bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-252: Single-cell mRNA profiling reveal transcriptional heterogeneity among pancreatic circulating tumor cells
Authors: Lapin Morten , Tjensvoll Kjersti , Oltedal Satu , Javle Milind , Smaaland Rune , Gilje Bjørnar , Nordgård Oddmund 
Published: July 2017

Abstract
Background: Single-cell analysis of the transcriptional heterogeneity of circulating tumor cells have the prospect of better understanding the biology of these cells and their involvement in the metastatic process. In addition, such analyses may reveal new knowledge about the mechanisms leading to chemotherapy resistance and tumor progression in pancreatic cancer patients.
Methods: Single circulating tumor cells were enriched from blood samples (n = 50) from patients with advanced pancreatic cancer using our previously established negative depletion strategy MINDEC, and detected by immuno-fluorescence microscopy. The single cells were isolated by micromanipulation, reverse transcribed, pre-amplified, and analyzed using single cell multiplex mRNA profiling to reveal transcriptional heterogeneity.
Results: Circulating tumor cells were detected in 29 (58%) of the examined blood samples. A total of 48 potential circulating tumor cells were isolated, in which 17 cells had detectable mRNA levels and were identified as circulating tumor cells by expression of
epithelial (KRT8, KRT19, EPCAM, E-Cadherin) or mesenchymal (Vimentin, N-Cadherin, ZEB1) markers. These pancreatic circulating tumor cells were revealed to heterogeneously express the examined transcripts, and also showed aberrant expression of cancer stem cell (CD24, CD44, ALDH1A1) markers and the extracellular matrix marker SPARC. Hierarchical clustering and principal component analyses revealed epithelial-like and mesenchymal-like circulating tumor cell subpopulations, which were distinct from white blood cells and cancer cell line cells. Further analyses of the transcript SPARC suggested a relation to epithelial-mesenchymal transition in pancreatic circulating tumor cells.
Conclusion: The analysis of single pancreatic circulating tumor cells defines distinct subpopulations and reveals aberrant expression of transcripts relevant for the dissemination of circulating tumor cells to distant sites.
Citation Format: Morten Lapin, Kjersti Tjensvoll, Satu Oltedal, Milind Javle, Rune Smaaland, Bjørnar Gilje, Oddmund Nordgård. Single-cell mRNA profiling reveal transcriptional heterogeneity among pancreatic circulating tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-252. doi:10.1158/1538-7445.AM2017-LB-252
Abstract LB-254: Thymidylate synthase gene polymorphisms is negatively associated with gastric cancer survival
Authors: Chen Jinfei , Wang Maggie Haitian , Zee Benny Chung-Ying 
Published: July 2017

Abstract
Background: Gastric cancer (GC) is a major public health problem in China and its carcinogenesis has not been fully understood. It was found that genetic variation played an important role in the etiology. Thymidylate synthase (TYMS) is a critical target for cancer chemo-therapy, which functions in DNA replication, synthesis and repair. However, the results of the relationship between TYMS and cancer is unclear. To find the genomic susceptibility in TYMS, bio-markers are necessary for preventing and understanding the etiology of gastric cancer.
Objectives: The research explores the relationship between TYMS and survival time of 876 Chinese gastric cancer patients.
Methods: A retrospective cohort of 876 surgically resected gastric cancer patients with clinicopathologic and follow up information were collected. The genotypes of SNPs were examined by SNaPshot method. The median survival time (MST) for each categorical variable and survival curve were estimated by Kaplan-Meier method. The overall survival was analyzed by univariate and multivariate Cox proportional hazard model.
Results: TYMS was significantly associated with survival time. The study found eight samples (1.0%) with the novel allele (4R). In univariate analysis, the group of including 4R allele had lowest survival condition (P value = 0.006). The hazard ratio of individual with 4R allele was 2.48 (95% CI: 1.10-5.58) after controlling age, gender, smoking, drinking and TNM stage.
Conclusion: Our study found a novel allele (4R) in TYMS in gastric cancer patients.
Key words: Gastric cancer; TYMS; overall survival
Citation Format: Jinfei Chen, Maggie Haitian Wang, Benny Chung-Ying Zee. Thymidylate synthase gene polymorphisms is negatively associated with gastric cancer survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-254. doi:10.1158/1538-7445.AM2017-LB-254
Abstract LB-258: Orphan nuclear hormone receptor, DAX-1, expression during progressive stages of invasive ductal carcimona
Authors: Dishington Erin 
Published: July 2017

