bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5097: Tissue stiffness regulates multinucleation in mammary epithelial cells
Authors: Simi Allison K. , Radisky Derek C. , Nelson Celeste M. 
Published: July 2016

Abstract
This study investigates how increased stiffness of the tumor microenvironment (TME) can facilitate cellular multinucleation.
Multinucleation is an easily observable marker for polyploidy, facilitating the quantification of this phenotype. Polyploidy is commonly an intermediate to aneuploidy, defined as an abnormal number of chromosomes, a phenotype found in 85% of solid cancers that can drive tumorigenesis. Up to 37% percent of tumors exhibit whole-genome doubling, which typically precedes other somatic copy number alterations. Additionally, induction of tetraploidy in human cells promoted increased tolerance for mutation, resistance to chemotherapeutic drugs, and transformation in culture.
Tumors are inherently stiffer than normal tissue, and this property has been shown to affect cell growth and proliferation. Similarly, cell cycle errors have long been linked to chromosomal abnormalities. Here, we used engineered two-dimensional substrata that mimic tumor and normal microenvironments to investigate how matrix stiffness regulates multinucleation in mammary epithelial cells.
Cells cultured on “stiff” substrata, representing tumor tissue, showed a nearly 14-fold increase in multinucleation compared to cells cultured on “soft” substrata, representing normal tissue. We found that multinucleation was regulated in part by signaling downstream of MMP3, a protease commonly upregulated in cancer. This signaling depended on expression of the Rac1 splice variant, Rac1b, production of reactive oxygen species (ROS), and expression of Snail. Under all conditions, cells cultured on soft substrata maintained a low frequency of multinucleation.
We also investigated biochemical effectors downstream of Snail. Aurora A kinase (Aurora A) is a mitotic regulator commonly elevated in cancer that has been shown to induce multinucleation in mammary epithelial cells and increase tumor incidence in mice. We found using microarray analysis that MMP3 increases the levels of Aurora A in mammary epithelial cells. We further discovered that upregulation of Aurora A in response to MMP3 signaling was limited to one transcript variant.
These data suggest that an increase in multinucleation is driven by the stiffening of the tissue during tumorigenesis, in part by MMP3-induced signaling and regulation of Aurora A splicing. More broadly, these data suggest a key role for the mechanical properties of the tumor microenvironment in cancer progression.
Citation Format: Allison K. Simi, Derek C. Radisky, Celeste M. Nelson. Tissue stiffness regulates multinucleation in mammary epithelial cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5097.
Abstract 5108: Glucagon like peptide 1 (GLP1) up-regulation in hypoxic and nutrient deprived microenvironment promotes neuroblastoma cell survival
Authors: Wesley Umadevi V. , Singh Nausheen , Dempsey Robert J. 
Published: July 2016

