bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1431: Id4 inhibits cancer metastasis through EMT regulation in lung cancer
Authors: Pan Szu-Hua , Hsu Yuan Ling , Hung Pei-Fang , Wang Chia-Jen , Wang Chi-Chung 
Published: August 2015

Abstract
Lung cancer is the leading cause of cancer related deaths worldwide. Delayed diagnosis and early metastasis are the major unsolved obstacles for most physicians in treating lung cancer patients. Thus, identifying novel metastatic genes and their action mechanisms involved in lung cancer progression and metastasis may provide new insights into the pathogenesis and management of lung cancer treatment. In a previous genome-wide gene expression profiling analysis using an invasion cancer cell lines model, we identified a panel of 589 genes whose expression was correlated with cell invasiveness. And Inhibitor of DNA binding 4 (Id4) was one of these candidates. In this study, we demonstrate that the expression of Id4 was inversely associated with cell invasiveness in different lung cancer cell lines. Through manipulating the expression of Id4, we found that the expression of Id4 not only attenuate cell migration and invasion in vitro, but also affect the regulation of Epithelial-mesenchymal transition (EMT), a critical step for cancer metastasis.
Additionally, we demonstrated that the expression Id4 was inversely correlated with lung cancer metastasis in vitro and in vivo and the reason Id4 affects metastasis probably is the regulation of EMT procession. Our data showed that Id4 could regulate EMT pathway by controlling the expression of Slug, a well-known EMT regulator, and recovering promoter activity of E-cadherin. Collectively, Id4 is a tumor suppressor in lung cancer, it can down-regulate EMT by reversing E-cadherin expression that represses by Slug. How to translate this research result for clinical application and develop potential therapeutic strategy for lung cancer treatment is our work in the future.
Citation Format: Szu-Hua Pan, Yuan Ling Hsu, Pei-Fang Hung, Chia-Jen Wang, Chi-Chung Wang. Id4 inhibits cancer metastasis through EMT regulation in lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1431. doi:10.1158/1538-7445.AM2015-1431
Abstract 1432: Role of ubiquitin-specific proteases 47 in epithelial-mesenchymal transition
Authors: Choi Bae-Jung , Surh Young-Joon 
Published: August 2015

Abstract
Metastatic spread from primary tumor is the last phase of cancer development. Approximately 90% of deaths from cancer are caused by metastasis. During the transition from a benign tumor to a metastatic one, tumor cells lose cell-cell contacts and gain cell motility for invasion. This is called epithelial-mesenchymal transition (EMT). EMT is considered to be a critical contributor of cancer metastasis. Hypoxia, which plays a critical role in development and tumor progression, orchestrates EMT through the coordinated regulation of different EMT regulators.
In this study, we found that a series of ubiquitin specific proteases (USP), particularly USP47, were induced in human colon cancer cells (DLD-1, HT-29 and SW-480) under the hypoxic condition based on cDNA microarray data. USPs are a subfamily of deubiquitinating enzymes (DUB) that primarily belong to the cysteine protease family and are known to remove the monoubiquitin and polyubiquitin chains from specific target proteins. Knockdown of USP47 substantially decreased expression of mesenchymal markers. Furthermore, hypoxia-inducible factor (HIF), especially HIF-2α, was found to regulate transcription of USP47. These results suggest USP47 as a novel regulator of EMT under hypoxic conditions.
Citation Format: Bae-Jung Choi, Young-Joon Surh. Role of ubiquitin-specific proteases 47 in epithelial-mesenchymal transition. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1432. doi:10.1158/1538-7445.AM2015-1432
Abstract 1433: CDKL2 promotes epithelial-mesenchymal transition and breast cancer progression
Authors: Li Linna , Chang Jeffrey , Du Guangwei , Amato Robert , Li Wenliang 
Published: August 2015

