bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B04: IKBKE integrates Gli and mTOR-AKT activation during Kras-induced pancreatic tumorigenesis
Authors: Rajurkar Mihir , Fernandez-Zapico Martin , Lewis Brian , Mao Junhao 
Published: May 2016

Abstract
Pancreatic Ductal Adenocarcinoma (PDAC) is one of the deadliest malignancies lacking effective therapeutic strategies. Here we show that the non-canonical IκB-related kinase, IKBKE, acts downstream of the Gli transcription factors and engages in reciprocal regulation of Gli signaling in pancreatic cancer cells. We find that loss of IKBKE inhibits the initiation and progression of pancreatic tumors in mice carrying pancreatic specific KRAS activation. Mechanistically, IKBKE does not play a major role in NF-κB activation in pancreatic cancer; but is critical for AKT activation in vivo. Moreover, we find that IKBKE promotes reactivation of AKT post-inhibition of mTOR in PDAC cells, and that combined inhibition of IKBKE and mTOR synergistically blocks pancreatic tumor growth. Together, our findings highlight the functional interaction of IKBKE with Hh/Gli and mTOR/AKT signaling in pancreatic cancer, and suggest IKBKE inhibition as a strategy to improve efficacy of mTOR inhibitors in the clinic.
Citation Format: Mihir Rajurkar, Martin Fernandez-Zapico, Brian Lewis, Junhao Mao. IKBKE integrates Gli and mTOR-AKT activation during Kras-induced pancreatic tumorigenesis. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr B04.
Abstract B21: DNp63 promotes stem cell activity in mammary gland development and basal-like breast cancer by enhancing Fzd7 expression and Wnt signaling
Authors: Chakrabarti Rumela , Sinha Satrajit , Kang Yibin 
Published: May 2016

Abstract
Emerging evidence suggests that cancer is populated and maintained by tumor initiating cells (TICs) with stem-like properties similar to that of adult tissue stem cells. Despite recent advances, the molecular regulatory mechanisms that may be shared between normal and malignant stem cells remain poorly understood. Here we show that the DNp63 isoform of the Trp63 transcription factor promotes normal mammary stem cell (MaSC) activity by increasing the expression of the Wnt receptor Fzd7 and thereby enhancing Wnt signaling. Importantly, Fzd7-dependent enhancement of Wnt signaling by DNp63 also governs tumor initiating activity of the basal subtype of breast cancer. These findings establish DNp63 as a key regulator of stem cells in both normal and malignant mammary tissues and provide direct evidence that breast cancer TICs and normal MaSCs share common regulatory mechanisms.
Citation Format: Rumela Chakrabarti, Satrajit Sinha, Yibin Kang. DNp63 promotes stem cell activity in mammary gland development and basal-like breast cancer by enhancing Fzd7 expression and Wnt signaling. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr B21.
Abstract IA08: Oxidative stress inhibits distant metastasis by human melanoma cells
Authors: Piskounova Elena , Agathocleous Michalis , DeBerardinis Ralph J. , Morrison Sean J. 
Published: May 2016

Abstract
Solid cancer cells commonly enter the blood and disseminate systemically but are highly inefficient at forming distant metastases for poorly understood reasons. We studied human melanomas that differed in their metastasis histories in patients and in their capacity to metastasize in NSG mice. All melanomas had high frequencies of cells that formed subcutaneous tumors, but much lower percentages of cells that formed tumors after intravenous or intrasplenic transplantation, particularly among inefficient metastasizers. Melanoma cells in the blood and visceral organs experienced oxidative stress not observed in established subcutaneous tumors. Successfully metastasizing melanomas underwent reversible metabolic changes during metastasis that increased their capacity to withstand oxidative stress, including increased dependence upon NADPH-generating enzymes in the folate pathway. Anti-oxidants promoted distant metastasis in NSG mice. Folate pathway inhibition using low-dose methotrexate, ALDH1L2 knockdown, or MTHFD1 knockdown inhibited distant metastasis without significantly affecting the growth of subcutaneous tumors in the same mice. Oxidative stress thus limits distant metastasis by melanoma cells in vivo.
Citation Format: Elena Piskounova, Michalis Agathocleous, Ralph J. DeBerardinis, Sean J. Morrison. Oxidative stress inhibits distant metastasis by human melanoma cells. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr IA08.
Abstract IA11: C. elegans GLP-1/Notch signaling: Direct targets and visualization in stem cells
Authors: Sorensen Erika B. , Lee ChangHwan Lee , Sorokin Elena , Groth Amy C. , Kimble Judith 
Published: May 2016

