bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2886: Epigenetic regulation of MUC1 in NF-kB target gene expression of pro-inflammatory cytokines in colon cancer
Authors: Cascio Sandra , Sciurba Joshua , Finn Olivera 
Published: August 2015

Abstract
MUC1 is a transmembrane glycoprotein normally expressed at low levels in a fully glycosylated form on the apical surface of epithelial cells but it is found overexpressed and hypoglycosylated in human adenocarcinomas as well as sites of chronic epithelial inflammations. Aberrant glycosylation of MUC1 in cancer cells alters its normal function and affects the behavior of cancer cells. The MUC1 extracellular domain also participates in activation of the NF-kB family members such as phospho-IkBa and phospho-p65. Our data showed that the tumor form of MUC1, in association with p65, regulates the transcriptional activity of pro-inflammatory cytokines, including IL-6 and TNF-alpha, by binding to their promoter regions in both mouse and human cancer cells. Because proteomic analysis showed that MUC1 is able to interact directly with histone proteins, we hypothesized that MUC1 might influence the transcriptional activity of cytokines by inducing epigenetic modification.
Here, we explored MUC1/p65-regulated transcription of IL-6 and TNF-alpha in colon cancer cells and discovered that MUC1/p65 complex modulated the expression and interaction of histone methyltransferase Enhancer of Zeste protein-2 (EZH2) with pro-inflammatory cytokine promoters. Interestingly, the contribution of EzH2 in controlling the MUC1/p65-modulated cytokines expression was independent of its histone H3K27 methyltransferase activity but it shows novel properties in regulating chromatin remodeling that are currently under detailed investigation To investigate the in vivo significance of MUC1/p65-induced cytokines expression in the tumor microenvironment, we used human MUC1 transgenic mice that express MUC1 on the colonic epithelial cells, treated with azoxymethane to initiate and dextran sulfate sodium (AOM/DSS) to promote colorectal carcinogenesis. MUC1.Tg mice showed higher tumor incidence and decreased survival when compared with wild-type mice. Consistent with the in vitro data, NF-kB family members and EzH2 expression were higher in MUC1.Tg mice when compared to wild-type mice. In addition, the number of infiltrating macrophages strongly increased in AOM/DSS-treated colon tissues of MUC1.Tg mice. These are important findings that may explain the mechanism by which MUC1 and NF-kB regulate cancer progression.
Citation Format: Sandra Cascio, Joshua Sciurba, Olivera Finn. Epigenetic regulation of MUC1 in NF-kB target gene expression of pro-inflammatory cytokines in colon 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 2886. doi:10.1158/1538-7445.AM2015-2886
Abstract 2890: Single mouse trials, a concept using patient-derived tumor xenografts for large scale in vivo screens
Authors: Gredy Christina , Schüler Julia B. , Zanella Nina , Fiebig Heinz-Herbert , Metz Thomas 
Published: August 2015

