bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1877: Coordination of Rac1 and Cdc42 by centrosomal microtubules in focal adhesion dynamics and directed cell migration
Authors: Kuo Jean-Cheng 
Published: July 2017

Abstract
Cancer metastasis causes the increase of mortality in most cancer patients, and abnormal cell migration contributes to this disease progression. To control cell migration, the dynamical control of a protein complex within focal adhesions has to be regulated appropriately. It is known that focal adhesions can be regulated dynamically by microtubules. To examine the effects of centrosomal microtubules and non-centrosomal microtubules in regulating focal adhesion dynamics and directed cell migration, we first generated centrosome-deficient cells. We find that centrosomal microtubules and non-centrosomal microtubules control focal adhesion dynamics through modulating focal adhesion composition, which dynamically control the activity of small GTPases Rac1 and Cdc42. Deficiency of centrosomal microtubules significantly disrupts the balance of Rac1 and Cdc42, thereby inhibiting directed cell migration. This study reveals the effects of centrosome in focal adhesions, and indicates an important role for Rac1 and Cdc42 activation that controls actin polymerization, cell polarization and directed cell migration.
Citation Format: Jean-Cheng Kuo. Coordination of Rac1 and Cdc42 by centrosomal microtubules in focal adhesion dynamics and directed cell migration [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 1877. doi:10.1158/1538-7445.AM2017-1877
Abstract 1879: Transcriptional regulation of KAI1 by p73 in colorectal cancer metastasis
Authors: Bae Woo Kyun , Yoo Kyung Hyun , Kang Keunsoo , Hennighausen Lothar , Chung Ik-Joo 
Published: July 2017

Abstract
Background: p73 is a member of the p53 family transcription factors and known tumor suppressor. However, its transcriptional activity is complex owing to its multiple isoforms, and limited information is available regarding the transcriptional and functional regulation of the p73 gene in colorectal cancer. In this study, we examined the role of p73 in colorectal cancer.
Methods: We established a TAp73 overexpressing cell line using the Tet-on inducible expression system and analyzed global RNA expression by RNA-sequencing (RNA-seq). We studied the effects of TAp73 expression on the migration, invasiveness, and EMT of colon cancer cells. We conducted experiments in animals with liver metastasis of colorectal cancer. To investigate the roles of p73 in colon cancer, we examined the samples from patients, who had undergone surgical resection for colorectal cancer between 2009 and 2013. mRNA expression of TAp73 and KAI1 was analyzed in 108 colorectal cancer specimen and adjacent non-cancerous tissues by real-time RT-PCR.
Results: RNA-seq showed the association between TAp73 and KAI1 expression. Migration and invasiveness of colon cancer cells were reduced by TAp73 expression, but induced by KAI1 knockdown. TAp73 regulates KAI1 expression in colon cancer cell lines. TAp73-induced decrease in invasiveness and epithelial-mesenchymal transition (EMT) was abrogated by KAI1 knockdown in TAp73 overexpressing cells. Migration ability of TAp73 overexpressing cells was recovered by KAI1 knockdown. Hepatic metastases were significantly reduced in mice injected with TAp73 overexpressing cells and increased in those injected with TAp73 overexpressing cells with KAI1 knockdown. mRNA expression of TAp73 and KAI1 was higher in colorectal cancer tissues than in adjacent non-cancerous tissues. Significant correlation between TAp73 and KAI1 mRNA expression was detected in early stage primary colorectal cancer, but not in the advanced stage.
Conclusions: This study suggests that p73 (TAp73) acts as a tumor suppressor in the progression of colorectal cancer and regulates the expression of KAI1, which is a key target of p73 in colorectal cancer liver metastases.
Note: This abstract was not presented at the meeting.
Citation Format: Woo Kyun Bae, Kyung Hyun Yoo, Keunsoo Kang, Lothar Hennighausen, Ik-Joo Chung. Transcriptional regulation of KAI1 by p73 in colorectal cancer metastasis [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 1879. doi:10.1158/1538-7445.AM2017-1879
Abstract 1886: mGluR1 drives invasion of proneural subtype of glioblastoma cells
Authors: Gladwin Alena , Peng Sen , Kiefer Jeff , Kim Seugchan , Berens Michael , Dhruv Harshil D. 
Published: July 2017