Abstract
My laboratory focuses on the in vivo regulation of stem cell self-renewal and differentiation in the germline tissue of the small nematode C. elegans. In this system, Notch signaling from a single-celled mesenchymal niche promotes maintenance of germline stem cells (GSCs)(1). My talk will focus on two broadly important questions. First, what key downstream effectors of Notch signaling are transcriptionally activated in stem cells to maintain their totipotent state? Second, how does Notch-dependent transcriptional activation maintain a pool of stem cells? We have known for some time that an RNA regulatory network acts downstream of Notch signaling to drives the choice between self-renewal and differentiation. We recently identified two Notch-dependent direct target genes, lst-1 and sygl-1, that fully account for the role of GLP-1/Notch signaling in GSC control (2). My talk will report recent efforts to understand lst-1 and sygl-1, to identify additional direct Notch targets in GSCs and to visualize Notch signaling within the stem cell pool.
References:
(1) Austin and Kimble (1987) Cell 51:589-599
(2) Kershner et al. (2014) PNAS,111(10):3739-3744.
Citation Format: Erika B. Sorensen, ChangHwan Lee Lee, Elena Sorokin, Amy C. Groth, Judith Kimble. C. elegans GLP-1/Notch signaling: Direct targets and visualization in stem cells. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr IA11.
Abstract IA21: YAP/TAZ biology in development and cancer: Hippo signaling and mechanotransduction
Authors: Piccolo Stefano 
Published: May 2016

Abstract
We study how cells sense their environment and use this information to build and maintain tissues with specific form, size and function, and how these systems are corrupted in diseases. At the centerpiece of these events is the activity of the transcriptional coactivators YAP and TAZ. Enhanced YAP/TAZ activity is emerging as a hallmark of multiple human tumors. I will discuss the cell and tissue-level mechanisms that lead to unrestrained YAP/TAZ activity, in turn essential for tumor formation and for tissue regeneration upon injury. I will also present new evidence on the function of YAP/TAZ in regulating the biology of normal somatic stem cell explanted from adult tissues.
Citation Format: Stefano Piccolo. YAP/TAZ biology in development and cancer: Hippo signaling and mechanotransduction. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr IA21.
Abstract IA22: Mechanisms of evasive resistance in cancer
Authors: Dazert Eva , Heim Markus , Beerenwinkel Niko , Hall Michael N. 
Published: May 2016

Abstract
Cancer is a major health problem due to the failure of current therapies to effectively eradicate the disease. Extensive research over decades has led to the development of therapies that target cancer-specific signaling pathways. However, tumors escape such therapies by activating compensatory signaling pathways, a process referred to as ‘evasive resistance’. The identities of the alternative signaling pathways and the functional interconnections that underlie evasive resistance remain widely unknown. Elucidating mechanisms of evasive resistance is currently a major challenge in cancer research. We integrate clinical, molecular, and computational sciences to understand the signaling defects that enable tumors to evade therapy. Within the framework of rigorously designed clinical studies, hepatocellular carcinoma (HCC) tissue is isolated before therapy, during treatment, or at the time of tumor progression. HCC was chosen as the focal cancer based on medical importance, accessibility to repeated sampling, and ethical considerations. The tumor tissue is obtained by needle biopsy and immediately snap frozen to preserve in vivo tumor properties. High- and low-throughput experimental and computational methods are then applied to determine, the underlying signaling defects. This endeavor will elucidate mechanisms of evasive resistance and will ultimately improve cancer diagnosis, treatment and clinical outcome. Recent progress in this ambitious project will be described.
Citation Format: Eva Dazert, Markus Heim, Niko Beerenwinkel, Michael N. Hall. Mechanisms of evasive resistance in cancer. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr IA22.
Abstract IA30: BAF complex structure and function in development and disease
Authors: Kadoch Cigall 
Published: May 2016

