bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A45: Investigating the role of ASCL1 in regulating differentiation of gliobastoma precursor cells
Authors: Park Nicole I. , Dirks Peter B. 
Published: August 2014

Abstract
Glioblastoma (GBM), the most common and lethal adult primary brain tumour, exhibits cellular heterogeneity and a subpopulation of tumour cells exhibits the neural precursor phenotype and drives tumourigenesis. These findings suggest that tumours may represent aberrant organogenesis with growth caused by unlimited proliferation and failure of differentiation of malignant precursor cells. It has yet to be determined the relative importance of aberrant self-renewal versus blocked differentiation in the brain tumour phenotype. As GBM-initiating cells have precursor cell properties, promotion of differentiation represents a potential strategy for treatment. Forcing glioblastoma precursor cells (GPCs) to differentiate terminally would limit clonal expansion and attenuate tumour growth. Data generated in our lab suggests that differentiation potential varies between different patient-derived GPC cultures. This study aims to determine what defines a blocked differentiation phenotype in human glioblastoma and to determine whether differentiation therapy is a feasible strategy for glioblastoma treatment.
A key regulator of neuronal differentiation is ASCL1 during normal development and adult neurogenesis. Microarray analysis of ASCL1 expression in GPCs (n = 33) revealed two subgroups of GPCs as having either high or low expression. Preliminary evidence suggests that GPCs with high expression of ASCL1 exhibit neuronal lineage commitment whereas GPCs with low expression of ASCL1 do not undergo lineage commitment. This was confirmed using immunocytochemistry, quantitative real-time PCR and Western blot analysis. Furthermore, an inverse correlation was observed between transcript levels of ASCL1 and DKK1, an antagonist of the Wnt signalling pathway, while a direct correlation was observed between ASCL1 and activated β-catenin (ABC). Treatment of GPCs with a GSK3β inhibitor resulted in the activation of Wnt signalling and concomitant increase in transcript levels of ASCL1 and neuronal lineage markers (i.e. TUJ1, MAP2).
This study aims to further investigate the role of ASCL1 in glioblastoma and to determine whether neuronal lineage commitment in the context of ASCL1 activity is mediated in a Wnt-dependent manner. Gain- and loss-of-function studies are in progress to determine whether ASCL1 is sufficient and/or necessary for neuronal lineage commitment and consequent effects on tumour-initiating properties (i.e. proliferation and self-renewal) will be examined in vitro and in vivo.
Citation Format: Nicole I. Park, Peter B. Dirks. Investigating the role of ASCL1 in regulating differentiation of gliobastoma precursor cells. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr A45.
Abstract A49: Repression of tumor survival pathways by novel, selective inhibitors of MNK1 and MNK2 kinases
Authors: Rzymski Tomasz , Dreas Agnieszka , Milik Mariusz , Kucwaj Katarzyna , Zarebski Adrian , Skuta Malgorzata Szajewska , Cierpich Anna , Fabritius Charles , Brzozka Krzysztof 
Published: August 2014