Abstract
The epithelial-mesenchymal transition (EMT) confers mesenchymal properties on epithelial cells and has been closely associated with the acquisition of aggressive traits by epithelial cancer cells. To identify novel regulators of EMT, we carried out cDNA screens that covered 500 human kinases. Subsequent characterization of candidate kinases led us to uncover cyclin-dependent kinase-like 2 (CDKL2) as a novel potent promoter for EMT and breast cancer progression. CDKL2-expressing human mammary gland epithelial cells displayed enhanced mesenchymal traits and stem cell-like phenotypes, which was acquired through activating a ZEB1/E-cadherin/beta-catenin positive feedback loop and regulating CD44 mRNA alternative splicing to promote conversion of CD24-high cells to CD44-high cells. Furthermore, CDKL2 enhanced primary tumor formation and metastasis in a breast cancer xenograft model. Notably, CDKL2 is expressed significantly higher in mesenchymal human breast cancer cell lines than in epithelial lines, and its over-expression/amplification in human breast cancers is associated with shorter disease-free survival. Taken together, our study uncovered a major role for CDKL2 in promoting EMT and breast cancer progression.
Citation Format: Linna Li, Jeffrey Chang, Guangwei Du, Robert Amato, Wenliang Li. CDKL2 promotes epithelial-mesenchymal transition and breast cancer progression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1433. doi:10.1158/1538-7445.AM2015-1433
Abstract 1435: Role of PRKD2 in HSP90- and hypoxia-mediated epithelial-to-mesenchymal transition
Authors: Azoitei Ninel , Becher Alexander , Diepold Kristina , Bobrovich Susanne , Brunner Cornelia , Chiosis Gabriela , Fröhling Stefan , Johan van Lint , Scholl Claudia , Seufferlein Thomas 
Published: August 2015

Abstract
The protein kinase D (PRKD) family of serine/threonine kinases belongs to the calcium/calmodulin-dependent protein kinase superfamily and comprises three isoforms, PRKD1, PRKD2 and PRKD3. We have recently identified PRKD2 as a novel client of HSP90 chaperone in several cancer cell lines. Depletion of PRKD2 protein following pharmacologic inhibition of HSP90 was associated with tumor cell death in vitro and in vivo. Furthermore, abrogation of PRKD2 in cancer cells prevented hypoxia-induced accumulation and promoter activity of HIF-1a, an oxygen sensor also shown to be regulated by HSP90. Since, both HSP90 and hypoxia/HIF-1a regulate epithelial-to-mesenchymal transition (EMT), we sought to investigate the role played by PRKD2 in this process.
Here we report that ectopic expression of PRKD2 was associated with a change in morphology, from epithelial polarized to a spindle-like phenotype, in lung and pancreatic cancer cells. This observation was associated with impaired E-cadherin and augmented vimentin protein levels. Pharmacologic inhibition of HSP90 was associated not only with PRKD2 degradation but also with decreased vimentin expression. However, the higher remaining PRKD2 levels after HSP90 inhibition of tumor cells expressing ectopic PRKD2 partially restored the vimentin expression suggesting a contribution of kinase to the chaperone-supported EMT. Incubation of cancer cells under low oxygen atmosphere showed decreased epithelial marker proteins and elevated vimentin levels, which was further enhanced by overexpressing PRKD2 suggesting that PRKD2 is involved in hypoxia-triggered EMT process. The fact that PRKD2 is able to interact with hypoxia-stabilized HIF-1a, which regulates EMT by controlling expression of Twist, a basic helix-loop-helix transcription factor reported to repress E-cadherin, suggests that PRKD2 may influence crucial EMT molecules via HIF-1a. Altogether, these findings 1) suggest PRKD2 as a crucial modulator of HSP90- and hypoxia-mediated EMT process, 2) suggest PRKD2 ablation through HSP90 inhibition as a potential therapeutic strategy in cancer with immediate implementation since several chaperone inhibitors are in clinical trials and 3) promote the intensification of designing specific PRKD2 inhibitors and their implementation in targeted therapy in human cancer.
Citation Format: Ninel Azoitei, Alexander Becher, Kristina Diepold, Susanne Bobrovich, Cornelia Brunner, Gabriela Chiosis, Stefan Fröhling, van Lint Johan, Claudia Scholl, Thomas Seufferlein. Role of PRKD2 in HSP90- and hypoxia-mediated epithelial-to-mesenchymal transition. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1435. doi:10.1158/1538-7445.AM2015-1435
Abstract 1437: The activity of plasma membrane V-ATPases is critical for the invasion of breast cancer cells
Authors: Cotter Kristina , Capecci Joseph , Sennoune Souad , Huss Markus , Maier Martin , Martinez-Zaguilan Raul , Forgac Michael 
Published: August 2015