Abstract
Patient-derived xenografts (PDX) passaged in immunocompromised mice are a well-established system for preclinical efficacy testing of anti-cancer agents. Typically, PDXs are pre-screened either in vitro or via molecular analysis, and selected models are then tested in groups of 8 to 12 mice to confirm or evaluate the efficacy of a treatment relative to a vehicle control group. This approach results in highly reliable and reproducible efficacy data. However, it is often desirable to test large panels of tumor models in vivo in order to properly take genetic diversity into account. Such experiments can be cost-prohibitive in conventional study layouts, which results in fewer models being tested.
The Single Mouse Trial (SMT) format addresses the need for compound testing in larger, more diverse tumor populations. This format employs a single mouse per PDX model and treatment arm, thereby enabling the investigation of efficacy in substantially larger panels of PDX models. In order to better mirror inter-patient response diversity observed in the clinic, less emphasis is put on the statistical robustness of response data for individual models.
In the study presented here, six SoC drugs were tested in the SMT format in colorectal (cetuximab, oxaliplatin, irinotecan, 5-FU) and non-small-cell lung cancer (cetuximab, paclitaxel) PDXs, and results were compared to those obtained from standard format experiments with 5 - 10 mice per group. Dosing and schedules were adapted to clinical standards. Data for 19 CXF and 16 NSCLC models showed that in 77% of the cases, results obtained from the single mouse trial format were in line with results from standard efficacy tests. Furthermore, in 10% of the cases, efficacy was similar by trend between the two formats. Notable discrepancies were seen mainly in tumors exhibiting intermediate sensitivity.
Our findings indicate that for the drugs tested here, the risk of misjudging the efficacy in a given PDX model based on SMT is low. This risk could be further lowered by increasing group sizes to 3 mice. For the identification of biomarkers which requires accurate efficacy data, such an intermediate format between the SMT and the standard format might be advantageous.
Citation Format: Christina Gredy, Julia B. Schüler, Nina Zanella, Heinz-Herbert Fiebig, Thomas Metz. Single mouse trials, a concept using patient-derived tumor xenografts for large scale in vivo screens. [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 2890. doi:10.1158/1538-7445.AM2015-2890
Abstract 2891: Chemokine-targeted models of human orthotopic colorectal cancer in immunocompetant mice
Authors: Lipkin Steven M. , Chen Huanhuan Joyce , Sun Jian , Huang Zhiliang , Hou Harry , Arcilla Myra , Rakhilin Nikolai , Joe Daniel , Choi Jiahn , Gadamsetty Poornima , Milsom Jeff , Nandakumar Govind , Longman Randy , Zhou Kathy , Edwards Robert , Chen Kai Yuan , Bu Pengcheng , Wang Lihua , Xu Yitian , Munroe Robert , Abratte Christian , Miller Andrew , Gümüş Zeynep , Shuler Michael , Nishimura Nozomi , Edelmann Winfried , Shen Xiling 
Published: August 2015

Abstract
Colorectal cancer (CRC) is a leading cause of cancer death. Current human CRC orthotopic xenograft models require survival surgery and do not robustly form tumors in liver, the most common site of metastasis in patients. Here, we use chemokine-targeting to develop cell line and primary patient-derived xenograft models that recapitulate the vast majority of common human somatic CRC mutations as primary gastrointestinal (GI) tumors in mice without requiring surgery. Importantly, we utilize early-stage mouse blastocyst microinjection techniques to extend this approach and model primary human CRCs in immunoproficient mouse hosts. Next, we show that primary GI tumors can inducibly and robustly metastasize to liver. Finally, we demonstrate that human CRC liver metastases in vivo have higher levels of DKK4 and NOTCH signaling and are more chemoresistant than paired sub-cutaneous xenografts. Overall, we anticipate that this experimental system can help improve our mechanistic understanding of human primary CRC progression to liver metastasis, and augment sub-cutaneous xenografts for pre-clinical drug screening.
Citation Format: Steven M. Lipkin, Huanhuan Joyce Chen, Jian Sun, Zhiliang Huang, Harry Hou, Myra Arcilla, Nikolai Rakhilin, Daniel Joe, Jiahn Choi, Poornima Gadamsetty, Jeff Milsom, Govind Nandakumar, Randy Longman, Kathy Zhou, Robert Edwards, Kai Yuan Chen, Pengcheng Bu, Lihua Wang, Yitian Xu, Robert Munroe, Christian Abratte, Andrew Miller, Zeynep Gümüş, Michael Shuler, Nozomi Nishimura, Winfried Edelmann, Xiling Shen. Chemokine-targeted models of human orthotopic colorectal cancer in immunocompetant mice. [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 2891. doi:10.1158/1538-7445.AM2015-2891
Abstract 2896: A flexible mouse model of malignant pleural mesothelioma
Authors: Cooper Jonathan , Giancotti Filippo 
Published: August 2015

