bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 276: Microtentacle stabilization during TGFβ-induced EMT as a new therapeutic target to reduce circulating tumor cell metastasis.
Authors: Slovic Jana , Vitolo Michele I. , Whipple Rebbecca A. , Boggs Amanda E. , Charpentier Monica S. , Bhandary Lekhana , Thompson Keyata , Martin Stuart S. 
Published: August 2014

Abstract
Circulating tumor cells (CTCs) have been identified as a predictive factor of patient outcome and disease progression in breast cancer. Solid tumor metastasis involves detachment of epithelial cells into the lymphatics or vasculature, and the subsequent reattachment in distant tissues to establish new tumors at metastatic sites. Our lab has identified tubulin-based protrusions, termed microtentacles (McTNs), which facilitate tumor cell re-attachment and can penetrate endothelial layers to promote the retention of CTCs in distant tissues. In the current study, we examine the role of the physiological cytokine, TGFβ, in the cytoskeletal changes that promote McTN formation. McTNs are induced during the epithelial-to-mesenchymal transition (EMT) that accompanies tumor progression, and previous studies have shown that TGFβ can promote an EMT in a pathologic setting, despite its normal role as an anti-proliferative factor. When we treated MCF10A nontumorigenic mammary epithelial cells and MCF-7 breast tumor cells with TGFβ, immunoblotting demonstrated changes in protein expression consistent with an EMT, such as increased vimentin and N-Cadherin and decreased E-Cadherin expression. Alongside these typical EMT-induced protein expression changes, levels of detyrosinated α-tubulin (Glu-tubulin) also increased, which is a marker of stabilized microtubules that also promotes McTN formation. Furthermore, immunofluorescence demonstrated that Glu-tubulin was highly diffuse in untreated cells, but became organized into distinct cytoplasmic filaments upon treatment of cells with TGFβ. Detached MCF10A and MCF-7 cells also showed increased McTNs following exposure to TGFβ. Real-time measurement of cell reattachment by electrical impedance demonstrated that the increased McTNs associated with TGFβ treatment resulted in more efficient and faster cell reattachment.
These results emphasize that the post-translational alterations in microtubules promoted by TGFβ can promote increased McTNs and that therapies targeting the molecular mechanisms underlying these TGFβ-induced cytoskeletal changes could provide new targets aimed at reducing CTC reattachment and metastasis.
Citation Format: Jana Slovic, Michele I. Vitolo, Rebbecca A. Whipple, Amanda E. Boggs, Monica S. Charpentier, Lekhana Bhandary, Keyata Thompson, Stuart S. Martin. Microtentacle stabilization during TGFβ-induced EMT as a new therapeutic target to reduce circulating tumor cell metastasis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 276. doi:10.1158/1538-7445.AM2013-276
Abstract 2763: Activity of dasatinib and potential escape mechanisms in diffuse intrinsic pontine glioma (DIPG) models.
Authors: Truffaux Nathalene , Dret Ludivine Le , Puget Stephanie , Vassal Gilles , Geoerger Birgit , Grill Jacques 
Published: August 2014