Abstract
Introduction: Glucagon-like peptide 1 (GLP1) an incretin has demonstrated to increase insulin secretion in a glucose-dependent manner and is shown to be neuroprotective. GLP1 also promotes angiogenesis. Hypoxia, a common feature in solid tumors including neuroblastoma, promotes tumor progression by upregulation of hypoxia responsive factors. Little is known about alterations of GLP1 expression in neuroblastoma under hypoxic condition. GLP1 is rapidly inactivated by dipeptidyl peptidase IV (DPPIV) mediated enzymatic cleavage. Previously we have shown that DPPIV suppresses neuroblastoma survival and angiogenesis. In this study, we examined whether GLP1, its receptor GLP1R, and DPPIV expressions are altered after exposing neuroblastoma cells to hypoxic conditions of oxygen and nutrient deprivation (OND). We then examined the direct effects of GLP1 on neuroblastoma proliferation and survival, and evaluated if DPPIV modulates GLP1 mediated functions.
Methods: We used Neuro-2a, a mouse neuroblastoma cells as a model. In vitro experiments were performed exposing these cells to conditions mimicking tumor areas that display oxygen and nutrient deprivation, followed by re-oxygenation. Immunofluorescence staining was used to analyze the protein expression of GLP1, GLP-1R, and DPPIV. RT-PCR was used to measure mRNA levels. Effects of DPPIV on GLP1 mediated Neuro-2a cell proliferation and survival was evaluated by MTT and live/dead cell assay. Levels of PI3K/AKT were determined by western blot analysis.
Results: Neuro-2a cells subjected to OND showed about 2 fold increase in the GLP1 protein and mRNA levels at four hours of
re-oxygenation after 4 hours of OND. However, GLP1 protein levels decreased drastically after one day of re-oxygenation, while DPPIV levels were highly upregulated. GLP1R was also downregulated at one day of re-oxygenation. At this time point, cell viability was decreased by 30-40%. Pre-treatment with DPPIV inhibitor rescued the protective effects of GLP1. Furthermore, exogenous GLP1 stimulated cell proliferation and increased Neuro-2a cell viability by 2-3 fold. GLP1dependent action was mediated via increased levels of phosphorylated AKT, a pro-survival signaling molecule. The effects of GLP1 were suppressed in presence of DPPIV.
Conclusion: The results indicate an inverse correlation between DPPIV and GLP1 levels in Neuro-2a cells. Together, these studies indicate that GLP1-DPPIV interaction may play an important role in promoting neuroblastoma cell proliferation and survival.
Citation Format: Umadevi V. Wesley, Nausheen Singh, Robert J. Dempsey. Glucagon like peptide 1 (GLP1) up-regulation in hypoxic and nutrient deprived microenvironment promotes neuroblastoma cell survival. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5108.
Abstract 5116: Phosphatidylserine-targeting antibodies augment anti-tumor activity of PD-1 antibodies and alter immuno-profiles in murine triple negative breast cancers
Authors: Gray Michael J. , Gong Jian , Parks Ryan N. , M.S. Hatch Michaela , Nguyen Van , Hughes Christopher C.W. , Hutchins Jeff T. , Freimark Bruce D. 
Published: July 2016

Abstract
Current treatments for triple negative breast cancers rely primarily upon surgical intervention and chemotherapy. Unfortunately, chemotherapies have the propensity to help establish an immunosuppressive condition in part though exposure of phosphatidylserine (PS) in the tumor microenvironment. We demonstrate that treatment of the murine triple negative breast cancer E0771 using a PS-targeting antibody inhibits in vivo growth, and significantly enhances the anti-tumor activity of antibodies directed to the checkpoint inhibitor PD-1. Combinational treatment by antibodies targeting PS and PD-1 increased the number of tumor infiltrating lymphocytes (TILs) to a greater extent than observed with single-arm therapies. Furthermore, combination of PS and PD-1 targeting antibodies provides a distinct survival advantage over treatment by either agent alone, which correlates with an increase in complete tumor regression and the onset of a durable immune mediated response capable of rejecting a secondary challenge by the same tumor. Finally, immune-profiling analysis of tumor RNA using Nanostring revealed that the combination antibody therapy enhanced immune regulatory pathways including MHC class I/II expression, antigen processing and presentation, and leukocyte and macrophage functions. Combined, our data suggest that in triple negative breast cancers antibody therapy blocking PS-associated immunosuppression may further enhance immunotherapies directed at immune checkpoint inhibitors, including those targeting the PDL-1/PD-1 axis.
Citation Format: Michael J. Gray, Jian Gong, Ryan N. Parks, Michaela M.S. Hatch, Van Nguyen, Christopher C.W. Hughes, Jeff T. Hutchins, Bruce D. Freimark. Phosphatidylserine-targeting antibodies augment anti-tumor activity of PD-1 antibodies and alter immuno-profiles in murine triple negative breast cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5116.
Abstract 513: Standardization of technologies for CTC, ctDNA and miRNA enrichment, isolation and analysis for liquid biopsies during the first year of IMI's CANCER-ID
Authors: Schlange Thomas , Stoecklein Nikolas , Neves Rui P. , Pleier Sabrina , Bender Sebastian , Brychta Nora , Luetke-Eversloh Merlin V. , Andree Kiki , Terstappen Leon , Krahn Thomas , Krahn Thomas 
Published: July 2016