Abstract
MNK1 and MNK2 are MAP kinase-interacting kinases involved in regulation of translation. Both kinases phosphorylate translation initiation factor eIF4E on a conserved serine 209. eIF4E can contribute to the oncogenic transformation both in vitro and in vivo and is highly expressed in diverse types of cancer. Interestingly, mice that lack both MNK1 and MNK2 do not have any apparent phenotype and therefore represent interesting possibility to develop targeted and safe anticancer therapies.
Herewith, we report the development of first selective small molecule inhibitors of MNK1 and MNK2 kinases and their in vitro cellular activity. Selvita developed a series of small molecule type I, ATP-competitive inhibitors targeting both MNK1 and MNK2 with mid nM activity range. Selected compounds were tested on a panel of 456 kinases and showed very high selectivity. Additionally, in cellular models such as serum stimulated SW480 cells, synthesized MNK1/2 inhibitors caused dose dependent inhibition of phosphorylation of eIF4e at Ser209 in line with the kinase activity profile. The observed cellular activity on biomarker inhibition was more potent than observed for reported in the literature MNK1/2 inhibitors such as cercosporamide and CGP57380. High activity of MNK1/2 inhibitors on in vitro biomarkers correlated with efficacy on cancer cells challenged with various stress conditions, typical for tumor microenvironment. These initial findings confirm that selective inhibition of MNK1/2 may repress major tumor survival pathways induced under stress and support further development of this class of compounds as a novel anticancer therapy with a promising therapeutic window.
Citation Format: Tomasz Rzymski, Agnieszka Dreas, Mariusz Milik, Katarzyna Kucwaj, Adrian Zarebski, Malgorzata Szajewska Skuta, Anna Cierpich, Charles Fabritius, Krzysztof Brzozka. Repression of tumor survival pathways by novel, selective inhibitors of MNK1 and MNK2 kinases. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr A49.
Abstract B09: Liver-specific knockout of GRP94 in mice disrupts cell adhesion, activates liver progenitor cells, and accelerates liver tumorigenesis
Authors: Chen Wan-Ting , Tseng Chun-Chih , Pfaffenbach Kyle , Kanel Gary , Luo Biquan , Stiles Bangyan L. , Lee Amy S. 
Published: August 2014

Abstract
Liver cancer is one of the most common solid tumors with poor prognosis and high mortality. Mutation or deletion of the tumor suppressor PTEN is strongly correlated with human liver cancer. Glucose-regulated protein 94 (GRP94) is a major endoplasmic reticulum (ER) chaperone protein, but its in vivo function is still emerging. To study the role of GRP94 in maintaining liver homeostasis and tumor development, we created two liver-specific knockout mouse models with the deletion of Grp94 alone, or in combination with Pten, using the albumin-cre system. We demonstrated that while deletion of GRP94 in the liver led to hyperproliferation of liver progenitor cells, deletion of both GRP94 and PTEN accelerated development of liver tumors, including both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) suggestive of progenitor cell origin. Furthermore, at the premalignant stage, we observed disturbance of cell adhesion proteins but no detectable overt liver injury. We further discovered that when GRP94 was deleted in PTEN-null livers, ERK was selectively activated, suggesting that this could be a potential molecular mechanism for enhanced liver tumorigenesis in this mouse model. Conclusion: We identify GRP94 as a novel regulator of cell adhesion, liver homeostasis, and tumorigenesis.
Citation Format: Wan-Ting Chen, Chun-Chih Tseng, Kyle Pfaffenbach, Gary Kanel, Biquan Luo, Bangyan L. Stiles, Amy S. Lee. Liver-specific knockout of GRP94 in mice disrupts cell adhesion, activates liver progenitor cells, and accelerates liver tumorigenesis. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr B09.
Abstract B48: Breast tumor cell TACE-shed MCSF promotes pro-angiogenic macrophages through NF-κB signaling
Authors: Rego Stephen L. , Helms Rachel , Dreau Didier 
Published: August 2014

Abstract
Mortalities associated with breast cancer, the most common malignancy in women, are mainly due to metastases. Tumor associated macrophages (TAMs) significantly contribute to the development of metastasis through promotion of the rate limiting step of angiogenesis through secretion of vascular endothelial growth factor (VEGF). Macrophage differentiation and migration are activated by macrophage colony stimulating factor (MCSF) and chemokine (C-C motif) ligand 2 (CCL2), respectively. Whereas tumor cells secrete CCL2, MCSF release is mediated by ectodomain shedding through tumor necrosis factor alpha converting enzyme activation (TACE). How tumor cells support macrophage promotion of angiogenesis remains unclear. In the present study, we determined whether MCSF shed by TACE from tumor cells promotes angiogenesis through the activation of NF-κB signaling in macrophages and subsequent VEGF release. These studies were modeled in vitro using a panel of murine mammary cells mimicking breast cancer progression from normal murine mammary gland (NMuMG) cells to metastatic 4T1 cells along with J774 macrophages. TACE and MCSF expressions were higher in metastatic cells compared to epithelial cells (p&lt;0.05). After incubation with 4T1 tumor conditioned media (CM), macrophages secreted significantly more VEGF and expressed of the activated NF-κB, and the resulting macrophage secretions promoted significantly high levels of endothelial cell tubes (p&lt;0.05). Furthermore, a similar activation of macrophages was generated by the combination of CCL2, also highly expressed by tumor cells, and MCSF. These results highlight the key role of tumor cell TACE-shed MCSF and secreted CCL2 in synergistically stimulating pro-angiogenic macrophages.
Citation Format: Stephen L. Rego, Rachel Helms, Didier Dreau. Breast tumor cell TACE-shed MCSF promotes pro-angiogenic macrophages through NF-κB signaling. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr B48.
Abstract C03: A comprehensive study of genomic alterations reveals deregulation of the cell cycle in most esophageal squamous cell carcinomas
Authors: Bai Jian , Wang Qiyan , Gong Kenan , Cai Hong , Ke Yang , Zeng Changqing 
Published: August 2014

