bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3892: Delineating the role of ZEB1 loss in the chemo and radioresistance of glioma stem cells
Authors: Madany Mecca , Edwards Lincoln , Yu John S. 
Published: July 2017

Abstract
The most prevalent brain cancer, Glioblastoma Multiforme (GBM) has an average survival of less than 2 years. Despite advances in therapy there is still an overall poor response to treatment which has been attributed to glioma stem cells (GSC’s), a subset of tumor cells that are able to self-renew, inhibit differentiation and are often chemo and radioresistant. The genetics and mechanisms underlying how glioma stem cells are able to repopulate tumors and affect patient survival desperately need to be defined. We are interested in delineating the role that ZEB1 (zinc finger e-box binding homeobox-1) loss has on GSC’s and what role this loss plays in the chemo and radioresistance of GSC’s. Most insights into ZEB1 regard it as tumorigenic and an initiator of EMT (epithelial mesenchymal transition). Surprisingly, in this study, we have shown that in TCGA datasets ZEB1 deletion frequently occurs and this loss actually results in poorer glioma patient survival. Copy number analysis as well as immunohistochemistry on patient samples shows that ZEB1 loss occurs both at the gene and protein level. Stable ZEB1 knockdown in our patient derived glioma stem cell lines results in increased proliferation and a resistance to differentiation. Following chemotherapy as well as radiotherapy, knockdown cell lines show increased cell viability as well as higher levels of secondary neurosphere formation. Decreased apoptosis and changes in cell cycle as well as the DNA damage response pathway were also observed in the knockdown lines following chemo and radiotherapy. Overall, this data indicates that loss of ZEB1 in GSC’s results in enhanced resistance to standard therapy. With these results, we have reason to believe that ZEB1 may be used as a novel therapeutic target to combat the chemo and radioresistance of glioma stem cells.
Citation Format: Mecca Madany, Lincoln Edwards, John S. Yu. Delineating the role of ZEB1 loss in the chemo and radioresistance of glioma stem 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 3892. doi:10.1158/1538-7445.AM2017-3892
Abstract 3897: Novel inhibitor of GBM stem cells targets unique CREB & Myc-mediated self-renewal pathways regulated by CDK5
Authors: Mukherjee Subhas , Tucker-Burden Carol , Zhang Changming , Kong Jun , Chau Monica , Read Renee , Brat Daniel J. 
Published: July 2017

Abstract
Cancer stem cells exert enormous influence on neoplastic behavior, in part by governing asymmetric cell division and the balance between self-renewal & multipotent differentiation. Growth is favored by deregulated stem cell division, which enhances the self-renewing population & diminishes the differentiation program. To uncover mechanisms relevant to deregulated cell division in human glioma stem cells, we first developed a novel adult Drosophila brain tumor model, 100% enriched with tumor stem cells. Using this model, we performed a suppressor screen for kinases and found brain-specific dCdk5 partially reverses the tumor phenotype. dCdk5 and its human ortholog CDK5 (79% identity) are atypical protein kinases because they do not regulate cell cycle in normal cells, but are critical for neurogenesis & survival of mature neurons. Interestingly, many cancers show overactivation of CDK5 signaling, regulating cell cycle & leading to uncontrolled proliferation. Our analysis of TCGA data shows that IDH wt GBM has significantly high level of CDK5 compared to the IDH wt lower grade glioma. Additionally, we found a strong positive correlation between CDK5 & several stem cell markers in GBM. To date, not much is known about the role of CDK5 in glioblastoma GBM) & glioma stem cell self-renewal. Using patient-derived (GBM) neurosphere cultures & in vivo xenograft tumors in mice, we further demonstrated that a novel pharmaceutical suppressor of CDK5 signaling axis can suppress self-renewal properties through a new CDK5 phosphorylation site on CREB and Myc. Together, our results show that the CDK5 signaling pathway is important for glioma stem cell survival & that suppressing CDK5 could be a novel therapeutic approach to eliminate glioma stem cells.
Citation Format: Subhas Mukherjee, Carol Tucker-Burden, Changming Zhang, Jun Kong, Monica Chau, Renee Read, Daniel J. Brat. Novel inhibitor of GBM stem cells targets unique CREB & Myc-mediated self-renewal pathways regulated by CDK5 [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 3897. doi:10.1158/1538-7445.AM2017-3897
Abstract 3909: Investigating the role of ANXA2R in metastatic prostate cancer
Authors: Torga Gonzalo , Pienta Kenneth J. 
Published: July 2017