Abstract
The orphan nuclear hormone receptor DAX-1 (Dosage Sensitive Sex Reversal Adrenal Hypoplasia Congenita on the X Chromosome, gene 1) plays an important role in the development of adrenal and gonadal tissues and functions as a global negative-regulator of steroidogenesis. In addition, it is known to play a role in several cancers including breast. DAX-1 immunoreactivity had been found to directly correlate with androgen receptor (AR), estrogen receptor (ER) expression and lymph node metastasis. Beyond this, DAX-1’s role in breast cancer is relatively poorly understood. In this study we investigated, using fluorescent immunohistochemistry, the expression of DAX-1 and AR during progressive stages of invasive ductal carcinoma with known estrogen receptor ER status. Additionally correlations with patient age, tumor grade, TNM score, progesterone receptor (PR), antigen Ki67 expression and human epidermal growth factor receptor 2 (Her2), were analysed. Comparing both bioinformatic and protein staining methodology we attempted to correlate DAX-1, AR and ER to cancer stage. In order to understand the mechanisms involved in cancer progression we employed epigenetic studies to determine if changes in DAX-1 expression correlated to changes in methylation status. Our data suggests DAX-1 is expressed more frequently in early stage breast cancer. Understanding the time points and mechanisms by which DAX-1 acts in breast cancer could potentially provide a novel target for therapeutic treatments.
Citation Format: Erin Dishington. Orphan nuclear hormone receptor, DAX-1, expression during progressive stages of invasive ductal carcimona [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-258. doi:10.1158/1538-7445.AM2017-LB-258
Abstract LB-263: P53 promotes replication genome stability by epigenetics-enabled MRE11 restart
Authors: Schlacher Katharina , Roy Sunetra , Tomaszowski Karl-Heinz 
Published: July 2017

Abstract
DNA damage activates p53, the most frequently mutated tumor suppressor, to guard the genome and control gene transcription, epigenetics and apoptosis. Yet, how p53 suppresses genome instability remains ill-defined and is clouded by its genome-wide alterations. Here, enabled by our kPOND technology for single-cell nascent DNA/protein interactions and single-molecule DNA spreading, we define p53’s role in promoting genomic stability by enabling replication restart of stalled replication forks. Mechanistically, p53 enables MRE11 nuclease recruitment for stalled replication fork restart via control of epigenetic factor. We find an apoptosis-proficient and tumor promoting p53 mutant allele to be replication restart defective, while an apoptosis defective and poorly tumor-promoting murine p53 allele remains mostly restart proficient, revealing an improved correlation of restart functions with tumorigenesis compared to apoptosis functions. Importantly, both null and p53 gain-of-function (GOF) mutant cells show restart defects resulting in replication dependent genomic instability, uncovering a common function defect aside gene transcription. Both mutant and p53 null cells show increased recruitment of error-prone repair factors and DNA polymerases, providing a mechanism for genomic instability observed in these cells by pathway homeostasis imbalance. Collective results unveil a common transcription-independent pathway defect for both p53 null and GOF mutants laying groundwork for new targeting strategies of p53 defects in cancer.
Note: This abstract was not presented at the meeting.
Citation Format: Katharina Schlacher, Sunetra Roy, Karl-Heinz Tomaszowski. P53 promotes replication genome stability by epigenetics-enabled MRE11 restart [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-263. doi:10.1158/1538-7445.AM2017-LB-263
Abstract LB-264: Preclinical evaluation of DNA-PK as a therapeutic target in prostate cancer
Authors: Dylgjeri Emanuela , Goodwin Jonathan F. , McNair Christopher M. , Shafi Ayesha A. , Kothari Vishal , Feng Felix , Rathkop Dana , Knudsen Karen 
Published: July 2017

