daniel Nomura. Mapping metabolic drivers of cancer using chemoproteomic and metabolomic platforms. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr IA16.
Abstract IA23: Use of viruses to study cancer metabolism
Authors: Christofk Heather R. 
Published: May 2016

Abstract
Viruses are powerful tools to study cancer metabolism. They trigger major metabolic changes in host cells to meet the bioenergetic and biosynthetic demands of virus infection - changes similar to the enhanced glycolysis and anabolic metabolism widely observed in cancer cells. However, unlike cancer cells, viruses undergo intense selection for efficiency, and rapidly and robustly reprogram host cell metabolism through activation of specific key flux-altering nodes, rather than whole metabolic pathway gene sets. We recently reported that adenovirus infection increases host cell anabolic glucose metabolism via MYC activation of specific metabolic target genes, only a subset of those turned on by MYC in many cancers. We are now investigating how adenovirus-induced MYC activation leads to selective transcription of target genes. Additionally, we have generated a list of the specific metabolic genes altered by adenovirus infection and are examining their role in anabolic metabolism, virus replication, and cancer proliferation. Because viruses are so efficient at reprogramming host cell metabolism towards increased anabolism, they represent a powerful tool to identify the most important metabolic enzymes for anabolic metabolism, and potentially the most promising cancer metabolism drug targets.
Citation Format: Heather R. Christofk. Use of viruses to study cancer metabolism. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr IA23.
Abstract A44: Clinical value of immunohistochemical expression of EGFL7 within high-grade serous ovarian cancer tissue.
Authors: Sznurkowski Jacek Jan , Zawrocki Anton , Pawlowski Maciej 
Published: May 2016

Abstract
Epidermal growth factor like domain 7 (Egfl7) is expressed by endothelial cells in normal tissues and by malignant cells in various human tumors.
Aim: to analyze patterns of immunohistochemical (IHC) staining of Egfl7 within high grade serous ovarian cancer (HGSOC) tissue and to assess clinical value of this biomarker.
Material and methods:
The IHC staining and pathological analyses were performed on paraffin-embedded primary tumours collected from 73 HGSOC patients with verified clinical history. Mouse anti-human monoclonal antibody against Egfl7, was used.
Egfl7 expressing tumors were classified qualitatively in accordance to intense of staining (HSCORE). The appropriate statistical analyses were performed. P-values of &lt;0.05 were regarded as significant.
Results: Egfl7 was expressed by the cancer cells within 63 of 73 primary HGSOC tumors (68.3%). Endothelial expression of this biomarker was sporadic. Cancer cells presented two patterns of staining: cytoplasmic only in 50/72 cases (69.4%) and nuclear/cytoplasmic in 13/72 cases (18%). Median duration of the follow-up was 47.25 months (range 17–79 months)
Cytoplasmic expression of Egfl7 was not correlated with any of clinico-pathological features as well as with prognosis.
The presence of nuclear/cytoplasmic staining within HGSOC predicts worse response for chemotherapy and correlates with increased preoperative levels of CA125.
Conclusion: Cancer endogenous expression of Egfl7 is frequent within HGSOC tissue.
Predictive value of nuclear/cytoplasmic staining of Egfl7 for chemoresistance should be further evaluated.
Citation Format: Jacek Jan Sznurkowski, Anton Zawrocki, Maciej Pawlowski. Clinical value of immunohistochemical expression of EGFL7 within high-grade serous ovarian cancer tissue. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr A44.
Abstract A56: Inhibition of Snail-induced EMT promotes anti-tumor immune response in ovarian cancer.
Authors: Taki Mana , Abiko Kaoru , Matsumura Noriomi , Baba Tsukasa , Hamanishi Junzo , Horikawa Naoki , Konishi Ikuo 
Published: May 2016