Abstract
Objective: Esophageal squamous cell carcinoma (ESCC) is a major cause of cancer related mortality. To determine the molecular basis of ESCC development, this investigation sought to comprehensively identify the characteristic genome-wide changes in ESCC, including exonic mutations and structural alterations. The clinical implications of these genetic changes are also analyzed.
Methods: Exome sequencing was applied to detect somatic mutations in nine pairs of ESCC and matched blood samples, followed by validation with MassARRAY genotyping and Sanger sequencing. Whole-genome SNP arrays were employed to study copy number changes and the loss of heterozygosity in 55 ESCCs.
Results: 108 non-synonymous mutations in 102 genes were identified and validated in nine patients, suggesting a low somatic mutation rate (average 12 per tumor) in our ESCC cases. The chromatin modification process was found to be enriched in gene ontology analysis. Mutated TP53 was seen in five of the nine tumors (55.6%) undergone exome sequencing and in 23/46 tumors in the validation set. Integrating with the SNP array data, we found that tumor genomes with TP53 mutations were much more unstable than those without these mutations. In the landscape of genomic alterations, deletion of 9p21.3 covering CDKN2A (30.9%), amplification of 11q13.3 covering CCND1 (30.9%), and point mutation of TP53 (50.9%) occurred in two-thirds of ESCCs, suggesting deregulation of G1 in cell cycle is the key event in ESCC. Furthermore, six minimal common regions were found to be significantly altered in ESCC and three (9p21.3, 7p11.2, 3p12.1) were associated with lymph node metastasis.
Conclusions: Frequent TP53 mutation and genomic instability are highly correlated in ESCC. The amplification of CCND1, deletion of CDKN2A/B, and somatic mutation of TP53 play pivotal roles via G1 deregulation and therefore classify this cancer into major groups. These findings provide clinical significance for future molecular diagnosis and therapeutic targeting.
Citation Format: Jian Bai, Qiyan Wang, Kenan Gong, Hong Cai, Yang Ke, Changqing Zeng. A comprehensive study of genomic alterations reveals deregulation of the cell cycle in most esophageal squamous cell carcinomas. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr C03.
Abstract C22: Differential Tks5 isoform expression contributes to metastatic invasion of lung adenocarcinoma
Authors: Li Carman Man-Chung , Chen Guoan , Dayton Talya , Kim-Kiselak Caroline , Beer David , Winslow Monte , Jacks Tyler 
Published: August 2014