Abstract
The V-ATPases are a family of ATP-driven proton pumps that have been implicated in breast cancer cell invasion. V-ATPases are found both intracellularly and on the plasma membrane of specialized acid-secreted cells and invasive cancer cells. As available inhibitors of the V-ATPase are membrane-permeable, it has not yet been examined whether intracellular or plasma membrane pumps are critical for invasiveness. It has been proposed that V-ATPases promote invasiveness by localizing to the plasma membrane. To test this hypothesis, we utilized two approaches to specifically inhibit the V-ATPases at the plasma membrane. First, we stably transfected invasive MB231 breast cancer cells with a V5-tagged construct of the membrane-embedded subunit c. This allows for extracellular expression of the V5 epitope. We then found that addition of an anti-V5 antibody specifically inhibited plasma membrane V-ATPase activity as well as in vitro invasion and migration of MB231 cells. Second, we utilized a biotin-conjugated form of the specific V-ATPase inhibitor bafilomycin to inhibit plasma membrane pumps. When bound to streptavidin, this compound is membrane impermeable. Addition of streptavidin-bound biotin-bafilomycin also inhibited in vitro invasion and migration of MB231 cells. These studies suggest that V-ATPases at the plasma membrane play a critical role in breast cancer cell invasion. We hypothesize that plasma membrane V-ATPases participate in invasion by creating an acidic microenvironment that promotes the activity of pH-dependent proteases. Overall, these results have significant implications for targeting the pump to prevent breast cancer metastasis.
Citation Format: Kristina Cotter, Joseph Capecci, Souad Sennoune, Markus Huss, Martin Maier, Raul Martinez-Zaguilan, Michael Forgac. The activity of plasma membrane V-ATPases is critical for the invasion of breast cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1437. doi:10.1158/1538-7445.AM2015-1437
Abstract 1441: Adapting the Syngraft mouse model to study metastatic recurrence of pancreatic cancer
Authors: Dudgeon Crissy , Tsang Ashley , Campbell Neil , Collisson Eric , Carpizo Darren 
Published: August 2015

Abstract
Pancreatic cancer is one of the most aggressive human malignancies with a 5-year survival rate for all stages of only 6%. While surgery remains the most effective treatment for pancreatic cancer, the majority of patients that undergo resection go on to die of pancreatic cancer recurrence. The biology of pancreatic recurrence is poorly understood due to the lack of sufficient mouse models to study this aspect of the disease. Our laboratory has adapted the Syngraft mouse model in order to study metastatic recurrence of pancreatic cancer. The Syngraft model is an orthotopic syngeneic mouse model using a pancreatic tumor cell line derived from the genetically engineered model (KrasG12D/+; Ink4a flox/flox) that has been modified with lentiviral vectors expressing mCherry and luciferase. After orthotopic injection, tumor formation was detected with the IVIS Spectrum using injected luciferin. Mice underwent distal pancreatectomy with spleenectomy when the primary pancreatic tumor measured ∼107 photons/sec/cm2, with a mean time to surgical resection at 19 days. Mice were then followed for metastatic recurrence to the liver using the IVIS Spectrum, with a mean time to recurrence of 23 days. We were able to establish a rate of metastatic recurrence in the Syngraft mouse model of 41% to the liver. Research is ongoing to enhance the metastatic efficiency of the injected cell lines and to further characterize the model for evidence of single cell and micrometastases in the liver. This model holds potential to be a useful tool to study the cell and molecular biology of pancreatic cancer recurrence.
Citation Format: Crissy Dudgeon, Ashley Tsang, Neil Campbell, Eric Collisson, Darren Carpizo. Adapting the Syngraft mouse model to study metastatic recurrence of pancreatic cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1441. doi:10.1158/1538-7445.AM2015-1441
Abstract 1447: Functional genomics identifying a TIS1-HIF-NOTCH signaling orchestrating epithelial-mesenchymal transition for tumor invasion
Authors: Hsieh Sen-Yung 
Published: August 2015