Abstract
Skeletal metastasis is the most life-threatening complication in prostate cancer. The molecular mechanisms behind the interactions between prostate cancer and the bone marrow premetastatic niche remain unknown. Understanding and preventing such interactions could lead to new promising therapeutic strategies against lethal prostate cancer. Annexin 2 receptor (ANXA2R) was originally identified as a cell surface receptor for Annexin 2 (ANXA2) that mediates the stimulatory effects of ANXA2 during osteoclastic activation and osteoblast mineralization. Moreover, ANXA2R is able to induce apoptosis independent of its ligand, partially through activating caspases using non-conventional apoptotic pathways. Osteoblasts and marrow endothelial cells express ANXA2 which functions as a regulator of hematopoietic stem cell engraftment. Previous studies demonstrated blocking ANXA2 or its receptor prevents prostate cancer cells from establishing bone metastases in mouse models. It has been recently proven that ANXA2R does not bind to ANXA2 directly but to S100A10 present in the complex annexin A2 heterotetramer (AIIt), composed of 2 ANXA2 bound to a S100A10 dimer. Higher levels of ANXA2 and S100A10 are associated with proliferating and invasive cancers and correlate with poor prognosis. However, the loss of ANXA2 expression appears to be specific for prostate cancer. Previous work on prostate cancer has focused solely on ANXA2 as a ligand. In this study, we demonstrate that S100A10 and ANXA2 are co-localized in prostate cancer, and their expression and ANXA2R levels vary with grade in primary tumors as well as within the different metastatic sites. Given prostate cancer cells as well as bone marrow stroma can simultaneously express the ligand and receptor and levels of AIIt decrease with tumor stage in the primary site, we hypothesize prostate cancer cells require S100A10 and not only ANXA2 to spread to bone and other tissues. ANXA2R could act as a dependence receptor, mediating withdrawal-induced programed cell death in prostate cancer cells in the absence of AIIt. Furthermore, AIIt-ANXA2R interactions between prostate cancer cells and the premetastatic bone marrow niche might play an important role in the development of skeletal metastasis by inducing selective pressures on prostate cancer cells to metastasize to the bone marrow which is abundant of AIIt.
Citation Format: Gonzalo Torga, Kenneth J. Pienta. Investigating the role of ANXA2R in metastatic 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 3909. doi:10.1158/1538-7445.AM2017-3909
Abstract 3912: Pancreatic cancer cell interaction with platelets impedes cell cycle progression and increases viability
Authors: Cannon Andrew C. , Kumar Sushil , Hall Bradley , Bhatia Rakesh , Singh Rakesh , Batra Surinder 
Published: July 2017

Abstract
Background: Metastasizing cancer cells rapidly associate with platelets in circulation, but the nature and functional consequences of this interaction have yet to be fully elucidated. Here we investigated the physical interaction of platelets with pancreatic cancer (PC) cells and the contribution of platelet-derived platelet factor 4 (PF4) mediated signaling in PC cells.
Methods: Immunohistochemistry (IHC) and western blot analysis were performed to characterize the expression of PF4 receptor, CXCR3, in 42 Whipple samples and 8 PC cell lines respectively. Physical interaction of human platelets with PC cell lines and its impact on PC cell proliferation in low attachment conditions was analyzed by flow cytometry. Cell viability was assayed by MTT analysis. Immunofluorescence analysis was performed to evaluate PF4 induced autophagy.
Results: IHC and western blot analysis in Whipple samples showed CXCR3 expression in 86 percent of the pancreatic tumors and on all the tested PC cell lines respectively. Flow cytometry demonstrated that 24 percent of Capan1 cells interacted with platelets. Interestingly, incubation of platelets with cell-cycle-synchronized Capan1 cells under low attachment conditions inhibited the proliferation of PC cells (~10 percent) at 24 but not 48 hours. This effect was abrogated by pharmacological inhibition of CXCR3 with AMG487. Concurrently, the viability of Capan1 cells grown in low attachment conditions and treated with platelets for 72 hours was greater than that of control and AMG487 with platelets treated groups as assessed by MTT assay. Mechanistic studies suggested that recombinant PF4 augments autophagosome formation as an early event and increases the expression of p21 as a late event. Of note, both LC3 punctation and p21 expression are abrogated by concomitant incubation with PF4 and AMG487.
Conclusion: Platelets appear to rapidly interact with cancer cells in suspension. Additionally, in a PF4-CXCR3 signaling dependent manner, platelets inhibit cell cycle progression and increase PC cell viability in low attachment conditions. Cumulatively, these data suggest that platelets aid in the metastatic dissemination of pancreatic cancer cells.
Citation Format: Andrew C. Cannon, Sushil Kumar, Bradley Hall, Rakesh Bhatia, Rakesh Singh, Surinder Batra. Pancreatic cancer cell interaction with platelets impedes cell cycle progression and increases viability [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 3912. doi:10.1158/1538-7445.AM2017-3912
Abstract 3914: KLF4-dependent perivascular plasticity enhances pre-metastatic niche formation and metastasis
Authors: Murgai Meera , Ju Wei , Eason Matthew , Kline Jessica , Kaplan Rosandra N. 
Published: July 2017