Abstract
Recent exon-wide sequencing studies in human cancer have revealed a striking frequency of mutations in the genes encoding subunits of the mSWI/SNF (BAF) ATP-dependent chromatin remodeling complexes we recently determined these mutations to be broadly recurrent in over 20% of all human cancers. To investigate the underlying mechanism, our group has studied rare, genomically well-defined cancer types, namely human synovial sarcoma (SS) in which 100% of tumors have a precise translocation involving a specific subunit, SS18, and BAF47-deficient malignant rhabdoid tumors. The utility of these disease settings has provided us with a powerful foundation upon which to understand the oncogenic mechanisms directed by altered structure and function of chromatin remodeling complexes. Here, we present studies focused on BAF complex pathway-of-assembly, complex subunit and associated protein factor composition of oncogenic BAF complexes, and mechanisms underlying BAF and polycomb opposition.
Citation Format: Cigall Kadoch. BAF complex structure and function in development and disease. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr IA30.
Abstract PR02: The SWI/SNF component Arid1a regulates regenerative capacity and carcinogenesis in a dose-dependent fashion
Authors: Sun Xuxu , Wang Sam , Maples Thomas , Li Lin , Nguyen Liem , Chuang Jen-Chieh , Sorouri Mahsa , Zhang Shuyuan , Wu Linwei , Celen Cemre , Zhu Hao 
Published: May 2016

Abstract
It is unclear if regenerative capacity can be dissociated from cancer risk, a question that is highly relevant for liver carcinogenesis. Frequent SWI/SNF and Arid1a loss-of-function mutations suggest tumor suppressive roles, but the functional impact of these mutations in tissue homeostasis and cancer is unclear. Mice without Arid1a possessed improved healing abilities after an array of injuries. After liver resection, chemical hepatocyte injury, and toxic bile duct injury, Arid1a deficient livers exhibited increased regeneration, reduced tissue damage, and improved organ function. Moreover, global homozygous Arid1a loss potentiated soft tissue healing after ear hole punch and hematopoietic recovery after irradiation. The chromatin state as reprogrammed by Arid1a loss restricted access to promoters by lineage-specific transcription factors that ordinarily suppress cell cycle reentry, thus increasing regeneration after injury. Intriguingly, the homozygous Arid1a deficient state protected mice from chemical injury induced hepatocellular carcinoma (HCC) and extended survival in a MYC-driven hepatoblastoma model. Since Arid1a mutations are most frequently heterozygous in human HCC genome studies, we examined the haploinsufficient state in these mouse models and observed accelerated carcinogenesis and metastasis. Transcriptome analysis identified dysregulated differentiation, proliferation, and metastasis programs. These models show that full deletion of Arid1a can enhance mammalian regeneration without increasing cancer risk, but that Arid1a’s tumor suppressor functions are highly sensitive to dose.
This abstract is also presented as Poster A16.
Citation Format: Xuxu Sun, Sam Wang, Thomas Maples, Lin Li, Liem Nguyen, Jen-Chieh Chuang, Mahsa Sorouri, Shuyuan Zhang, Linwei Wu, Cemre Celen, Hao Zhu. The SWI/SNF component Arid1a regulates regenerative capacity and carcinogenesis in a dose-dependent fashion. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr PR02.
Abstract A16: Restoration of gefitinib sensitivity and upregulation of BIM by simvastatin in T790M mutated non-small cell lung cancer cells
Authors: Young Mo Jin , Uk Lim Jeong , Young Lee Hwa , Kyoung Kim In , Haak Lee Sang 
Published: May 2016