Abstract
Human hepatocellular carcinoma (HCC) is characterized by frequent local invasion and recurrence, which are strongly associated with poor overall survival of HCC patients. Epithelial-mesenchymal transition (EMT) is an initiating event driving tumour invasion and metastasis. However, the molecular mechanisms of EMT in HCC remains largely unknown. We have performed a human kinome/phosphatome RNAi screen to identify novel genes that are involved in invasion and metastasis of HCC cells using Hep3B, a low motile HCC cell line, and identified TIS1 (Tumor Invasion Suppressor 1) as a potential cell motility suppressor. Mechanistic studies revealed that TIS1 was a novel actin binding protein that sequestrated globular actins and prevented actin filament (F-actin) formation, thereby suppressing the formation of filopodia, lamillepodia and invadopodia. Silencing of TIS1 enhanced EMT and tumor cell migration and invasion. Notably, F-actin polymerization induced by TIS1 silencing led to activation of the NOTCH signalling via induction of HIF1A, which in turn further supports EMT for sustaining tumor invasion and metastasis. Clinically, TIS1 was frequently downregulated in many human cancers including HCC and strongly associated with tumor recurrence, local invasion, and poor prognosis. In conclusion, a novel TIS1-HIF/NOTCH signaling forms a positive feedback loop sustainingly driving mesenchymal transition of cancer cells for invasion and metastasis. This TIS1-mediated tumor invasion and metastasis signaling may serve as therapeutic targets for prevention and treatment of HCC invasion and metastasis.
Citation Format: Sen-Yung Hsieh. Functional genomics identifying a TIS1-HIF-NOTCH signaling orchestrating epithelial-mesenchymal transition for tumor invasion. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1447. doi:10.1158/1538-7445.AM2015-1447
Abstract 1448: Dynamic chromatin modification by tumor secreted Hsp90 modulates EMT and tumor invasion
Authors: Nolan Krystal D. , Hance Michael W. , Franco Omar E. , Hayward Simon W. , Isaacs Jennifer S. 
Published: August 2015

Abstract
Tumor metastasis is the main cause of prostate cancer lethality. Pathological reactivation of the developmental genetic program epithelial to mesenchymal (EMT) is associated with increased tumorigenesis and invasion, and is considered a primary culprit for tumor dissemination. Hallmarks of EMT include upregulation of the core transcription factors Zeb and Snail, concomitant with suppression of the junctional protein E-cadherin. Overexpression of the epigenetic repressor EZH2, a histone methyltransferase, is also implicated in EMT activation. Although these molecular events are well known to trend with cancer progression, a paucity of knowledge exists regarding identification of the clinically-relevant upstream triggers capable of setting these events into motion. We recently demonstrated that tumor secreted extracellular heat shock protein 90 (eHsp90) initiates EMT events in prostate cancer cells. Moreover, we reported the presence of surface Hsp90 in human prostatectomy specimens, an event highly correlated with elevated expression of a subset of EMT transcripts. The present study reveals novel mechanistic aspects of eHsp90 action. We define an epigenetic function for eHsp90 as a significant regulator of EZH2 expression and activity. This eHsp90-EZH2 axis was found to govern a majority of eHsp90's pro-EMT activity in vitro, and was essential for E-cadherin suppression and tumor invasion in vivo. Upon further investigation, it was revealed that eHsp90 sustained ERK activation. This eHsp90-ERK pathway was required for the increased expression of EZH2, as well as for its directed recruitment to the E-cadherin promoter. Moreover, eHsp90-ERK signaling augmented the epigenetic landscape of Zeb and Snail towards a profile permissive for transcriptional activation. Hence, our findings indicate that eHsp90-ERK signaling has profound effects upon key drivers of cancer progression via the concerted action of epigenetic modulation of EMT effectors and increased EZH2 expression. Collectively, these data support a model wherein tumor eHsp90 functions as an upstream rheostat for EZH2 expression and activity to orchestrate mesenchymal properties and coincident aggressive behavior. Importantly, our findings suggest that eHsp90 may be a clinically relevant instigator in the transition from localized to invasive disease.
Citation Format: Krystal D. Nolan, Michael W. Hance, Omar E. Franco, Simon W. Hayward, Jennifer S. Isaacs. Dynamic chromatin modification by tumor secreted Hsp90 modulates EMT and tumor invasion. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1448. doi:10.1158/1538-7445.AM2015-1448
Abstract 1452: In vivo TK-NOG liver-humanized model to predict patient pharmacological profile of anti-cancer agents
Authors: Mignard Caroline , Duchamp Olivier , Nemati Fariba , Cassoux Nathalie , Roman-Roman Sergio , Ohnishi Yasuyuki , Suemizu Hiroshi 
Published: August 2015