Abstract
Within the European Innovative Medicines Initiative (IMI) consortium CANCER-ID (www.cancer-id.eu), scientists at academic, clinical and industrial sites across Europe and in the US joined forces to evaluate innovative technologies in the field of liquid cancer biopsies. This project aims at implementing standard operating procedures (SOPs) for pre-analytical sample handling, enrichment, isolation and analysis of Circulating Tumor Cells (CTCs), circulating free tumor DNA (ctDNA) and microRNAs (miRNAs) as novel blood-based biomarkers, with a focus on Non-Small Cell Lung Cancer (NSCLC) and HER2-treatment refractory breast cancer. In order to determine sensitivity and specificity of different technologies for CTC isolation and analysis (e.g. detection of mutations, amplifications, protein phosphorylation), complex samples comprising a mixture of NSCLC or breast cancer cell lines spiked in healthy donor blood were distributed to different CANCER-ID partner sites. These cell lines have been selected based on their molecular/genetic properties to reflect clinically relevant subtypes of the disease and have been further characterized in terms of cell-surface marker expression and cell size distribution. The use of complex spiked samples better models the heterogeneity of real-life patient material. Furthermore, healthy donor and patient derived plasma samples are investigated using different technology platforms to validate tumor-specific miRNA or ctDNA profiles that might characterize molecular tumor subtypes. To this end, differences in exosome-derived versus free circulating miRNAs are of special interest. As for CTCs the development of ctDNA and miRNA standards that can be used to compare and validate different technologies are in the focus of this effort. In summary, our results pave the way for the next phase of CANCER-ID, which includes the analysis of cancer patient samples in clinical studies using different technologies and thereby advance the concept of liquid biopsy particularly in indications in which conventional tissue biopsies are difficult to obtain.
Citation Format: Thomas Schlange, Nikolas Stoecklein, Rui P. Neves, Sabrina Pleier, Sebastian Bender, Nora Brychta, Merlin V. Luetke-Eversloh, Kiki Andree, Leon Terstappen, Thomas Krahn, Thomas Krahn. Standardization of technologies for CTC, ctDNA and miRNA enrichment, isolation and analysis for liquid biopsies during the first year of IMI's CANCER-ID. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 513.
Abstract 5138: The PD-1/PD-L1 axis and clinical outcomes in head and neck squamous cell carcinomas
Authors: Trivedi Sumita , Seethala Raja R. , Ferris Robert L. 
Published: July 2016

Abstract
Although novel therapeutic agents targeting PD-L1 and PD-1 have emerged, our understanding of the complex interaction between the tumor microenvironment and this checkpoint receptor-ligand axis remains incomplete. PD-L1 protein expression has been demonstrated by immunohistochemistry in several solid tumors including head and neck squamous cell carcinomas (HNSCC). However, the prognostic significance of PD-L1 overexpression in HNSCC remains inconclusive. Furthermore, the interaction between human papillomavirus (HPV) positive tumors, PD-L1 on tumor cells and PD-1 on immune cells has yet to be demonstrated in an architecturally intact tumor environment.
Here we demonstrate PD-L1 expression in a large cohort of mixed HPV+ and HPV-, surgically treated HNSCC using immunohistochemistry. Our findings confirm that more HPV+ tumors express PD-L1 compared with HPV- tumors (72% compared with 44%). Clinically, this correlates with improved overall and disease-free survival in in patients with HPV+ PD-L1+ tumors compared with HPV- PD-L1- tumors. By examining the intact tumor, we visualized distinct patterns of PD-L1 staining, either peripherally, at the tumor front or non-peripherally. Tumors with a peripheral staining pattern showed a trend towards decreased overall and disease-free survival, compared to those with a non-peripheral pattern of staining. By double staining PD-L1 and PD-1, we analyzed the co-expression of the ligand on tumor cells and its receptor on neighboring immune cells. Interestingly, patients whose tumors displayed co-localization of PD-1 and PD-L1 showed a trend towards improved disease-free survival compared to tumors where there was no co-localization of PD-1 and PD-L1.
In conclusion, out data suggest that the presence of PD-L1 and PD-1 alone may not be sufficient to guide clinical treatment rather; careful examination of the intact tumor microenvironment may inform more targeted therapy.
Citation Format: Sumita Trivedi, Raja R. Seethala, Robert L. Ferris. The PD-1/PD-L1 axis and clinical outcomes in head and neck squamous cell carcinomas. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5138.
Abstract 5148: Angiotensin II type I receptor drives cancer progression through the FLJ10540/S100A9 pathway in oral cancer
Authors: Chen. Chang-Han 
Published: July 2016