Abstract
Background: Peritoneal dissemination is a common mode of tumor progression in ovarian cancer, and one of the most important unfavorable prognostic factors. Epithelial-mesenchymal transition (EMT) has been indicated to be a key process in tumor invasion and metastasis. Recent studies demonstrate that EMT suppresses anti-tumor immunity in some types of cancer. The aim of the current study is to elucidate the relationship between EMT-related gene Snail and local immunity in ovarian cancer.
Methods: The expression of Snail and patient survival was analyzed in two microarray datasets, TCGA, and KOV75 (75 ovarian cancer cases operated in our department).
Using mouse ovarian cancer cell line HM-1, the influence of Snail expression on EMT, peritoneal dissemination, survival, and local immunity was analyzed using both in vitro and in vivo models. Snail-silenced cell line, HM1-sh-snail was established, and compared with the control HM-1.
Results: Among 4 subtypes of high grade serous ovarian cancer, Mesenchymal subtype, which show marked stromal reaction in histopathology, shows the worst prognosis (TCGA, KOV75). Snail expression was significantly high in Mesenchymal subtype (TCGA, p&lt;0.0001; KOV75, p&lt;0.05). High Snail expression was significantly related to short overall survival in TCGA (p&lt;0.05).
In HM1-sh-snail, expression of vimentin and fibronectin was decreased in RT-PCR analysis. Cell migration was inhibited in wound-healing assay (p&lt;0.001), but the cell proliferation was not altered in WST assay. In mouse peritoneal dissemination model, HM1-sh-snail group demonstrated longer survival than the control group (p&lt;0.05). In mouse subcutaneous tumor model, HM-1-sh-snail group revealed smaller tumor than the control group (p&lt;0.05), although there was no difference between two groups in nude mouse model.
Flow cytometric analysis of mouse tumors revealed that infiltration of CD4+ T cells and CD8+ T cells were all increased and MDSCs were decreased in HM1-sh-snail group.
Conclusion: Snail-induced EMT inhibits local immune reaction and promotes peritoneal dissemination in ovarian cancer. Snail may be a potential therapeutic target in ovarian cancer.
Citation Format: Mana Taki, Kaoru Abiko, Noriomi Matsumura, Tsukasa Baba, Junzo Hamanishi, Naoki Horikawa, Ikuo Konishi. Inhibition of Snail-induced EMT promotes anti-tumor immune response in ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr A56.
Abstract B01: Mutagenic and tumorigenic effects of follicular fluid in the context of p53 loss: Initiation of fimbria carcinogenesis.
Authors: Chu Tang-Yuan , Huang Hsuan-Shun , Hsu Che-Fang 
Published: May 2016

Abstract
Ovulation is the strongest risk factor for ovarian high-grade serous carcinoma (HGSC) that largely originates from the fallopian tube fimbriae and always carries loss-of-function mutations of TP53 in both early and late lesions. Mature ovarian follicle contains high level of reactive oxygen species (ROS). When released from ovulation, follicular fluid (FF) bathes the fimbriae and may lead to DNA double strand break (DSB) and neoplastic transformation. In this study, we examined the mutagenic and tumorigenic activities of human pre-ovulatory FFs. A subset (6/11) of FFs was found with high levels of ROS whereas the antioxidant capacities were indifferent. These ROS-high FFs induced intracellular ROS and DSBs in the secretory cell population of fimbriae epithelium. In the context of p53 and Rb deficiency in an E6/E7 immortalized fimbria secretory cell line, FF-exposed secretory cells overcame apoptosis and maintained the population carrying ROS and DSB. The cancer initiation effects of FF were further recapitulated in Trp53-/- mice. When introduced into the mammary fat pad, ROS-high but not ROS-low FFs induced early-onset B-cell lymphoma. Cotreatment with physiological concentration of melatonin, a potent antioxidant, ameliorated the mutagenic and tumorigenic effect of ROS-high FF in vitro and in vivo. The study revealed ROS and mitogens in mature ovarian follicles could initiate the transformation of fimbria epithelium in the context of p53 loss and melatonin is a potent preventive agent.
Citation Format: Tang-Yuan Chu, Hsuan-Shun Huang, Che-Fang Hsu. Mutagenic and tumorigenic effects of follicular fluid in the context of p53 loss: Initiation of fimbria carcinogenesis. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr B01.
Abstract B49: Giant cancer stem cells of high-grade ovarian serous carcinoma .
Authors: Liu Jinsong 
Published: May 2016