Abstract
Background
Diffuse intrinsic pontine glioma (DIPG) have a dismal prognosis and their biology is not yet well explored. Using an integrated molecular profiling approach we revealed PDGFRA gene amplification and mutations in the extracellular domain as a characteristic of the oligodendroglial subgroup in newly diagnosed pediatric DIPG. Therefore we explored the therapeutic potential of dasatinib, an inhibitor of the PDGFR, Src, and Ephrin tyrosine-kinases in newly developed DIPG models.
Materials and Methods
A unique panel of 12 DIPG cell lines has been established from fresh tumor material biopsies in newly diagnosed children with DIPG with a 100% success rate. Four were oligoastrocytomas Grade 2 and 3, five astrocytomas Grade 2, 1 GBM and 2 non further specified; two had a gain of the PDGFRA gene. Effects of dasatinib on proliferation, invasion and cytotoxicity in vitro were determined at concentrations of 0.001-1 μM using the Live-cell imaging assay of the IncuCyte system. Cell growth and cell invasion were monitored by confluence algorithm, and cytotoxicity was determined by loss of membrane integrity generating nuclear staining by a fluorescent live-cell imaging reagent. Tyrosine-kinase receptors (RTK) and downstream signaling expression was assessed by phospho-RTK array and Western blot analysis.
Results
Anti-proliferative effects of dasatinib were observed in all 6 cell lines tested with IC50s between 0.02-0.07 μM. This compared favorably with the sensitive adult glioma T98G cell line and the pediatric supratentorial glioma SF188 cell line (0.15 μM and 0.3 μM, respectively). Significant dose-dependent cytotoxic effects were observed in two DIPG cell lines (NEM145 and NEM 168) and anti-invasive effects were seen in all cells at 0.1 μM.
The two most sensitive cell lines exhibited PDGFRA activation and their primary tumors had a gain of PDGFRA. While Src was activated in all cell lines, we noticed that the less sensitive cell lines had MET overexpression.
Conclusion
Primary DIPG cell lines are highly sensitive in vitro to dasatinib suggesting its exploration is children with DIPG. Sensitivity may be linked not exclusively to PDGFRA activation but also to Src activation. The role of MET activation in escape mechanisms is currently explored.
Citation Format: Nathalene Truffaux, Ludivine Le Dret, Stephanie Puget, Gilles Vassal, Birgit Geoerger, Jacques Grill. Activity of dasatinib and potential escape mechanisms in diffuse intrinsic pontine glioma (DIPG) models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2763. doi:10.1158/1538-7445.AM2013-2763
Abstract 2835: Combined stimulation of TLR9 and 4.1BB receptors enhances Trp2 peptide-mediated B16 melanoma regression by increasing Ag-specific CTL activity and infiltration to tumor sites.
Authors: Sin Jeong-Im , Ryoo Hun Mo 
Published: August 2014

Abstract
We previously reported that intratumoral electroporation (IT-EP) with IL-12 cDNA (IT-EP/IL12) led to the eradication of established B16 melanoma tumors in mice. Tumor eradication required the participation of CD8+ T cells, but not CD4+ T cells and NK cells. IT-EP/IL12 induced antigen-specific CD8+ T cell responses against the immunodominant Trp2180-188 epitope and generated a systemic response, resulting in significant therapeutic effects against distal, untreated tumors. In this study, we observed that when Trp2180-188 self-peptides were combined with the TLR9 agonist, CpG-oligodeoxynucleotide (ODN) for antitumor immune therapy, self-tolerance was broken, giving rise to induction of Trp2-specific CTL responses and some antitumor activity against established melanoma (7 mm in mean diameter). A combination of anti-4.1BB antibodies with Trp2 peptides plus CpG-ODN increased the antitumor regression rate from 0 to 75%. This effect was concomitant with greater induction of Ag-specific CD8+ CTLs and their infiltration into the tumor sites, highlighting the importance of combined stimulation of TLR9 and 4.1BB for achieving tumor eradication. These findings may have implications for designing peptide-based therapeutic vaccines for cancer-patients.
Citation Format: Jeong-Im Sin, Hun Mo Ryoo. Combined stimulation of TLR9 and 4.1BB receptors enhances Trp2 peptide-mediated B16 melanoma regression by increasing Ag-specific CTL activity and infiltration to tumor sites. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2835. doi:10.1158/1538-7445.AM2013-2835
Abstract 2929: HIF is necessary, but not sufficient for the hypoxia response.
Authors: Hu Cheng-Jun , Pawlus Matthew , Sena Johnny , Wang Liyi 
Published: August 2014