Abstract
A major cause for the therapeutic failure and subsequent morbidity and mortality of glioblastoma (GBM) is the aggressive invasion of malignant cells into the surrounding normal brain that effectively renders complete surgical resection impossible and virtually assures recurrent tumor growth. Multi-omic profiling of GBM led to their molecular sub-classification into two distinct molecular subtypes: proneural (PN) and mesenchymal (MES). However, very little is known about shared or distinct invasion processes of cells in these genomically different subtypes. Using Microarray gene expression profiles of microdissected paired stationary core and invasive rim samples from 19 patients, we demonstrated that invasive gene signature of MES subtypes differs from PN. Specifically, using three orthogonal but intersecting bioinformatic approaches, i.e. gene set variation analysis, causal network analysis, and iRegulon analysis; we discovered that genes differentially expressed between PN core and rim could, to a meaningful degree, be accounted for based on their annotation as “regulated by the transcription factor REST”. REST functions as a repressor of gene expression. Of the genes repressed by REST, mGluR1 (Metabotropic Glutamate Receptor 1) was significantly overexpressed at the rim of PN glioma cells as compared to the core. Finally, we also investigated the role of mGluR1 in glutamate induced glioma cell migration; our results show that glutamate stimulates migration of proneural-like glioma cells (A172) as compare to non-proneural-like glioma cell (T98G). mGluR1 activation by glutamate has shown to induce activation of Pyk2 and Src in astrocytes; knockout of mGluR1 is not embryonic lethal. In summary, our data demonstrate that glutamate-induced glioma cell migration of PN subtype of GBM is dependent on mGluR1 and thus raises the prospect that therapeutic targeting of mGluR1 may be a novel approach to controlling the invasion of this deadly disease.
Citation Format: Alena Gladwin, Sen Peng, Jeff Kiefer, Seugchan Kim, Michael Berens, Harshil D. Dhruv. mGluR1 drives invasion of proneural subtype of glioblastoma 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 1886. doi:10.1158/1538-7445.AM2017-1886
Abstract 1916: Peptidylarginine deiminase IV (PADI4) is a novel tumor suppressor that may contribute to regulation of breast cancer stem cell dynamics
Authors: Moshkovich Nellie 
Published: July 2017

Abstract
Breast cancer is a global problem that accounts for almost a fourth of all cancers in women. Despite the many therapeutic strategies currently in use, treated patients often suffer from cancer relapse and metastasis due to the presence of a subpopulation of tumorigenic cells capable of self-renewal and termed cancer stem cells (CSCs). To address the properties of this critical sub-population, we utilized our recently-developed lentiviral CSC reporter carrying an Oct4/Sox2 response element coupled to a green fluorescent protein (SORE6-GFP) to detect and isolate the CSC population in a low-grade ER+ human breast cancer model, MCF10Ca1h, by FACS. Whole transcriptome sequencing analysis (RNA-seq) on the sorted cells identified Peptidylarginine deiminase IV (PADI4) as differentially expressed between CSCs and non-CSCs. PADI4 was recently shown to regulate citrullination of histone H1, displacing it from chromatin and resulting in global chromatin decondensation and pluripotency induction in embryonic stem cells (Christophorou, et al., 2014, Nature 507:104). Thus, we hypothesized that PADI4 may also regulate the stemness phenotype in breast cancer CSCs, likely through effects on chromatin structure. We showed that PADI4 protein expression is higher in luminal breast cancer cell lines than other subtypes, and we did shRNA knockdown (KD) of PADI4 in the luminal MCF10Ca1h model. PADI4 KD increased tumorosphere formation and clonogenicity indicating increased CSC population/activity. Additionally, MCF10Ca1h cells treated with a PADI4 selective inhibitor showed an increase in CSCs as assessed using the SORE6-GFP stem cell reporter. In vivo limiting dilution studies demonstrate that PADI4 KD increased tumor incidence at low cell inoculum, reflecting a statistically significant 2-4 fold increase in CSCs upon PADI4 KD. Our findings suggest that PADI4 may function as a tumor suppressor in luminal breast cancer. In support of this conclusion, deep deletions of PADI4 locus are found in 1% of human breast cancers in the TCGA datasets. Analysis of the effect of PADI4 KD on chromatin organization in the CSC and non-CSC compartments is ongoing.
Citation Format: Nellie Moshkovich. Peptidylarginine deiminase IV (PADI4) is a novel tumor suppressor that may contribute to regulation of breast cancer stem cell dynamics [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 1916. doi:10.1158/1538-7445.AM2017-1916
Abstract 1922: S-SHIP promoter expression identifies a putative cancer stem cell population in C3(1)/Tag murine mammary tumors
Authors: Tian Lu , Lagadec Chann , Adriaenssens Eric , Bouchaert Emmanuel , Roy Hélène Bauderlique-Le , LeBourhis Xuefen , Bourette Roland P. 
Published: July 2017