Abstract
To overcome some limitations of existing models, CIEA developed a novel experimental in vivo liver-humanized model. To do this, a herpes simplex virus type 1 thymidine kinase (HSVtk) transgene was expressed within the liver of highly immunodeficient NOG mice (TK-NOG). Mouse liver cells expressing this transgene were ablated after a brief exposure to a non-toxic dose of ganciclovir (GCV), and transplanted human liver cells are stably maintained within the liver (humanized TK-NOG) without exogenous drug. We have shown that the reconstituted liver is mature and functional and could generate:
1)A human-specific profile of anti-cancer drug metabolism. The humanization of the liver of TK-NOG mice modified the pharmacokinetic profile of the sorafenib anti-cancer agent. We were also able to detect the N-oxide metabolite of the sorafenib in humanized mice with a ratio of 8% of the non-metabolized sorafenib, in comparison to a 10% ratio in patients and 0% (not detectable) in non-humanized mice.
2)An efficient environment for metastatic cell homing in patient-derived-xenograft (PDX) model of UVeal melanoma. In two PDX UVeal melanoma models orthotopically xenografted in liver-humanized TK-NOG mice, we were able to detect liver metastasis, ranging from 10 to 50% of animals, whereas metastases have never been detected in non-humanized mice.
This novel in vivo system provides an optimized platform for increasing our predictivity of patient anti-cancer drug metabolism, potential toxicology, and efficacy.
Citation Format: Caroline Mignard, Olivier Duchamp, Fariba Nemati, Nathalie Cassoux, Sergio Roman-Roman, Yasuyuki Ohnishi, Hiroshi Suemizu. In vivo TK-NOG liver-humanized model to predict patient pharmacological profile of anti-cancer agents. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1452. doi:10.1158/1538-7445.AM2015-1452
Abstract 1454: Patient-derived xenograft model using peritoneal fluid of gastric cancer patients
Authors: Kim Jeong Min , Lee Won Suk , Kwon Woo Sun , Park Han Na , Lee Hye Rin , Kim Hyun Myong , Kim Tae Soo , Kim Hyunki , Roh Jae Kyung , Chung Hyun Cheol , Rha Sun Young 
Published: August 2015

Abstract
Peritoneal metastasis is the most frequent pattern of recurrence in patients with gastric cancer (GC). Patient derived xenograft (PDX) models using peritoneal fluid have been required to understand its biology and for the drug screening. So, we established the PDX model by peritoneal fluid in stage IV GC patients. First, we confirmed the preparation condition of peritoneal fluid cells for PDX model as approximately 1×107 cells in PBS. Then, we observed the engraftment rate of PDX which was 15.8% (3 of 19 patients, P2, P10 and P11). The time to 100 mm3 tumor size at F1 of 3 models was 47 ± 1, 26.7 ± 0.6 and 68 days respectively. Then, we checked the change of serial engraftment rate until F3. The more passage was progressed, the higher engraft rate was, 75% (3 of 4 mice) to 90% (9 of 10 mice) at P2, 60% (3 of 5 mice) to 85% (17 of 20 mice) at P10 and 33.3% (1 of 3 mice) to 86.7% (13 of 15 mice) at P11. In addition, time to 100mm3 tumor size of engrafted PDXs was faster at F3 than F1 in all 3 cases (41.1% in P2, 46.4% in P10 and 47.5% in P11). Also, tumor doubling time showed decreased in all engrafted PDXs according to passage (70.8% in P2, 11.5% in P10 and 71.5% in P12). Then, we checked the re-engraftment rate after thawing the frozen F3 tissue section of P2. F4 PDXs were re-engrafted 100% (3/ 3 mice) after thawing, and time to 100mm3 tumor size and tumor doubling times were not different between F3 and F4. It means that freezing and thawing of tumor fragment did not affect to engraft. After that, we compared the characterization of F0 peritoneal fluid of patient, F1∼F3 PDX tumor and the cell line established from F0. The morphologies of them were comparable by H&E staining. Also, molecule expressions ofF0 to F3 and cell lines were analogous. The genetic alterations according to passages in F0 to F3 are on-going. As a result, we observed PDX from peritoneal fluid of advanced gastric cancer is feasible but various according to each patient. The PDX model by peritoneal fluid of GC patients might be helpful the biological understanding and drug development for personalized therapies.
Citation Format: Jeong Min Kim, Won Suk Lee, Woo Sun Kwon, Han Na Park, Hye Rin Lee, Hyun Myong Kim, Tae Soo Kim, Hyunki Kim, Jae Kyung Roh, Hyun Cheol Chung, Sun Young Rha. Patient-derived xenograft model using peritoneal fluid of gastric cancer patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1454. doi:10.1158/1538-7445.AM2015-1454