Abstract
Metastasis causes most cancer deaths, and new therapies that are based on a deeper understanding of this process are required to improve patient survival. Metastatic tumor cell colonization and growth is facilitated by a pre-metastatic niche microenvironment composed of hematopoietic cells, stromal cells, and extracellular matrix that support tumor survival and growth. Perivascular cells, including vascular smooth muscle cells (vSMCs) and pericytes, are a key cell population involved in new vessel formation critical to primary tumor development. Given the well-described plasticity of perivascular cells, we sought to determine whether perivascular cells regulate tumor cell survival and proliferation at metastatic sites. Using perivascular cell-specific and pericyte-specific lineage tracing models, we demonstrated that perivascular cells lose traditional vSMC/pericyte marker expression in response to tumor-secreted factors, and exhibit increased proliferation, migration and extracellular matrix (ECM) synthesis. Expression of the pluripotency gene Klf4 is increased and is critical for this phenotypic transition to a less differentiated state characterized by increased proliferation and ECM production. Genetic inactivation of Klf4 specifically in perivascular cells decreases pre-metastatic perivascular cell proliferation and consequently integrin-fibronectin dependent tumor metastasis. Our data reveal a previously unidentified role for perivascular cells in pre-metastatic niche formation, and suggest that modulation of stromal cell plasticity may provide a novel strategy for limiting metastasis.
Citation Format: Meera Murgai, Wei Ju, Matthew Eason, Jessica Kline, Rosandra N. Kaplan. KLF4-dependent perivascular plasticity enhances pre-metastatic niche formation and 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 3914. doi:10.1158/1538-7445.AM2017-3914
Abstract 3922: NR2F1 limits dissemination and stemness of early breast cancer cells
Authors: Sosa Maria Soledad 
Published: July 2017

Abstract
Tumor cells derived from MMTV-Neu mouse models or human ErBb2+ primary tumors are known to be able to complete all steps of the metastatic cascade. However, new evidence show that Neu+ early cancer cells derived from early stages of tumor progression (before detection of palpable tumors), can disseminate and, as disseminated cancer cells (early DCCs), enter a non-proliferative state for prolonged periods of time at secondary organs. We recently showed that early DCCs contributed to metastasis formation together with late-arriving DCCs (those coming from overt tumors). However, the mechanisms that would allow these early cancer cells, considered sessile and with few genetic alterations, to complete all steps of metastasis are unknown. Here we report that downregulation of the orphan nuclear receptor NR2F1 in Neu+ early cancer mammary epithelial cells (MECs) further activated a motile phenotype and this was coincident with previously described detection of circulating cancer cells (CCCs) and lung and bone marrow DCCs in MMTV-Neu mouse model. Knock down of basal NR2F1 levels in Neu+ early cancer cells induced cell motility, loss of laminin-V deposition, β-catenin delocalization from the membrane, dramatic loss of E-cadherin junctions and increased percentage of leader cells positive for CK14 and PRRX1 staining. Interestingly, TWIST and PRRX1 levels became upregulated upon NR2F1 depletion in 3D structures. These results suggest that NR2F1 expression maintains epithelial identity and suppresses epithelial-mesenchymal transition (EMT). Knock down of NR2F1 in Neu+ early cancer cells enhanced mammosphere formation efficiency and this was accompanied by upregulation of the pluripotency transcription factor NANOG and EMT master regulator TWIST. Interestingly, early dormant DCCs (negative for proliferation markers) showed re-expression of NR2F1 levels while micrometastases (cycling cells) had reduced levels of NR2F1. This result suggests that downregulation of NR2F1 in early DCCs may contribute to the dormancy escape of early DCCs and consequently metastatic relapse. Our findings provide for the first time evidence that NR2F1 functions as a suppressor of stemness and dissemination during early stages of tumor progression. We propose that therapies that restore expression of NR2F1 might limit early dissemination and the progression of early and late-arriving DCCs toward metastatic outgrowth.
Citation Format: Maria Soledad Sosa. NR2F1 limits dissemination and stemness of early breast 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 3922. doi:10.1158/1538-7445.AM2017-3922
Abstract 3932: Dual role of p120ctn in cancer: epithelial vs mesenchymal
Authors: Fonseka Pamali , Mathivanan Suresh , Liem Michael , Atukorala Ishara 
Published: July 2017