Abstract
Breast cancer is the most common cancer in women worldwide. The isolation and characterization of breast cancer stem cells (CSC) are crucial for understanding cancer biology and revealing potential therapeutic targets. One of the major issues in the study of CSC is the lack of reliable markers. A transgenic mouse model (Tg 11.5kb–GFP) was generated using the 11.5kb s-SHIP (stem-SH2-containing 5’-Inositol Phosphatase) promoter that specifically expressed enhanced green fluorescent protein (GFP) in embryonic and various tissue stem cells. In the mammary gland, previous experiments showed that GFP labels puberty cap cells and pregnancy basal alveolar bud cells, and it has been demonstrated that these mammary GFP+ cells are activated tissue stem cells. In order to determine if s-SHIP promoter expression could also mark mammary cancer stem cells, we generated a bi-transgenic mouse model by crossing Tg 11.5kb-GFP mice with Tg C3(1)/Tag mice. Tg C3(1)/Tag mice express SV40 T antigen under the regulatory control of the rat prostatic steroid binding protein C3(1) gene. In female mice, the transgene is expressed primarily in the mammary gland. Mice develop mammary hyperplasia by 3 months of age with subsequent development of mammary adenocarcinoma by 6 months of age.
Here we show the presence of a rare population of GFP+ cells in mammary tumors of female bi-transgenic mice by using immunohistochemical and flow cytometry analysis. The GFP+ mammary cancer cells are also CD24+/CD49f+/CD29+. As compared to GFP- cells, GFP+ cells exhibit both a higher tumor sphere-forming potential, and a higher tumorigenicity when transplanted into SCID and FVB recipient mice. Moreover, upon subsequent transplantation, the GFP+ cells generated heterogeneous tumors that displayed properties similar to the primary tumor. Currently, we are conducting transcriptomic analysis of these GFP+ and GFP- cells in order to reveal differentially expressed genes. Altogether, these results suggest that s-SHIP promoter expression may be a new marker of mammary CSC that enables their identification and isolation via a single consistent parameter. Furthermore, our bi-transgenic C3(1)/Tag x 11.5kb-GFP mice provide a novel model for study of mammary cancer stem cells and investigation of potential therapeutic targets for breast cancer.
Citation Format: Lu Tian, Chann Lagadec, Eric Adriaenssens, Emmanuel Bouchaert, Hélène Bauderlique-Le Roy, Xuefen LeBourhis, Roland P. Bourette. S-SHIP promoter expression identifies a putative cancer stem cell population in C3(1)/Tag murine mammary tumors [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 1922. doi:10.1158/1538-7445.AM2017-1922
Abstract 1955: Targeting ribonucleotide reductase (RNR) in Ewing sarcoma
Authors: Goss Kelli , Koppenhafer Stacia , Harmoney Kathryn , Gordon David 
Published: July 2017