Abstract
Polyploid giant cancer cells (PGCCs) have been observed by pathologists for over a century. PGCCs or nuclear atypia are an important diagnosis feature for high grade serous carcinoma and frequently present in post-chemotherapy patients and contribute to tumor heterogeneity, but their functions are largely undefined. Little attention has been given to these cells, largely because PGCCs have been generally thought to originate from repeated mitosis/cytokinesis failure and have no capacity for long-term survival and cell proliferation. Here we report that we successfully purified and cultured PGCCs from human ovarian cancer cell lines and primary ovarian cancer. These cells are highly resistant to oxygen deprivation and could form through endoreduplication or cell fusion, generating regular-sized cancer cells through budding or burst. They are positive for normal and cancer stem cell markers, divided asymmetrically and cycled slowly. They can differentiate into adipose, cartilage, bone, and erythroid cells. A single PGCC formed cancer spheroids in vitro and generated tumors in immunodeficient mice. PGCC-derived tumor gained a mesenchymal phenotype with increased expression of cancer stem cell markers CD44 and CD133 and become more resistant to the treatment of cisplatin. Together, our results reveal that the PGCCs present a resistant form of human cancer cells like mother cancer stem cells that can contribute to generation of daughter cancer stem-like cells. The PGCCs may play a fundamental role in regulating tumor heterogeneity, stemness, and chemoresistance in human cancer. In contrast to the phenotype unstable cancer stem cells selected by cell surface markers, PGCCs can be stably passaged and maintained, thus these cells provide reproducible experimental system to study mechanisms involved in generation of ovarian cancer stem cells.
Citation Format: Jinsong Liu. Giant cancer stem cells of high-grade ovarian serous carcinoma . [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr B49.
Abstract B64: Suboptimal cytoreduction in ovarian carcinoma is associated with molecular pathways characteristic of increased stromal activation.
Authors: Liu Zhenqiu , Beach Jessica A. , Agadjanian Hasmik , Jia Dongyu , Aspuria Paul-Joseph , Karlan Beth Y. , Orsulic Sandra 
Published: May 2016

Abstract
Suboptimal cytoreductive surgery in advanced epithelial ovarian cancer (EOC) is associated with poor survival but it is unknown if poor outcome is due to the intrinsic biology of unresectable tumors or insufficient surgical effort resulting in residual tumor-sustaining clones. Our objective was to identify the potential molecular pathway(s) and cell type(s) that may be responsible for suboptimal surgical resection. By comparing gene expression in optimally and suboptimally cytoreduced patients, we identified a gene network associated with suboptimal cytoreduction and explored the biological processes and cell types associated with this gene network. We show that primary tumors from suboptimally cytoreduced patients express molecular signatures that are typically present in a distinct molecular subtype of EOC characterized by increased stromal activation and lymphovascular invasion. Similar molecular pathways are present in EOC metastases, suggesting that primary tumors in suboptimally cytoreduced patients are biologically similar to metastatic tumors. We demonstrate that the suboptimal cytoreduction network genes are enriched in reactive tumor stroma cells rather than malignant tumor cells. Our data suggest that the success of cytoreductive surgery is dictated by tumor biology, such as extensive stromal reaction and increased invasiveness, which may hinder surgical resection and ultimately lead to poor survival.
Citation Format: Zhenqiu Liu, Jessica A. Beach, Hasmik Agadjanian, Dongyu Jia, Paul-Joseph Aspuria, Beth Y. Karlan, Sandra Orsulic. Suboptimal cytoreduction in ovarian carcinoma is associated with molecular pathways characteristic of increased stromal activation. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr B64.