Abstract
Hypoxia is a common characteristic of many solid tumors. Hypoxia inducible factor HIF1α and HIF2α have been shown to drive malignant progression by activating genes involved in angiogenesis, proliferation, anaerobic metabolism, and other processes that enable tumor cells to survive or to escape their O2-deficient microenvironments. While the major players in the hypoxia-mediated HIFα protein stability and the functions of HIF1α/ARNT and HIF2c/ARNT proteins in activating hypoxia-inducible genes are well established, the role of other transcription factors and how HIF regulates its target genes in the hypoxic transcriptional response are much less understood. We report here that the “Signal Transducer and Activator of Transcription-3” (STAT3) and the basic-helix-loop-helix-leucine-zip transcription factor, upstream stimulatory factor-2 (USF2) are required for the hypoxic transcriptional response, specifically for hypoxic activation of HIF1 and HIF2 target genes respectively. Mechanistically, STAT3 (or USF2) activates HIF1 (or HIF2) target genes by binding to HIF1 (or HIF2) target gene promoters, interacting with HIF1α (or HIF2α) protein and recruiting co-activators CBP and p300 to form enhanceosome complexes that contain HIFα, USF2, CBP, p300 and RNA Pol II on HIF target gene promoters. Interestingly, we found that HIF1α/ARNT and HIF2α/ARNT activate their target genes by recruiting Brm/Brg-1 SWI/SNF complexes to remodel HIF target gene promoter and thus increase HIF target gene activation. These studies established additional players in hypoxic transcriptional response post HIFα protein stabilization by hypoxia. In addition, our studies also showed that co-activators USF2/STAT3 and HIF cooperatively promote the hypoxia response by recurring histone acetylases and chromatin remolding complexes respectively. Uncovering the role of STAT3 and USF2 in the hypoxia response established the foundation to specifically inhibit HIF1 or HIF2 activity for solid tumor treatment.
Citation Format: Cheng-Jun Hu, Matthew Pawlus, Johnny Sena, Liyi Wang. HIF is necessary, but not sufficient for the hypoxia response. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2929. doi:10.1158/1538-7445.AM2013-2929
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 3020: The gep protooncogene Gα12 mediates LPA-stimulated activation of CREB in ovarian cancer cells.
Authors: Ha Ji Hee , Dhanasekaran Danny , Ward Jeremy , Yang Yoon Mi , Kim Sang Geon , Varadarajalu Lakshmi 
Published: August 2014

Abstract
Lysophosphatidic acid (LPA), plays a critical role in the pathophysiology of ovarian cancers. Our previous studies have shown that LPA stimulates the proliferation of ovarian cancer cells through GNA12, the gep protooncogene Gα12. The present study is focused on identifying the Gα12-dependent mechanism through which LPA stimulates the proliferation of ovarian cancer cells. Using ovarian cancer cells in which the expression of Gα12 is silenced, we demonstrate here that Gα12-dependent mitogenic signaling by LPA involves the atypical activation of the transcription factor, cAMP-response element binding protein (CREB). Protein/DNA array analyses using LPA-stimulated Hey8 cells in which the expression of Gα12 was silenced indicated the potent but Gα12-dependent activation of CREB by LPA. After validating the array data with immunoblot analysis using antibodies specific to Ser133-phosphorylated active form of CREB, we demonstrate that the expression of the constitutively activated mutant of Gα12 stimulate the activation of CREB even in the absence of LPA whereas silencing of Gα12 abrogates such LPA-stimulated activation in multiple ovarian cancer cell lines. Furthermore, our results indicate that the robust activation of CREB by LPA is an early event, which can be monitored upon LPA stimulation from 3 minutes onwards. In addition, we establish that LPA/Gα12-dependent activation of CREB involves an atypical cAMP-independent mechanism involving Ras and ERK. More significantly, our findings indicate that the expression of the dominant negative mutant of CREB (S133A) leads to a reduction in LPA-stimulated increase in Cyclin A levels along with an attenuation of LPA-stimulated proliferation of these cells. Thus, these studies unravel a novel Gα12-dependent mechanism involving CREB through which LPA stimulates the proliferation of ovarian cancer cells.
Citation Format: Ji Hee Ha, Danny Dhanasekaran, Jeremy Ward, Yoon Mi Yang, Sang Geon Kim, Lakshmi Varadarajalu. The gep protooncogene Gα12 mediates LPA-stimulated activation of CREB in ovarian cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3020. doi:10.1158/1538-7445.AM2013-3020
Abstract 3031: The receptor tyrosine kinase layer of breast cancer cell lines is predictive of the response to therapeutic drugs.
Authors: Niepel Mario , Hafner Marc A. , Pace Emily A. , Schoeberl Birgit , Sorger Peter K. 
Published: August 2014