Abstract
Ewing sarcoma is a highly aggressive bone and soft tissue cancer that is caused by the EWS-FLI1 fusion protein. The EWS-FLI1 oncoprotein functions, in part, as an aberrant transcription factor and is required for tumor growth and survival. In order to identify downstream targets of EWS-FLI1, we used human embryonic stem cells that express inducible EWS-FLI1 to model the initiation and development of Ewing sarcoma in a genetically defined system. We then used this model system and a gene expression based approach to identify that Ewing sarcoma cells are uniquely vulnerable to inhibitors of ribonucleotide reductase (RNR), which impair DNA replication by blocking the synthesis of deoxyribonucleotides. Here we report that the treatment of Ewing sarcoma cells with gemcitabine, an irreversible inhibitor of the RRM1 subunit of RNR, results in impaired DNA replication, cell cycle arrest, and apoptosis in Ewing sarcoma cells. Additionally, we have found that the effect of gemcitabine on the viability of Ewing sarcoma cells is sustained even after removal of the drug from the cell culture medium. Moreover, ataxia telangiectasia and rad3-related protein (ATR) and checkpoint kinase 1 (CHK1) inhibitors increase the toxicity of gemcitabine in Ewing sarcoma cells by blocking the adaptive response to impaired DNA replication. Currently, ongoing work is focused on the in vivo testing of gemcitabine, alone and in combination with CHK1 and ATR inhibitors, as a novel therapeutic approach for the treatment of Ewing sarcoma.
Citation Format: Kelli Goss, Stacia Koppenhafer, Kathryn Harmoney, David Gordon. Targeting ribonucleotide reductase (RNR) in Ewing sarcoma [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 1955. doi:10.1158/1538-7445.AM2017-1955
Abstract 1959: MTA1 promotes tumor progression and bone metastasis in prostate cancer via positive regulation of MUC1 and CTSB
Authors: Kumar Avinash , Dhar Swati , Campanelli Gisella , Butt Nasir A. , Gomez Christian R. , Schallheim Jason M. , Levenson Anait S. 
Published: July 2017

Abstract
About 80% of the time that prostate cancer cells metastasize, they spread to the bones. Metastasis involves activation of invasive programs through genetic and epigenetic alterations, including changes in expression of chromatin remodeler proteins. We have previously identified metastasis-associated protein 1 (MTA1), a chromatin remodeler, as a component of vicious cycle of bone metastasis and confirmed significantly higher expression of MTA1 in bone metastatic samples from patients. In an attempt to dissect molecular mechanisms of MTA1 action, we performed integrative analysis of our bone metastasis signature data along with MTA1 ChIP-Seq data, which revealed mucin 1 (MUC1) and cathepsin B (CTSB) as strong potential candidates responsible for MTA1-driven invasiveness.Here, we show that loss of function studies with MTA1 in PC3M cells exhibit reduced expression for MUC1 and CTSB. We also demonstrate that depletion of MTA1 in PC3M aggressive prostate cancer cellsdoes not affect cell proliferation but leads to decrease in colony forming ability, invasive and migratory property of these cells. When PC3M cells silenced for MTA1 and tagged with luciferase are used to generate subcutaneous or intracardiac xenografts, it leads to reduced tumor progression or decreased metastasis to bone, respectively as evident by bioluminescent measurements and histology of tumors. Ongoing experiments aim to validate the role of MUC1 and CTSB in MTA1-driven invasiveness and metastasis in prostate cancer.
Citation Format: Avinash Kumar, Swati Dhar, Gisella Campanelli, Nasir A. Butt, Christian R. Gomez, Jason M. Schallheim, Anait S. Levenson. MTA1 promotes tumor progression and bone metastasis in prostate cancer via positive regulation of MUC1 and CTSB [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 1959. doi:10.1158/1538-7445.AM2017-1959
Abstract 1960: Upregulation of MCP-1 regulates invasiveness in triple negative breast cancer
Authors: Dutta Pranabananda , Paico Kimberly , Yuwanita Inez , Wu Yanyuan , Sarkissyan Marianna , Vadgama Jaydutt 
Published: July 2017