Abstract
Metastasis accounts for the vast majority of cancer related deaths, yet the molecular mechanisms that drive metastatic spread remain poorly understood. Here we report that Tks5, which has been linked to formation of proteolytic cellular protrusions known as invadopodia, undergoes an isoform switch during metastatic progression in a genetically-engineered mouse model of lung adenocarcinoma. Non-metastatic primary tumor-derived cells predominantly expressed a short isoform Tks5short, while metastatic primary tumor- and metastasis-derived cells acquired increased expression of the full-length isoform Tks5long. This elevation of Tks5long-to-Tks5short ratio correlated with a commensurate increase in invadopodia activity in metastatic cells compared to non-metastatic cells. Further characterization of these isoforms by knockdown and over-expression experiments demonstrated that Tks5long promoted invadopodia in vitro and increased metastasis in transplant models and an autochthonous model of lung adenocarcinoma. Conversely, Tks5short decreased invadopodia stability and proteolysis, acting as a natural dominant-negative inhibitor to Tks5long. Importantly, high Tks5long and low Tks5short expressions in human lung adenocarcinomas correlated with metastatic disease and predicted worse survival of early-stage patients. These data indicate that tipping the Tks5 isoform balance to a high Tks5long-to-Tks5short ratio promotes invadopodia-mediated invasion and metastasis.
Citation Format: Carman Man-Chung Li, Guoan Chen, Talya Dayton, Caroline Kim-Kiselak, David Beer, Monte Winslow, Tyler Jacks. Differential Tks5 isoform expression contributes to metastatic invasion of lung adenocarcinoma. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr C22.
Abstract IA11: MicroRNAs in oncogenic and tumor suppressor signaling pathways
Authors: Mendell Joshua T. 
Published: August 2014

Abstract
MicroRNA (miRNA) gain- and loss-of-function can potently influence cellular behavior in normal physiologic states and in diseases such as cancer. The regulation of miRNA expression and activity by cellular signaling cascades can therefore result in dramatic phenotypic outputs. We previously demonstrated extensive control of miRNA expression by well-characterized oncogenic and tumor suppressor networks including the Myc, Kras, and p53 pathways. We are now employing novel mouse models with gain and loss of miRNA function to investigate the physiologic functions of the miRNAs embedded within these signaling pathways and the pathologic consequences when their functions are disrupted. Insights gained from these studies are revealing unanticipated roles for miRNAs in vivo and are informing our understanding of how dysregulated miRNA activity contributes to tumorigenesis. I will present our latest findings related to the regulation and function of mammalian miRNAs in normal physiology and in cancer and how these findings may be exploited for the development of novel therapeutic approaches.
Citation Format: Joshua T. Mendell. MicroRNAs in oncogenic and tumor suppressor signaling pathways. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr IA11.
Abstract IA2: Somatic alterations in human cancer genomes
Authors: Meyerson Matthew 
Published: August 2014

Abstract
The advent of high-throughput genome sequence analysis has enabled systematic discovery of somatic genome alterations through genome, exome, and transcriptome sequencing of paired human cancer and germline nucleic acids. These discoveries have led to the identification of somatic genome alterations in new pathways including epigenetic regulators, RNA splicing factors, and immune response regulators, in addition to previously known signal transduction, cell cycle, and transcriptional pathways. I will discuss alterations in these pathways by copy number disruption, mutation, and re-arrangement, especially as seen through the lens of recent and ongoing large-scale studies of lung adenocarcinoma and squamous cell lung carcinoma genomes, from The Cancer Genome Atlas and beyond'and will discuss the implications for the understanding of cancer pathogenesis and for the development of targeted and immunomodulatory therapies.
Citation Format: Matthew Meyerson. Somatic alterations in human cancer genomes. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr IA2.
Abstract IA27: Cell fate determinants as regulators of cancer metastasis
Authors: Kang Yibin 
Published: August 2014