Abstract
Objectives: Epidermal growth factor receptor (EGFR) gene mutation sensitize non-small cell lung cancer (NSCLC) cells to EGFR inhibitors. As the first line treatment on NSCLC, the tyrosine kinase inhibitors (TKIs) are effective, however T790M acquired resistant mutation reduces the therapeutic effect. Statins, 3-hydroxy-3-methyl-gluteryl-CoA (HMG-CoA) reductase inhibitors have pleotrophic effects to induce cell cycle arrest and death in certain type of cancer cells by inhibition of cholesterol synthesis and protein prenylation. The antitumor activities of statin in NSCLC cells inhibiting EGFR signaling proteins including PI3K/Akt and MAPK had been reported, but those in gefitinib resistant lung cancer cells harboring T790M mutation were not known. Recently, BH3-only polypeptide BIM (BCL2 like 11) was reported as one of the molecular mechanisms of T790M resistance in NSCLC cells. This study clarified the roles of simvastatin in the regulation of EGFR signaling and BH3-only protein BIM.
Methods: The cytotoxic effects of simvastatin on the gefitinib sensitive (HCC827, E716-A750del) and resistant (H1975, T790M + L858R) NSCLC cells were compared. Cell proliferation, intrinsic apoptosis and the expression of EGFR signaling proteins were evaluated. Expression of BIM was determined with western blot analysis and RT-PCR in H1975 cells after the time-dependent treatment of simvastatin or gefitinib.
Results: After the treatment of 2μM simvastatin for 24hrs and 48hrs, H1975 cells showed significantly decreased viability compared to HCC827 cells, (50% vs. 98% and 40% vs. 95%). Expression of Bax, cleaved caspase 3 and p-PARP proteins were increased in H1975 cells which showed the intrinsic apoptosis from simvastatin. Activity of EGFR signaling proteins, phosphorylation of EGFR, Akt and Erk were not affected with 2μM simvastatin for 12, 24 and 48 hours in H1975 cells. With gefitinib (1μM) treatment, BIM was suppressed in H1975 cells compared to HCC827 cells. Notably, BIM was induced after the exposure of simvastatin (2μM) for 12, 24 and 48 hours in H1975 cells.
Conclusions: T790M mutation, major mechanism of acquired resistance to EGFR-TKI, was associated with decreased BIM proteins. Simvastatin restored the expression of BIM to induce mitochondrial apoptosis in cells harboring T790M mutation and not in gefitinib sensitive mutation. Our study suggests the possibility of simvastatin to overcome gefitinib resistance with T790M mutation.
Citation Format: Mo Jin Young, Lim Jeong Uk, Lee Hwa Young, Kim In Kyoung, Lee Sang Haak. Restoration of gefitinib sensitivity and upregulation of BIM by simvastatin in T790M mutated non-small cell lung cancer cells. [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 A16.
Abstract A28: Bioenergetic analysis of primary human mammary epithelial cells (hMECs)
Authors: Henchey Elizabeth M. , Schneider Sallie S. , Jerry D. Joseph , Yadava Nagendra 
Published: May 2016

Abstract
We have demonstrated reversible suppression of the tumor suppressor protein p53 by respiratory chain deficiency. Further, a recent study from a different group also suggests genetic inactivation of p53 by the impairments of oxidative metabolism, and mutations in mtDNA and TP53 gene coexist in cancers. Therefore, we predict that variation in oxidative metabolism can result in differences in p53 response among individuals. Conditions that suppress oxidative metabolism can impair p53, and thereby promote cancer development. Toward testing this hypothesis, our approach is to quantify the variation in respiratory activity of normal human mammary epithelial cells (hMECs), and then determine the correlation between respiratory activity and p53 response. Thus, we have performed in situ respirometry using 24-well Seahorse Bioscience's Extracellular Flux (XF) Analyzer on hMECs (at passage 2) isolated from breast cancer patients (n=23). The hMECs were isolated from cancer affected (AB) and non-affected (NAB) breasts and differences in parameters affecting mitochondrial bioenergetics under normal and treated (IGF1, TNFα;) conditions were assessed. Our data show 6-9 fold variation in hMECs basal respiratory activity (n=23). Further, 48%, 30% and 22% of patients showed either no difference in mitochondrial respiratory capacity upon addition of pyruvate (-2±5%), or showed at least 10% increase (26±18%) or decrease (-15±3%), respectively. Treatments with selected cytokines such as IGF1 and TNFα; for 24 hours altered the mitochondrial bioenergetics of hMECs. Overall they reduced respiratory activity in cells; and altered response to pyruvate addition in some individuals. Interestingly, matched normal hMECs from affected (AB) and not affected (NAB) breasts showed differences in the respiratory activity even at passage 2 suggesting that local environments play a critical role in the bioenergetics of normal cells and these changes do not revert ex vivo immediately when cells are removed from their environment.
Acknowledgements: This work was supported by funds from Rays of Hope and Incubator grants from the Baystate Health Foundation, CEAR at the PVLSI supported by an award (A00000000004448) from Massachusetts Technology Collaborative as administrator of the John Adams Innovation Institute.
Citation Format: Elizabeth M. Henchey, Sallie S. Schneider, D. Joseph Jerry, Nagendra Yadava. Bioenergetic analysis of primary human mammary epithelial cells (hMECs). [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 A28.
Abstract A32: Structural and molecular mechanisms of human hexokinase 2 in cancer metabolism and apoptosis
Authors: Rabeh Wael 
Published: May 2016