Abstract
Background: Triple negative breast cancer (TNBC) poses a critical problem for targeted therapy due to lack of significant expression of estrogen, progesterone receptor or Her2/neu oncogene. Hence, it is imperative to identify novel therapeutic strategies to target TNBC. Our study is aimed to examine whether Monocyte Chemoattractant Protein -1 (MCP-1) is a specific marker for TNBC metastasis. Experimental
Design: We employed ELISA to determine secreted MCP-1 in cell conditioned media, as well as Real-time PCR to determine the status of MCP-1 in TNBC cell lines. Boyden chamber assay was used to determine the effect of recombinant MCP-1 on cellular metastasis. Cellular proliferation was measured with MTT assay. Immunofluorescence staining was utilized for protein of interest in breast cancer cells. MCP-1 knockdown was performed using lentiviral vector with shRNA targeting MCP-1 coding regions.
Results: Our data show that the key inflammatory chemokine MCP-1 is upregulated in TNBC cell lines both transcriptionally as well as in terms of secretion compared to ER-positive cell line, MCF-7. MCP-1 stimulation in MDA-MB231 and MCF-7cells does not affect cellular proliferation. However, MCP-1 enhances metastatic properties of MDA-MB-231 cells along with BT-549 cells. Inhibiting Chemokine receptor 2/4 (CCR2/4), cognate receptor for MCP-1, with small molecule antagonists negatively affects invasiveness in MDA-MB-231 cells as evidenced by Boyden chamber assay. Knocking down MCP-1 by shRNA decreases cell invasion in TNBC cell line, BT-549 along with downregulation of key epithelial to mesenchymal transition markers, N-cadherin and Vimentin. MCP-1 induced cell invasion in TNBC may involve activation of p44/p42 MAPK Thr202/Tyr204.
Conclusion: Our study suggests that high MCP-1 levels in TNBC is driving up metastasis potential in cells. Thus MCP-1 and its mediated pathways could be potential therapeutic targets for the treatment of TNBC.
Citation Format: Pranabananda Dutta, Kimberly Paico, Inez Yuwanita, Yanyuan Wu, Marianna Sarkissyan, Jaydutt Vadgama. Upregulation of MCP-1 regulates invasiveness in triple negative breast 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 1960. doi:10.1158/1538-7445.AM2017-1960
Abstract 1997: Charting the DNA methylation landscape of prostate cancer associated fibroblasts
Authors: Lawrence Mitchell G. , Pidsley Ruth , Zotenko Elena , Niranjan Birunthi , Statham Aaron , Song Jenny , Armstrong Nicola , Pedersen John , Frydenberg Mark , Taylor Renea , Stirzaker Clare , Risbridger Gail , Clark Susan 
Published: July 2017

Abstract
Most studies of the genome and epigenome landscape of tumors focus on the aberrations in epithelial cancer cells. However, the growth and progression of solid tumors involves dynamic cross-talk between cancer epithelium and the surrounding microenvironment, including cancer-associated fibroblasts (CAFs). The molecular landscape of these cells is still poorly understood, so it is important to define the epigenetic features that underpin the functional differences between CAFs and non-malignant prostate fibroblasts (NPFs) and influence cancer progression. Therefore, we used whole-genome bisulphite sequencing to chart the epigenome landscape of CAFs at single base resolution. Our data revealed that NPFs and CAFs from localized prostate cancer have remarkably different epigenome profiles characterized by locus-specific rather than global changes in DNA methylation. CAFs exhibited more than 7500 differentially methylated regions compared to NPFs. In contrast, no recurrent genomic aberrations were detected in CAFs, emphasising the importance of epigenome changes in reinforcing their pro-tumorigenic phenotype. Many differentially methylated regions occurred at known regulatory loci and were associated with differentially expressed genes measured using RNAseq. The methylation and gene expression changes were highly consistent across patients when validated using an independent cohort of patient-matched NPFs and CAFs. Remarkably, a subset of differentially methylated regions in CAFs is shared with prostate cancer epithelial cells, revealing the new concept of tumour-specific epigenome modifications in the tumour and its microenvironment. Collectively, these data demonstrate that CAFs are defined by an enduring epigenetic signature that comprises a distinct set of locus-specific DNA methylation alterations in cancer-related regulatory loci. The distinct methylome of CAFs provides a novel epigenetic hallmark of the cancer microenvironment and promises new biomarkers to improve interpretation of diagnostic samples.
Citation Format: Mitchell G. Lawrence, Ruth Pidsley, Elena Zotenko, Birunthi Niranjan, Aaron Statham, Jenny Song, Nicola Armstrong, John Pedersen, Mark Frydenberg, Renea Taylor, Clare Stirzaker, Gail Risbridger, Susan Clark. Charting the DNA methylation landscape of prostate cancer associated fibroblasts [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 1997. doi:10.1158/1538-7445.AM2017-1997