Abstract
Prostatic adenocarcinoma (PCa) is dependent on androgen receptor (AR) signaling at all stages of disease, as AR activation induces both cell proliferation and survival. Though organ–confined disease can be treated, the response is transient. Reactivation of AR leads to castration resistant prostate cancer (CRPC), which remains fatal. Previously published studies demonstrate that AR activation promotes tumor cell survival and proliferation through a feed-forward loop involving the DNA repair factor DNA-dependent protein kinase (DNA-PK). Recent data from our lab has highlighted the role of DNA-PK in DNA damage repair as well as transcriptional regulation of pro-metastatic signaling. Strikingly, DNA-PK is the most deregulated kinase in metastatic CRPC. DNAPK is highly elevated and hyperactivated, and is an independent predictor of metastasis and overall survival in patients with high-risk disease. Concordantly, DNAPK suppression attenuated DNA-PK functions in NHEJ and transcriptional regulation. DNA-PK inhibition is sufficient to prevent proliferation in vitro and ex vivo, as well as tumor metastasis in vivo. Combined these findings highlight importance of DNA-PK functions as a transcriptional regulator and a mediator of NHEJ DNA repair and nominate it as a therapeutic target in PCa.
Data presented here will interrogate the translational capacity of a specific DNA-PK inhibitor, a dual DNA-PK/TOR kinase inhibitor and a specific TOR kinase inhibitor in CRPC models. Currently, CC-115, a dual kinase inhibitor, is the only DNA-PK inhibitor in Phase1/2 trial in combination with Enzalutamide in PCa. Unbiased transcriptomic analyses were performed and will be used to identify mechanisms of action that lead to suppression of PCa growth in vitro and ex vivo. These findings will provide insight in the effectiveness of DNA-PK inhibitors as a single agent or combinatorial treatments and provide rational for its placement in the correct clinical space.
Citation Format: Emanuela Dylgjeri, Jonathan F. Goodwin, Christopher M. McNair, Ayesha A. Shafi, Vishal Kothari, Felix Feng, Dana Rathkop, Karen Knudsen. Preclinical evaluation of DNA-PK as a therapeutic target in prostate 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 LB-264. doi:10.1158/1538-7445.AM2017-LB-264
Abstract LB-267: Metabolic alterations in tumors cause cachexia in pancreatic cancer
Authors: Dasgupta Aneesha , Shukla Surendra K. , Gunda Venugopal , Chaika Nina V. , Singh Pankaj K. 
Published: July 2017

Abstract
Cancer-associated cachexia is a complex metabolic syndrome which leads to excessive loss of skeletal muscle and adipose deposits. Up to 80% of pancreatic cancer patients suffer from cachexia and nearly one third die due to complexities related to the syndrome. Treatment of cachexia will not only improve the standard of living of pancreatic cancer patients but would also improve the patient survival. In the clinic, the majority of cancer patients are diagnosed at the refractory phase of cachexia, which cannot be reversed by dietary interventions. Till late, cachexia has mainly been attributed to systemic inflammation caused by cytokines released from the host and the tumor. But anti-inflammatory therapies have not shown promising results in clinical trials. Hence, there is an urgent need to identify new targets to combat cancer cachexia. It has been previously shown that there are constant metabolic interactions between the host body and the tumor. Increase in tumor burden and its demand for nutrition forces the host body to reprogram its metabolism leading to the breakdown of host body proteins into amino acids, which gets taken up and converted into carbohydrates by the tumor. To study the role of metabolic pathways in tumor cells on cachectic factor secretion, we pre-treated pancreatic cancer cells with metabolic inhibitors 3-Bromopyruvic acid and bis-2-(5-phenylacetomido-1, 2, 4-thiadiazol-2-yl) ethyl sulfide (BPTES). The conditioned media from control and treated cells were then evaluated for myotube degeneration potential in C2C12-dfferentitaed myotubes by measuring myotube thickness, protein content and expression of muscle specific ubiquitin ligases. We observed that that pre-treated conditioned-media had reduced myotubes degenerating potential as compared to controls. Furthermore, we inhibition of glycolytic flux in tumor cells by treatment with ketone bodies also diminished myotubes degenerating potential. Tumor-bearing mice had decreased tumor growth and cachexia when fed on a ketogenic diet. In conclusion, metabolic reprograming of tumor cells plays an important role in inducing pancreatic cancer-induced cachexia and delineating the metabolic pathways is crucial to elucidate important therapeutic targets for cancer cachexia.
Citation Format: Aneesha Dasgupta, Surendra K. Shukla, Venugopal Gunda, Nina V. Chaika, Pankaj K. Singh. Metabolic alterations in tumors cause cachexia in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-267. doi:10.1158/1538-7445.AM2017-LB-267
Abstract LB-270: Hexokinase II (HK2) regulates stemness of ovarian cancer cells
Authors: JIANG Yuxin , Siu Michelle KY , Wang Jingjing , Leung Thomas HY , Cheung Annie NY , Ngan Hextan YS , Chan Karen KL 
Published: July 2017