Abstract
Oral cancer is the eighth most common cancers and a growing problem worldwide. Despite the easy approach for visual examination, oral cancer is often detected at advanced stages leading to severely decreased patient survival. Identifying reliable molecular markers for oral cancer provided in developing new therapeutic interventions is urgently needed. In this study, we explored that angiotensin II type I receptor (AT1R) was overexpression in tumor tissues of oral cancer patients, and its expression also significantly correlated with advanced TNM-stage, lymph node stage, and the poor 5-year survival rate. Functionally, gain-of function of AT1R in oral cancer cells promoted tumor cell growth in vitro and in xenograft model by MTT/colony formation/BrdU incorporation/time-lapse/IVIS, and 3D-Sonographic imaging appraoches. Furthermore, using the same cell panels, the migratory and invasive abilities were increased by wound healing and Transwell assays and the epithelial-mesenchymal transition (EMT) markers, such as N-cadherin, fibronectin and vimentin were also elevated. Conversely, loss-of function of AT1R in oral cancer cells by using siRNA and CRISPR/Cas9 systems demonstrated that the abilities of tumor proliferation, and motility were decreased in vitro and in vivo. By using syn-expression concept combinging with bioinformatic appraoch, we found that FLJ10540 was a novel dwonstream target of AT1R. FLJ10540 expression was not only regulated by AT1R, but also participated in AT1R-elicited cancer progression in vitro and in vivo. We established FLJ10540 knockout oral cancer cell lines by CRISPR/Casp9 to perform DNA microarray and found that S100A9 was a top ranking target among the differrentially expression in down-regulated candidate sets. By using biochemical approaches and xenograft model, the post-transcriptional level of S100A9 was modulated by FLJ10540. In addition, the AT1R-elicited cancer progression was required for FLJ10540/S100A9 expression. Finally, immunohistochemical analysis of human aggressive oral cancer specimens showed a significant positively correlation between AT1R/FLJ10540 and S100A9 expression. Taken together, these findings suggest that AT1R is not only an important prognostic factor but also a new therapeutic target in the FLJ10540/S100A9 pathway for human cancer.
Citation Format: Chang-Han Chen. Angiotensin II type I receptor drives cancer progression through the FLJ10540/S100A9 pathway in oral cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5148.
Abstract 5165: ADAM17: a common effector for RAS and MET-driven transformation of primary keratinocytes
Authors: Cataisson Christophe , Klosterman Mary , Shibuya Kelly , Merlino Glenn , Yuspa Stuart H. 
Published: July 2016

Abstract
The purpose of the current study is to determine the contribution of the metalloproteinase ADAM17 (a disintegrin and metalloprotease 17) to the transformation driven by activated MET or oncogenic RAS in primary keratinocytes. Transgenic keratinocytes overexpressing HGF (MT-HGF) to activate MET and keratinocytes transduced with an oncogenic RAS share identical phenotypic and biochemical features of transformation and produce squamous tumors in vivo. In both keratinocyte populations, these common features arise from autocrine activation of EGFR through elevated expression and release of EGFR ligands. Amphiregulin (AREG) blockade in MT-HGF keratinocytes decreases MET-mediated EGFR transactivation. Inhibition of EGFR ablates the initiated signature of MT-HGF keratinocytes in vitro and causes regression of tumors from MT-HGF keratinocytes tranplanted in vivo. Deletion or knock-down of ADAM17 decreases EGFR activation in both RAS and MT-HGF keratinocytes and reverses the transformation associated gene signature in RAS keratinocytes. Using AREG release as an indicator of ADAM17 activity, we determined that knock-down of either the SRC kinase or inactive Rhomboid 2 (iRhom2) reduces the ability of keratinocytes to release AREG upon HGF stimulation. Collectively our data suggest that MET-mediated transformation of keratinocytes occurs through EGFR transactivation and that ADAM17 is a necessary effector for RAS and MET-driven transformation.
Citation Format: Christophe Cataisson, Mary Klosterman, Kelly Shibuya, Glenn Merlino, Stuart H. Yuspa. ADAM17: a common effector for RAS and MET-driven transformation of primary keratinocytes. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5165.
Abstract 5166: Gene expression microarray analysis identifies association of genes in the integrin/fak signaling pathway with claudin-7 in human colon cancer tissue
Authors: Kong Lu , Ding Lei 
Published: July 2016