Abstract
Neuroblastoma, a paediatric cancer, accounts for 15% of childhood cancer mortality. Even though neuroblastoma is an aggressive cancer, the exact mechanisms by which the cells resist treatment is poorly understood. Here, we hypothesise that neuroblastoma cells have high expression of mesenchymal markers and hence could attribute to the aggressive phenotype. P120ctn is downregulated in epithelial cancers and is known to play a major role in EMT and aggressiveness. In this study, immunohistochemical staining of neuroblastoma patient tissues suggested that p120ctn is highly abundant. Hence, the role of p120ctn and N-Myc in neuroblastoma aggressiveness was investigated by using RNA interference. Amplification of N-Myc oncogene occurs in 20% of neuroblastoma patients and is considered high risk as it correlates with aggressiveness and poor prognosis. Interestingly, knockdown of p120ctn down regulated N-Myc both at mRNA and protein levels. Upon knockdown of p120ctn and N-Myc, the proliferation, invasion and migration of neuroblastoma cells were significantly reduced. Quantitative proteomic and qPCR analysis of the wild type and knockdown cells revealed that p120ctn knockdown cells underwent mesenchymal-to-epithelial transition. Confocal microscopy and Western blotting analysis of subcellular fractionation showed nuclear accumulation of β-catenin upon p120ctn knockdown. Once in the nucleus, β-catenin activated Wnt signalling pathway and up regulated Wnt target genes including C-Myc. Interestingly, down regulation of p120ctn sensitised the neuroblastoma cells to doxorubicin. Currently, there is no published study that explores the role of p120ctn in neuroblastoma. However, these findings are contradictory to scientific literature in the context of the functional role of p120ctn in epithelial cancer. Hence to validate our findings, we established knockdown of p120ctn in epithelial colorectal cancer cells. Consistent with the literature, knockdown of p120ctn induced EMT, proliferation and migration. These results suggest that the role of p120ctn is cell type dependent. Overall, the findings from this study suggest that p120ctn plays a pivotal role in progression of neuroblastoma.
Citation Format: Pamali Fonseka, Suresh Mathivanan, Michael Liem, Ishara Atukorala. Dual role of p120ctn in cancer: epithelial vs mesenchymal [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 3932. doi:10.1158/1538-7445.AM2017-3932
Abstract 3965: Epithelial membrane protein-2 is a novel regulator of immune editing in breast cancer
Authors: Tsui Jessica , Ashki Negin , Chang Yuling , Patel Deven , Sjarif Jasmine , Wadehra Madhuri 
Published: July 2017

Abstract
Cancer immuno-editing is a process that describes the interaction between immune cells and tumor cells. This interaction can result in elimination of a developing tumor, tumor dormancy, or tumor cells that are capable of surviving in an immune-competent host. We have recently uncovered a novel mechanism of immunoediting by the tetraspan protein Epithelial membrane protein or EMP2. We propose that EMP2 serves as a bridge between innate and adaptive immunity via tumor mediated type I interferon expression. Most tumor cells evade the immune system through suppression or ignorance. EMP2 levels promote type I interferon expression which was found to correlate with PDL1 expression in a number of cell lines. Concordantly, in vivo, in multiple breast cancer cell lines, EMP2 promoted tumor growth. In contrast, reduction in EMP2 levels correlated with a reduction in tumor size and a corresponding increase in tumor associated macrophages. Given that tumors with lower levels of EMP2 grow poorly, we hypothesized that targeting EMP2 may provide a therapeutic benefit. Recently, we have developed a panel of novel IgG1 monoclonal antibodies to EMP2 and tested their ability to treat both xenograft and syngeneic mouse models. Our results show that anti-EMP2 IgG1 significantly reduces tumor load in both models in part through the recruitment of M1 macrophages. To explore this observation more fully, experiments using murine syngeneic models were employed. Anti-EMP2 therapy elicits a robust ADCC response, producing an immune infiltrate rich in macrophages, NK cells, and lymphocytes. In addition, we show that CD8 cells show reduced exhaustion in the presence of anti-EMP2 antibodies. Conclusions: EMP2 is a protein upregulated in a number of cancers in women including breast, ovarian, and endometrial tumors. Our work collectively show that EMP2 is a novel immune regulator where its expression creates an immunosuppressive tumor microenvironment. We thus predict that targeting EMP2 may improve therapeutic outcomes for cancers in women.
Citation Format: Jessica Tsui, Negin Ashki, Yuling Chang, Deven Patel, Jasmine Sjarif, Madhuri Wadehra. Epithelial membrane protein-2 is a novel regulator of immune editing in 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 3965. doi:10.1158/1538-7445.AM2017-3965