Abstract
Currently, clinicians use the levels of the hormone receptors for estrogen (ER) and progesterone (PR) and amplifications of the ErbB2 receptor tyrosine kinase (RTK) to distinguish three groups of breast cancers and guide the choice of therapeutic treatments. In this work we show that a limited number of measurements characterizing breast cancer cell lines at the level of RTKs can be used to predict cell line sensitivity to therapeutic inhibitors.
We chose a panel of approximately 40 breast cancer cell lines, treated them with 22 different growth factors and cytokines at a saturating and subsaturating dose for 10, 30, and 90 min and measured the phosphorylation of key kinases downstream of the receptors. In addition, we measured the expression and phosphorylation levels of approximately 20 RTKs under serum starvation conditions. We used the measurements to predict the GI50 values of the cell lines in response to over 45 therapeutic inhibitors by partial least square regression. We found that our measurements are sufficient to predict the response to about half of the drugs studied. The majority of drugs we are able to predict target RTKs directly or kinases immediately downstream of the receptors. In some cases we are able to predict the response to drugs that target processes seemingly unrelated to our measurements. We are currently exploring the data to uncover what drives sensitivity and resistance to drugs, gain mechanistic insight in the action of cancer therapeutics, and find predictors of drug response that may be useful in a clinical setting.
Our results suggest that a carefully selected set of measurements might be sufficient to classify responsiveness of breast cancers to a number of cancer drugs currently used in the clinic. This is particularly relevant in the case of cancers like triple negative breast cancers for which choosing effective treatment has proven difficult.
Citation Format: Mario Niepel, Marc A. Hafner, Emily A. Pace, Birgit Schoeberl, Peter K. Sorger. The receptor tyrosine kinase layer of breast cancer cell lines is predictive of the response to therapeutic drugs. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3031. doi:10.1158/1538-7445.AM2013-3031
Abstract 3034: Determining the profiles and parameters for gene amplification testing of growth factor receptors in lung cancer.
Authors: Pros Eva , Lantuejoul Sylvie , Sanchez-Verde Lydia , Castillo Sandra D. , Suarez-Gauthier Ana , Conde Esther , Cigudosa Juan C. , Lopez-Rios Fernando , Torres-Lanzas Juan , Castellví Josep , Ramon y Cajal Santiago , Brambilla Elisabeth , Sanchez-Cespedes Montse 
Published: August 2014

Abstract
Growth factor receptors (GFRs) are amenable to therapeutic intervention in cancer and it is important to select patients appropriately.
One of the mechanisms for activation of GFRs is gene amplification (GA) but discrepancies arising from the difficulties associated with data interpretation and the lack of agreed parameters confound the comparison of results from different laboratories. Here, we attempt to establish appropriate conditions for standardization of the determination of GA in a panel of GFRs. A NSCLC tissue microarray panel containing 302 samples was screened for alterations at ALK,
FGFR1, FGFR2, FGFR3, ERBB2, IGF1R, KIT, MET and PDGFRA by FISH, immunostaining and/or real-time quantitative RT-PCR. Strong amplification was found for FGFR1, ERBB2, KIT/PDFGRA and MET, with frequencies ranging from 1 to
6%. Thresholds for overexpression and GA were established. Strong immunostaining was found in most tumors with ERBB2, MET and KIT amplification, although some tumors underwent strong immunostaining in the absence of GA. KIT and PDFGRA were always co-amplified, but only one tumor showed PDGFRA overexpression, indicating that KIT is the main target.
Amplification of FGFR1 predominated in squamous cell carcinomas, although the association with overexpression was inconclusive. Interestingly, alterations at ALK,
MET, EGFR, ERBB2 and KRAS correlated with augmented levels of phospho-S6 protein, suggesting activation of the mTOR pathway, which may prove useful to pre-select tumors for testing.
Overall, here, we provide with parameters for the determination of GA at ERBB2, MET, KIT, and PDGFRA which could be implemented in the clinic to stratify lung cancer patients for specific treatments.
Citation Format: Eva Pros, Sylvie Lantuejoul, Lydia Sanchez-Verde, Sandra D. Castillo, Ana Suarez-Gauthier, Esther Conde, Juan C. Cigudosa, Fernando Lopez-Rios, Juan Torres-Lanzas, Josep Castellví, Santiago Ramon y Cajal, Elisabeth Brambilla, Montse Sanchez-Cespedes. Determining the profiles and parameters for gene amplification testing of growth factor receptors in lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3034. doi:10.1158/1538-7445.AM2013-3034
Abstract 3040: Cavin-1 alters oncogenic effects of caveolin-1 microdomains in prostate cancer.
Authors: Moon Hyeongsun , Lee C Soon , Sharma Sowmya , Inder Kerry , Black Debra , Lê Cao Kim-Anh , Winterford Clay , Ling Patrick ,   the Australian Prostate Cancer BioResource, Craik David , Parton Robert , Russell Pamela , Hill Michelle 
Published: August 2014