Abstract
Patients with advanced malignant pleural mesothelioma (MPM) have extremely limited treatment options. To develop targeted therapies necessary to radically alter the clinical course of MPM, it is important to identify oncogenic mutations and signaling pathways that drive its development and progression. About 75% of MPMs carry inactivating mutations at the NF2 locus, which encodes the FERM domain protein Merlin, and often also have deletions of the CDKN2A locus, encoding the CDK inhibitor p16 and the p53 activator ARF. Since traditional cancer therapies target dysregulated oncogenes, it is important to elucidate the pathogenically relevant proteins that are dysregulated downstream of MPM tumor suppressors. We have developed a flexible and rapid mouse model that can be used to dissect genetics of MPM, to evaluate the preclinical efficacy of novel therapies, and to provide a platform for MPM shRNA genetic screens. We injected into the pleural cavity of mice lentivirus encoding Cre recombinase and miR30-based shRNA cassettes to simultaneously deplete four of the most commonly lost proteins in mesothelioma - Nf2, p16INK4a/ARF, and BAP1. Cre recombinase deletes the Nf2 conditional allele and simultaneously activates a Luciferase reporter gene in the pleural mesothelium, allowing for bioluminescent imaging of infected cells that develop MPM tumors. Lentiviral miR30-based shRNA cassettes simultaneously deplete Ink4a/ARF and Bap1, helping to drive tumorigenesis. To evaluate MPM genetics, mice with conditional alleles for putative drivers of MPM pathogenesis (i.e. Dcaf1 and Ptk2) in addition to the Nf2 conditional allele can be injected with the virus to determine whether these genes are necessary and sufficient for MPM development or progression. Moreover, knockdown of putative MPM drivers can be easily carried out by adding corresponding shRNA cassettes to the lentiviral vector. Using these methods, we have developed a rapid genetically engineered mouse model that recapitulates human MPM and can be used to explore MPM genetics. This flexible MPM mouse model will allow us to unravel MPM genetics and help to identify novel therapeutic targets as well as provide an efficient preclinical test of these therapies.
Citation Format: Jonathan Cooper, Filippo Giancotti. A flexible mouse model of malignant pleural mesothelioma. [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 2896. doi:10.1158/1538-7445.AM2015-2896
Abstract 2909: LC3 protein expression associates with UV exposure in melanoma histopathology
Authors: White Kirsten A. M. , Torres Salina , Thompson Todd A. , Hu Chien-An A. , Myers Orrin , Berwick Marianne 
Published: August 2015

Abstract
The 5-year survival rate for stage IV melanoma is estimated to remain unchanged at only 15%, even with new therapies. One emerging hallmark of cancer is the reprogramming of energy metabolism including the role of autophagy. In cancer, autophagy appears to be an important energy source for nutrient-depleted tumors. Ultraviolet-radiation (UVR) exposure is an established risk factor for melanoma and increases autophagic flux. We hypothesize that UV exposure is independently associated with both levels of autophagy and melanoma survival. To address this hypothesis, we are investigating the association between UVR exposure, autophagy, and development of melanoma. Basal levels of autophagy appear to vary by tumor stage, and higher levels of autophagy are associated with poor clinical prognosis. Melanoma cells contain high levels of autophagosomes, a cellular structure associated with autophagy, as measured by the proxy marker LC3. Also, the expression of the autophagy marker Beclin 1 has been associated with increased risk of early death from melanoma. These findings suggest that autophagy provides metabolic support for tumors as it localizes to hypoxic tumor areas, supports tumor cell survival, and is activated in response to stress. Autophagy can act as a cytoprotective mechanism against UV-induced apoptosis. We have shown that rates of autophagy vary by oncogene status. Autophagy was evaluated in formalin-fixed, paraffin embedded melanoma and normal tissue sections, by staining for LC3 and Beclin 1 using IHC. These markers of autophagy, along with clinical tumor characteristics, were correlated with extensive questionnaire data on UV exposure from the same patients to evaluate the impact of estimated lifetime sun exposure and sunburns on survival. A trend in the expression of Beclin1 was not observed; however, LC3 expression was increased in melanoma sections compared to normal. Our results provide enticing support that lifetime UVR exposure is associated with autophagy protein expression in melanoma.
Citation Format: Kirsten A. M. White, Salina Torres, Todd A. Thompson, Chien-An A. Hu, Orrin Myers, Marianne Berwick. LC3 protein expression associates with UV exposure in melanoma histopathology. [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 2909. doi:10.1158/1538-7445.AM2015-2909
Abstract 291: Targeting the stroma to hit the tumor: MMP11 as a novel target for cancer immunotherapy
Authors: Luberto Laura , Mancini Rita , Di Napoli Arianna , Peruzzi Daniela , Mori Federica , Roscilli Giuseppe , Marra Emanuele , Cappelletti Manuela , Ciliberto Gennaro , Aurisicchio Luigi 
Published: August 2015