Abstract
An emerging class of genes dictating malignant behavior is cell fate regulators. In the orderly development of a given tissue, the balance between cellular differentiation and division/migration is precisely controlled by a number of lineage specific transcription factors to maintain normal tissue architecture. Deregulation of such cell fate determinants have been increasingly linked to cancer metastasis, and have been shown to play critical roles in regulating cancer stem cell activity, epithelial-mesenchymal transition (EMT), tumor invasion and metastatic colonization.
In our study of the mammary gland development, we found that the transcription factor Elf5, a key regulator of alveologenesis in the mammary gland, also plays a critical role in regulating the stem/progenitor function of the mammary epithelium. Targeted deletion of Elf5 in the mammary glands leads to accumulation of cell types with dual luminal/basal properties such as coexpression of K8 and K14 and an increase in CD61(+) luminal progenitor population during pregnancy. Further interrogation suggests that the abnormal increase in K14(+) K8(+) cells may represent the CD61(+) luminal progenitors blocked in differentiation. Remarkably, Elf5 deficiency in mammary epithelium also triggers an increase of adult mammary stem activity as evidenced by the accumulation of mammary stem cell (MaSC)-enriched cell population in both pregnant and virgin mice and further confirmed by mammosphere and transplantation assays.
In addition to controlling cell fate determination, Elf5 also inhibits EMT in both mammary gland development and metastasis. This specific role for Elf5 in suppressing EMT and metastasis was uncovered via analyses of Elf5 conditional knockout animals, various in vitro and in vivo models of EMT and metastasis, an MMTV-neu transgenic model of mammary gland tumor progression, and clinical breast cancer samples. Furthermore, we demonstrate that this role of Elf5 is mediated by the direct transcriptional repression of Snail2/Slug, a master regulator of mammary stem cells and a known inducer of EMT. These findings establish a broad molecular function of Elf5 that extends from being a key cell lineage regulator during normal mammary gland development to serving as a suppressor of EMT and metastasis in breast cancer.
Citation Format: Yibin Kang. Cell fate determinants as regulators of cancer metastasis. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr IA27.
Abstract A10: Stromal CAIX expression in oral squamous cell carcinoma and corresponding lymph node metastases
Authors: Chandarana Shamir , Bose Pinaki , Klimowicz Alexander C. , Petrillo Stephanie K. , Konno Mie , Rudmik Luke , Nakoneshny Steven C. , Matthews Wayne T. , Magliocco Anthony M. , Dort Joseph C. , Brockton Nigel T. 
Published: August 2014

Abstract
Background: Hypoxia is an almost ubiquitous feature of human solid tumours. However, the direct measurement of oxygen concentration in head and neck squamous cell carcinoma (HNSCC) has been conducted almost exclusively in the metastatic lymph nodes, not the primary tumor. Hypoxia is associated with resistance to both radiotherapy (RT) and chemotherapy in squamous cell cancers (SCCs). However, endogenous markers of hypoxia (EMH) have not reproducibly predicted clinical outcome. However, historically, the method used to assign hypoxic status according to directly measured oxygen concentration (polarographic electrode) and EMH (typically immunohistochemistry) have fundamentally differed.
Methods: Demographic data and clinical outcomes of 61 patients with oral squamous cell carcinoma (OSCC) treated with primary surgery +/- adjuvant radiation were collected. Tissue microarray's with representative samples of patients' tumors were constructed from paraffin-embedded blocks. Automated quantitative immunohistochemistry (AQUA) was performed to measure expression and distribution of carbonic anhydrase IX (CAIX). Kaplan-Meier survival analysis and the log-rank test was used to assess the impact of vimentin-defined stromal CAIX (in both primary tumor and nodal metastases) on survival.
Results: High stromal CAIX expression in the primary tumor was associated with significantly worse 5-year disease-specific survival. There was a statistically significant but relatively weak correlation between stromal CAIX expression in the primary tumor and the corresponding lymph nodes (r2:0.359; p=0.013). Stromal CAIX expression in the lymph node metastases was not significantly associated with 5-year disease-specific survival.
Conclusions: Previous literature presenting the prognostic impact of directly measured hypoxia, using a polarographic electrode, was based predominantly on measurements from lymph nodes, not the primary tumor. Furthermore, comparisons with EMH were based solely on percentage of tumor cells that were positively stained, not the intensity of staining. We present the results of a tumor comparment-specific, quantitative fluorescent IHC method and the survival associated with EMH in the tumor microenvironment in the primary tumor and lymph node metastases.
Citation Format: Shamir Chandarana, Pinaki Bose, Alexander C. Klimowicz, Stephanie K. Petrillo, Mie Konno, Luke Rudmik, Steven C. Nakoneshny, Wayne T. Matthews, Anthony M. Magliocco, Joseph C. Dort, Nigel T. Brockton. Stromal CAIX expression in oral squamous cell carcinoma and corresponding lymph node metastases. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr A10.