Abstract
Cancer stem cells (CSCs) constitute a small proportion of tumor cells and can drive tumor growth, metastasis and recurrence. Identification of CSCs in ovarian cancer has been reported. However, the mechanisms regulating ovarian cancer CSCs remain unknown. High lactate production and low glucose oxidation, despite oxygen availability, termed as the Warburg effect, are commonly found in cancers. Hexokinase 2 (HK2) converts glucose to glucose-6-phosphate, the first committed step in the Warburg effect. HK2 regulates tumorigenesis in different cancers. Yet, roles of HK2 and its underline mechanisms in ovarian cancer remain to be explored. In this study, we investigate the clinical significance, effects and mechanisms of HK2 on cell metastasis and CSCs regulation in ovarian cancer. HK2 was found to be up-regulated in ovarian cancer patients by immunohistochemistry when compared with benign ovarian cystadenomas. Significantly higher HK2 immunoreactivity was detected in metastatic foci than their corresponding primary tumors and associated with shorter disease-free survival. Decreased lactate production, impaired cell migration and invasion were detected in HK2 knockdown A2780CP cells using lactate assay, Transwell migration and invasion assays, respectively. Oppositely, ectopic expression of HK2 increased lactate production, cell migration and invasion in SKOV3 cells. We also found ectopic expression of HK2 in SKOV3 cells promoted anchorage-independent growth by soft agar assay. Then we further investigated the effect of HK2 on CSC load of ovarian cancer. Stable knockdown of HK2 in OVCAR3 cells led to impaired capacity to grow as multi-cellular spheroids in stem-condition culture system by sphere formation. Knockdown of HK2 in OVCAR3 cells down-regulated CD117 as measured by flow cytometry, which was accompanied by decreased mRNA/protein expression of Nanog, Bmi-1 and Klf-4, genes related to ovarian CSCs. Inversely, ectopic expression of HK2 in SKOV-3 cells promoted spheroids growth and increased CD117 proportion, which was accompanied by increased Nanog, Bmi-1 and Klf-4 mRNA/protein expression. Our data suggested that HK2 was associated with ovarian cancer progression, metastasis and stemness. HK2 could be a novel prognostic marker and potential therapeutic molecular target in ovarian cancer.
Citation Format: Yuxin JIANG, Michelle KY Siu, Jingjing Wang, Thomas HY Leung, Annie NY Cheung, Hextan YS Ngan, Karen KL Chan. Hexokinase II (HK2) regulates stemness of ovarian cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-270. doi:10.1158/1538-7445.AM2017-LB-270
Abstract LB-273: Comprehensive sequencing analyses of uterine and ovarian carcinosarcoma
Authors: Mori Seiichi , Gotoh Osamu , Sugiyama Yuko , Kato Kazuyoshi , Noda Tetsuo 
Published: July 2017

Abstract
Carcinosarcoma (CS) of the uterus or the ovary, known as malignant mixed Muellerian tumor, is a biphasic neoplasm composed of malignant epithelial (carcinoma) and mesenchymal (sarcoma) elements. CS is a rare disease (two per 100,000 women) and exhibits poor prognosis (5-year survival rates: uterus and ovary; 31 and 7.5 %, respectively). Treatment regimen for CS follows to that for endometrioid adenocarcinoma (EC) since CS has been considered as an aggressive form of high-grade EC. However, CS has a significantly worse prognosis than EC. Identification of a molecular target and/or a molecular mechanism in tumorigenesis from a large cohort study may improve unfavorable outcomes. Toward this aim, we perform targeted resequencing analysis with a panel of 596 genes, which were previously implicated as critical not only for uterine, ovarian or sarcomatus oncogenesis but also for molecular targets in therapeutics. Through analyses of 109 cases of uterine and ovarian CS, consensus clustering with deregulated pattern of CS genome identified four genomic subtypes that correlate with genetic or epigenetic alterations, histopathology and patient outcomes. Moreover, potentially actionable alterations were found in a substantial number of genes (including PIK3CA, MTOR, KRAS and CCNE1). This study would provide deep insights into the development of novel diagnostic and personalized treatment for CS patients.
Citation Format: Seiichi Mori, Osamu Gotoh, Yuko Sugiyama, Kazuyoshi Kato, Tetsuo Noda. Comprehensive sequencing analyses of uterine and ovarian carcinosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-273. doi:10.1158/1538-7445.AM2017-LB-273
Abstract LB-289: Computational detection of oncogene-centric pathway members
Authors: Broyde Joshua , Simpson David , Murray Diana , Lachmann Alexander , Giorgi Federico M. , Honig Barry , Sweet-Cordero Alejandro E. , Califano Andrea 
Published: July 2017