Abstract
Cancer utilizes glucose at elevated levels to support its growth and proliferation, historically known as “ Warburg effect”. Targeting glucose metabolism in cancer cells to limit its growth will enhance patients' survival rate. Hexokinase catalyzes glucose phosphorylation, and is a major step in regulation of glycolysis. Four isozymes are present in human with Hexokinase 2 (HK2) being the most active and specifically expressed in verity of different cancers. In addition, gene expression profiling experiments of different types of cancer showed high expression levels of HK2, and various biological studies highlighted the importance of HK2 in tumor metastasis making it an ideal target to characterize cancer metabolism and for the development of new class of cancer therapeutics.
We solved the crystal structure of human HK2 in complex with glucose and glucose-6-phosphate (PDB code: 2NZT), where it is a homodimer with catalytically active N- and C-terminal domains linked by a seven-turn helix. Through biochemical and biophysical characterization of HK2, we found that the N-terminal domain not only catalyzes a reaction but it thermodynamically stabilities the entire enzyme, where deletion of the N-terminal helix altered the stability and catalytic activity of the full-length enzyme. Also, conformation of the N-terminal active site but not C-terminal is important in stabilizing the enzyme. Understanding the structural and molecular mechanisms of human HK2 in cancer metabolism and apoptosis will accelerate the design and development of new class of cancer therapeutics.
Citation Format: Wael Rabeh. Structural and molecular mechanisms of human hexokinase 2 in cancer metabolism and apoptosis. [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 A32.
Abstract A55: Novel nilotinib derivatives inhibit cell proliferation by targeting 5' AMP-activated protein kinase in hepatocellular carcinoma
Authors: Su Jung-Chen , Hsueh Ting-ting , Huang Jui-Wen , Shiau Chung-Wai 
Published: May 2016

Abstract
5' AMP-activated protein kinase constitutes a network for energy homeostasis, cellular metabolic and proliferation, thus providing a potential therapeutic target for metabolic diseases including diabetes and cancers. In response to the increasing cellular ratio of AMP /ADP to ATP, the binding of AMPK and AMP or ADP promote or maintain the activation of AMPK through the phosphorylation of threonine 172, leading to phosphorylate and activate downstream substrates for cellular processes. Our previous study has shown that nilotinib, a BCR-ABL kinase inhibitor for the treatment of chronic myeloid leukemia, induces AMPK activation in carcinoma cells. We further apply the scaffold of nilotinib to design and synthesize a series of new derivatives which show the higher potency in activating AMPK and inhibiting cell proliferation in hepatocellular carcinoma. These new agents pave a road for the development of hepatocellular carcinoma and other metabolic diseases.
Citation Format: Jung-Chen Su, Ting-ting Hsueh, Jui-Wen Huang, Chung-Wai Shiau. Novel nilotinib derivatives inhibit cell proliferation by targeting 5' AMP-activated protein kinase in hepatocellular carcinoma. [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 A55.