Abstract
The role and mechanism of the integrin/focal adhesion kinase (FAK)/ERK signaling pathway in the progression of many malignant tumor types, including colon cancer, have been widely reported. The claudin family of proteins is integral to the structure and function of tight junctions. The role of claudin-7 (Cldn-7, CLDN7) in the regulation of the integrin/FAK/ERK signaling pathway remains poorly understood. Therefore, we investigated differences in gene expression, primarily focusing on CLDN7 and integrin/FAK/ERK signaling pathway genes, in colon cancer and adjacent normal tissues. Quantitative real-time RT-PCR verified the results for mRNA expression, and immunohistochemistry verified the results for protein expression. In silico analysis was used to predict co-regulation between Cldn-7 and integrin/FAK/ERK signaling pathway members. Our results showed marked cancer stage-specific decreases in the protein expression of Cldn-7, Gelsolin, MAPK1 and MAPK3 in colon cancer samples. The observed changes in the expression of all proteins except Cldn-7 were in agreement with the changes in the corresponding mRNA levels. Cldn-7 was predicted not to directly regulate any genes in the integrin/FAK/ERK signaling pathway, but these factors may participate in a common network that regulates cancer progression, in which the MAPK pathway is the central node.
Citation Format: Lu Kong, Lei Ding. Gene expression microarray analysis identifies association of genes in the integrin/fak signaling pathway with claudin-7 in human colon cancer tissue. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5166.
Abstract 5170: Snail-dependent ESRP1 silencing drives malignant conversion of human pulmonary epithelial cells
Authors: Walser Tonya C. , Jing Zhe , Tran Linh , Lin Ying , Zhu Li , Sharma Sherven , Ooi Aik , Gomperts Brigitte N. , Shay Jerry W. , Larsen Jill E. , Gao Boning , Minna John D. , Fishbein Micihael C. , Dubinett Steven M. 
Published: July 2016

Abstract
The significance of Snail expression in the early pathogenesis of non-small cell lung cancer has not been determined. Here, we report robust Snail expression in premalignant lung lesions relative to histologically normal-appearing pulmonary and lung cancer tissues. Utilizing immortalized human bronchial epithelial cells (HBECs) to isogenically model the contribution of the transcriptional repressor Snail to lung carcinogenesis, we document Snail-dependent anchorage-independent growth of pulmonary epithelial cells in vitro, as well as their transformation, primary tumor growth, and metastatic behavior in vivo. We delineate ESRP1 tumor suppressor silencing as a requirement for the Snail-driven transformation and identify ESRP1 silencing in Snail-expressing pulmonary premalignant lesions in situ. Utilizing this HBEC lung carcinogenesis model, we determined that Snail drives the expansion and malignant conversion of an ALDH+CD44+CD24- subset of pulmonary stem cells. Apoptosis-resistance and expression changes in oncogenes and tumor suppressors were noted, and ESRP1 was identified as a mediator of the malignant conversion of these Snail-primed pulmonary. Collectively, this is the initial report of a Snail-ESRP1-cancer axis that is operative during lung carcinogenesis and the first characterization of potentially targetable mediators of this normal to cancer continuum.
Citation Format: Tonya C. Walser, Zhe Jing, Linh Tran, Ying Lin, Li Zhu, Sherven Sharma, Aik Ooi, Brigitte N. Gomperts, Jerry W. Shay, Jill E. Larsen, Boning Gao, John D. Minna, Micihael C. Fishbein, Steven M. Dubinett. Snail-dependent ESRP1 silencing drives malignant conversion of human pulmonary epithelial cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5170.