Abstract
Elucidation of the full complement of members of oncogenic signaling pathways is critical for understanding dysregulated function in cancers. Our knowledge of experimentally verified human gene-regulatory networks and protein-protein interactions remains incomplete, thus limiting their use for predicting novel members of these critical pathways. We present a method that uses a machine learning approach to predict novel members of these aberrantly activated or inactivated pathways. We integrate predictions of protein-protein interactions, gene regulatory networks, post-translational modifications and co-segregation of mutational status and protein activity. This approach produces novel predictions for these pathways. For the Kras and EGFR pathway, these predictions are highly enriched for genes known to by synthetic lethal for these two pathways. Knockdown of top candidates derived from this approach decreased growth in a Kras-activated context, indicating their importance in Kras regulated pathways.
Citation Format: Joshua Broyde, David Simpson, Diana Murray, Alexander Lachmann, Federico M. Giorgi, Barry Honig, Alejandro E. Sweet-Cordero, Andrea Califano. Computational detection of oncogene-centric pathway members [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-289. doi:10.1158/1538-7445.AM2017-LB-289
Abstract LB-291: Identification of CMTM6 and CMTM4 as PD-L1 protein regulators
Authors: Sun Chong , Mezzadra Riccardo , Jae Lucas T. , Gomez-Eerland Raquel , Vries Evert de , Wu Wei , Xiao Yanling , Heck Albert J. , Borst Jannie , Brummelkamp Thijn R. , Schumacher Ton N. 
Published: July 2017

Abstract
The clinical benefit in patients with diverse types of metastatic cancers that is observed upon blockade of the PD-1 - PD-L1 interaction has highlighted the importance of this inhibitory axis in the suppression of human tumor-specific T cell responses. In spite of the key role of PD-L1 expression by cells within the tumor microenvironment, our understanding of the regulation of the PD-L1 protein is limited. Using a haploid genetic screen, we here identify CMTM6, a poorly described type 3 transmembrane protein of previously unknown function, as a regulator of the PD-L1 protein. Interference with CMTM6 expression results in impaired PD-L1 protein expression in all tumor cell types tested and also in primary human dendritic cells. Furthermore, through both a haploid genetic modifier screen in CMTM6 deficient cells and genetic complementation experiments, we demonstrate that this function is shared by its closest family member CMTM4, but not by all other CMTM members tested. Notably, CMTM6 increases the PD-L1 protein pool without affecting PD-L1 transcript levels. Rather, we demonstrate that CMTM6 is present at the cell surface, associates with PD-L1 protein, and increases PD-L1 protein half-life. Consistent with this role, T cell inhibitory capacity of PD-L1 expressing tumor cells is enhanced by CMTM6. Collectively, our data reveal that PD-L1 relies on CMTM6/4 to efficiently carry out its inhibitory function, and suggest potential new avenues to block this pathway.
[C.S., R.M., and L.T.J. contributed equally to this work. T.R.B. and T.N.M.S. are both corresponding authors.]
Citation Format: Chong Sun, Riccardo Mezzadra, Lucas T. Jae, Raquel Gomez-Eerland, Evert de Vries, Wei Wu, Yanling Xiao, Albert J. Heck, Jannie Borst, Thijn R. Brummelkamp, Ton N. Schumacher. Identification of CMTM6 and CMTM4 as PD-L1 protein regulators [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-291. doi:10.1158/1538-7445.AM2017-LB-291