Abstract
Caveolin-1 is associated with prostate cancer progression and has been suggested to be a biomarker and therapeutic target. Mature caveolin-1 resides in lipid raft domains at the plasma membrane, where it forms caveolae upon co-expression of cavin-1 (also known as PTRF; polymerase I and transcript release factor). In the absence of cavin-1, caveolin-1 does not form caveolae but are found on flat membrane. To determine if oncogenic caveolin-1 in prostate cancer is present in caveolae, we examined the relative expression of caveolin-1 and cavin-1 in normal, non-malignant and malignant prostate tissues. We found that caveolin-1 is induced in prostate cancer without cavin-1, an expression pattern mirror in the PC3 cell line. Previously we showed that expression of cavin-1 in PC3 cells recruits flat membrane caveolin-1 to caveolae and reduced transmigration. Here we report that cavin-1 expression reduces tumour size and metastasis of PC3 cells in vivo, using an orthotopic prostate cancer xenograft mouse model. To determine if cavin-1 acts by neutralizing oncogenic caveolin-1, we expressed cavin-1 in caveolin-1 negative LNCaP and 22Rv1 cells. While caveolin-1 over-expression increased anchorage-independent growth of LNCaP and 22Rv1 cells, cavin-1 over-expression had no effect. Furthermore, co-expression of cavin-1 in LNCaP+caveolin-1 cells reversed caveolin-1 effect. Taken together, these results suggest that caveolin-1 in prostate cancer is present outside of caveolae, and caveola formation by cavin-1 co-expression alters the oncogenic effect of non-caveolar caveolin-1 microdomains.
Citation Format: Hyeongsun Moon, C Soon Lee, Sowmya Sharma, Kerry Inder, Debra Black, Kim-Anh Lê Cao, Clay Winterford, Patrick Ling, the Australian Prostate Cancer BioResource, David Craik, Robert Parton, Pamela Russell, Michelle Hill. Cavin-1 alters oncogenic effects of caveolin-1 microdomains in prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3040. doi:10.1158/1538-7445.AM2013-3040
Abstract 3047A: Differential subcellular localization and trafficking of RET isoforms.
Authors: Crupi Mathieu J. F. , Richardson Douglas S. , Mulligan Lois M. 
Published: August 2014

Abstract
The RET proto-oncogene encodes a receptor tyrosine kinase (RTK) necessary for development of the kidneys and enteric nervous system. Two distinct isoforms of the growth factor receptor arise through alternative splicing of the 3’ exons, and are termed RET9 and RET51 to denote the number of amino acids in each C-terminal tail. These isoforms induce unique transphosphorylation patterns on intracellular tyrosine residues, differentially bind downstream signalling proteins, and possess different intrinsic abilities to cause cellular transformation. Subcellular localization and trafficking of RTKs have increasingly been recognized as important post-receptor activation regulatory mechanisms, involving protein-protein interactions. Here, we explore the differential subcellular localization and trafficking of RET isoforms in human cell line models. We have observed that RET51 is efficiently matured and localized to the cell membrane, while immature RET9 accumulates in a perinuclear region and matures more slowly, leading to lower relative expression on the plasma membrane. Subsequent to RET activation, both isoforms at the cell surface are internalized through the clathrin coated-pit pathway into endosomes, where signaling persists. Although RET51 is internalized more rapidly than RET9, a portion of RET51 molecules recycles back to the plasma membrane, maintaining high expression levels at the cell surface. Recycling prevents efficient degradation of RET51, allowing for prolonged downstream signaling relative to RET9. We predict that progress through these trafficking steps is modulated by specific protein interactions between RET isoforms and sorting proteins, and these interactions are also determined at later stages by modifications on RET itself, most notably ubiquitination. Future studies could allow us to identify these key proteins/binding sites which may differ between RET9 and RET51. Since RET51 has a longer residency time in an endosomal compartment, where sustained Erk1/2 signaling promotes mitogenesis, this may in part explain the greater transforming potential of RET51. Together, our data suggest that differences in RET isoform subcellular localization and trafficking would lead to differences in signal transduction and may in part explain the functional differences observed between RET isoforms.
Citation Format: Mathieu J. F. Crupi, Douglas S. Richardson, Lois M. Mulligan. Differential subcellular localization and trafficking of RET isoforms. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3047A. doi:10.1158/1538-7445.AM2013-3047A