Abstract
Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that mediate a number of physiological and pathological processes, such as matrix degradation, tissue remodeling, inflammation and tumor metastasis. The objective of this study was to develop and characterize a vaccine targeting stromal antigens expressed by cancer associated fibroblasts (CAFs). We focused on MMP11 (or stromelysin 3, ST3), that has been detected primarily in CAFs and its expression correlates with aggressive clinical behavior and invasiveness of different types of carcinoma. We demonstrated that intramuscular injection of genetic vectors such as Adenovirus (Ad) and plasmid DNA encoding MMP11 engineered variants followed by in vivo electroporation (DNA-EP) resulted in breakage of immune tolerance and induction of both cell mediated and humoral immune response. Importantly, MMP11 vaccine was able to confer significant antitumoral protection in a chemically induced, MMP11 overexpressing colon cancer model both in prophylactic and therapeutic settings. To determine the mechanism of action of MMP11 vaccine, we have utilized IFNgamma- and μmicroMT-knock out mice, devoid of T- and B-cell immune response, respectively. Our results show that both arms of the immune response are important to confer the therapeutic effect. Moreover, MMP11 stromal vaccine showed synergic effects when combined with genetic vaccines targeting classic tumor associated antigens, such as telomerase reverse transcriptase (TERT) and carcinoembryonic antigen (CEA). Finally, to assess the immunogenicity and the safety of MMP11 vaccine in a large animal model, nonhuman primates have been vaccinated with Ad and DNA-EP. A strong immune response was measured with no detectable side effects. In addition, MMP11 detection and spontaneous immune responses in the blood of breast and prostate cancer patients further corroborate MMP11 as a valid target for immune intervention.
Taken together, these data support the use of MMP11 as a potential candidate for cancer immunotherapy in human clinical trials.
Citation Format: Laura Luberto, Rita Mancini, Arianna Di Napoli, Daniela Peruzzi, Federica Mori, Giuseppe Roscilli, Emanuele Marra, Manuela Cappelletti, Gennaro Ciliberto, Luigi Aurisicchio. Targeting the stroma to hit the tumor: MMP11 as a novel target for cancer immunotherapy. [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 291. doi:10.1158/1538-7445.AM2015-291
Abstract 2913: Transcriptional reprogramming of pancreatic stroma induces metabolic changes in pancreatic tumor cells
Authors: Baddour Joelle , Yang Lifeng , Achreja Abhinav , Padmabandu Seth , Shah Pari , Curtis Rebecca N. , Plackemeier Thomas , Khalid Radina , Marini Juan C. , Franco-Barraza Janusz , Cukierman Edna , Hu Chaoxin , Maitra Anirban , Nagrath Deepak 
Published: August 2015

Abstract
Pancreatic cancer remains one of the most lethal of all solid tumors largely due to an aggressive stroma that constitutes the bulk of the tumor. The notion of a reprogrammed stroma suggests the re-establishment of a physiologically normal tumor microenvironment with quiescent stellate cells and fibroblasts. The induction of a quiescent phenotype hinders the aberrant tumor-stroma crosstalk and enables the increased intratumoral delivery of chemo drugs. A combinatorial transcriptional therapy has proven successful at normalizing the tumor microenvironment by reverting the activated state of stromal cells back to quiescence, both at the phenotypic and genetic levels. Indeed, we have observed a reduction in the activation markers of primary human stellate cells and fibroblasts, accompanied by an increase in the quiescence markers. Observations from methylation/hydroxymethylation profiling and metabolic rewiring through isotopomer flux analysis revealed potential targets for therapeutic intervention. In addition, the differential metabolic rewiring induced by a quiescent stroma in cancer cells suggests a tumor suppressive environment aimed at weakening an otherwise aggressive cancer.
Citation Format: Joelle Baddour, Lifeng Yang, Abhinav Achreja, Seth Padmabandu, Pari Shah, Rebecca N. Curtis, Thomas Plackemeier, Radina Khalid, Juan C. Marini, Janusz Franco-Barraza, Edna Cukierman, Chaoxin Hu, Anirban Maitra, Deepak Nagrath. Transcriptional reprogramming of pancreatic stroma induces metabolic changes in pancreatic tumor 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 2913. doi:10.1158/1538-7445.AM2015-2913
Abstract 2918: Peptide probe-based in vivo imaging of apoptosis and early decision on stomach tumor response to treatment
Authors: Khan Fatima , Gurung Smriti , Jung Hyun-Kyung , Baek Moon-Chang , Choi Yong Woo , Kim In San , Lee Byung Heon 
Published: August 2015

Abstract
Early decision on tumor response after anti-cancer treatment is still an unmet medical need. Here we exploited ApoPep-1 peptide that binds to histone H1 exposed on apoptotic cell surface as a probe and investigated whether in vivo imaging of apoptosis using near-infrared fluorescence dye-labeled linear and cyclic (disulfide-bonded) form of ApoPep-1 at an early stage after treatment could enable us predict tumor response to the treatment later. Treatment of SNU16 stomach tumor cells with cistplatin and cetuximab alone significantly induced apoptosis of the cells, while combination of cisplatin and cetuximab more efficiently induced apoptosis, as detected by staining with linear and cyclic form of ApoPep1. However, the differences among groups were more remarkable when detected with cyclic form of ApoPep-1 compared to the linear counterpart. In tumor-bearing mice, apoptosis imaging was performed at the first and second week after the initiation of treatment, and tumor sizes and weights were measured 3 weeks after treatment. In vivo fluorescence imaging signals by the homing of ApoPep-1 to tumor was most remarkable in the group injected with cyclic form of ApoPep-1 at the first week after combined treatment with cisplatin plus cetuximab. There were no significant differences in tumor sizes and weights between groups injected with linear and cyclic form of ApoPep-1. Correlation analysis revealed that imaging signals 1 week after treatment with cisplatin and cetuximab in combination were most closely related with tumor volume changes (r2 = 0.934). These results demonstrate that in vivo apoptosis imaging using the cyclic form of Apopep-1 is a sensitive and predictive tool for early decision on stomach tumor response after anti-cancer treatment.
Citation Format: Fatima Khan, Smriti Gurung, Hyun-Kyung Jung, Moon-Chang Baek, Yong Woo Choi, In San Kim, Byung Heon Lee. Peptide probe-based in vivo imaging of apoptosis and early decision on stomach tumor response to treatment. [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 2918. doi:10.1158/1538-7445.AM2015-2918
Abstract 2925: WAVE3 is associated with chemoresistance in TNBC by activating tumor angiogenesis downstream of the STAT1/Hif-1α/VEGF-A signaling axis
Authors: Davuluri Gangarao , Plow Edward F. , Schiemann William P. , Sossey-Alaoui Khalid 
Published: August 2015

Abstract
Chemoresistance is the main cause of disease recurrence and eventual death of breast cancer patients, particularly those harboring triple-negative breast cancer (TNBC) tumors for which effective FDA-approved drugs currently do not exist. However, a recent study determined that TNBCs can be segregated into 6 genetically distinct subtypes that do in fact exhibit differential rates of pathological complete response (pCR) to standard-of-care chemotherapies. Interestingly, the mesenchymal and mesenchymal stem-like subtypes of TNBCs exhibit the lowest rates of pCR when treated with standard-of-care chemotherapies. WAVE3 is an actin-cytoskeleton remodeling protein, and recent studies have highlighted a potential role for WAVE3 in promoting tumor progression and metastasis in TNBC. However, whether WAVE3 activity is involved in the development of chemoresistance in TNBCs, remains unclear. Here we show that loss of WAVE3 expression resensitizes human TNBC cells to Doxorubicin and Docetaxel, as measured by increased apoptosis and cell death. We also show that WAVE3 knockdown in the chemotherapy-treated TNBC cells results in inhibition of STAT1 phosphorylation, as well as a significant decrease in expression levels of its downstream effector Hif-1α. Since Hif-1α is a major activator of VEGF-A production, and therefore, a stimulator of tumor angiogenesis, loss of Hif-1α in the WAVE3-knocdown cells resulted in the inhibition the chemotherapy-mediated VEGF-A secretion and the downstream activation of angiogenesis, a phenomenon that often accompanies chemoresistance. Our data identify a critical role of WAVE3 in sensitizing TNBC to chemotherapy by inhibiting the STAT1⌠Hif-1α⌠VEGF-A signaling axis, and support the possibility of WAVE3 inhibition as a promising approach for TNBC cancer therapy.
Citation Format: Gangarao Davuluri, Edward F. Plow, William P. Schiemann, Khalid Sossey-Alaoui. WAVE3 is associated with chemoresistance in TNBC by activating tumor angiogenesis downstream of the STAT1/Hif-1α/VEGF-A signaling axis. [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 2925. doi:10.1158/1538-7445.AM2015-2925