bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 110: PPARγ loss increases the metastatic potential of HER2+ breast cancer
Authors: Lightbody Elizabeth D. , O'Connell Kathleen MJ , Newton Hailey T. , Rubino Rachel R. , Apostoli Anthony J. , Ren Kevin , SenGupta Sandip K. , Nicol Christopher J. 
Published: August 2018

Abstract
Breast tumors that overexpress human epidermal growth factor receptor 2 (HER2+) grow and spread faster than HER2-negative tumors, resulting in poor patient prognosis. Peroxisome proliferator-activated receptor (PPAR)γ is a nuclear transcription factor that controls the expression of genes essential for normal metabolism of fats and sugars in the body. Our laboratory previously showed that PPARγ expression suppresses environmental carcinogen DMBA-mediated breast tumor progression in vivo, and PPARγ-activating drugs further enhance this effect. However, the role of PPARγ and PPARγ agonists on HER2+ breast tumorigenesis and patient survival is unclear. We hypothesized that PPARγ loss enhances HER2+ breast tumor progression. To test this, this study generated a novel mouse model referred to as NIC:PPARγ-KO, which has targeted PPARγ deletion in the same HER2+ transformed mammary epithelial cells that drive breast tumorigenesis. Compared to NIC:PPARγ-WT mice, NIC:PPARγ-KO mice have increased mammary tumor incidences and lung metastases. Protein analysis of NIC:PPARγ-KO tumors shows PPARγ loss is inversely correlated with increased HER2 phosphorylation at tyrosine 877 (pY877HER2) in primary and metastatic tumorigenic tissue. Immunofluorescence also showed HER2 H-scores were significantly highest among tumors from NIC:PPARγ-KO mice, but also correlated with targeted PPARγ loss in DMBA-induced primary and metastatic mammary tumors among PPARγ-WT and PPARγ-KO mice (p&lt;0.05). To further investigate the role of PPARγ in the metastatic process, we established cell lines from the freshly isolated lung metastatic tumors harvested from the NIC:PPARγ-KO model (NIC:PPARγ-KO-lmet). In vitro analysis of several human HER2+ breast cancer cells lines and our NIC:PPARγ-KO-lmet cells shows migration, invasion and tumorsphere-forming potential were significantly increased after epidermal growth factor (EGF, 20ng/mL) treatment and, more interestingly, that co-treatment with a PPARγ-activating drug (rosiglitazone, 10μM) significantly abrogated these effects (p&lt;0.05). Together, these data provide the first evidence that PPARγ may be a useful prognostic/predictive biomarker for HER2+ breast tumors, and suggest that the novel inclusion of PPARγ-activating drugs may benefit a subset of HER2+ breast cancer patients.
Citation Format: Elizabeth D. Lightbody, Kathleen MJ O'Connell, Hailey T. Newton, Rachel R. Rubino, Anthony J. Apostoli, Kevin Ren, Sandip K. SenGupta, Christopher J. Nicol. PPARγ loss increases the metastatic potential of HER2+ breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 110.
Abstract 1103: Colorectal cancer-derived small extracellular vesicles establish an inflammatory premetastatic niche through macrophage polarization in liver metastasis
Authors: Shao Yingkuan , Chen Ting , Zheng Xi , Zheng Shu 
Published: August 2018

Abstract
Liver metastases develop in more than half of patients with colorectal cancer (CRC) and indicate a poor prognosis. In this study, we aim to investigate CRC-derived small extracellular vesicles (CRC-sEVs) participating in liver-specific metastasis. Fluorescence-labeled CRC-sEVs were found to accumulate in macrophages in mouse liver and prime macrophage polarization toward an interleukin-6 (IL-6)-secreting pro-inflammatory phenotype (macrophage expresses different programs in response to different microenvironmental signals called macrophage polarization). By analyzing miRNA expression profiles of the CRC-sEVs and their parental cells (SW480 and SW620), we identified miR-21-5p (miR-21) as the top ranked miRNA that was highly upregulated both in the sEVs and their parental CRC cells. The majority of macrophage-secreted inflammatory signaling pathways are activated by Toll-like receptor (TLR). Macrophages treated with miR-21 analogs exhibited enhanced expression of pro-inflammatory cytokines such as IL-6 and TNF-α. Silencing either miR-21 in CRC-sEVs, or the Toll-like receptor 7 (TLR7) in macrophages which miR-21 binds to, abolished the effect of CRC-sEVs in inducing pro-inflammatory macrophage polarization. Upon intravenous injection, CRC-sEVs promoted miR-21 expression and macrophage infiltration in the mouse liver, followed by the up-regulation of inflammatory genes. Accordingly, the multiplicity of liver metastases was increased upon transplantation of CRC cells in mice treated with CRC-sEVs. Furthermore, miR-21 expression in plasma-derived sEVs positively correlated with tumor stage and liver metastasis in CRC patients. Finally, co-expression of the miR-21 and IL-6 macrophages markers was observed in liver metastatic tissues from CRC patients. Together, our data point to a pivotal role of CRC-sEVs in inducing an inflammatory pre-metastatic niche through the miR-21-TLR7-IL6 axis. Moreover, sEVs-miR-21 represents a potential prognostic marker and therapeutic target for CRC patients with liver metastasis.
Citation Format: Yingkuan Shao, Ting Chen, Xi Zheng, Shu Zheng. Colorectal cancer-derived small extracellular vesicles establish an inflammatory premetastatic niche through macrophage polarization in liver metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1103.
Abstract 1118: DOT1L epigenetically regulates cancer stem cell properties and tumor progression in glioblastoma brain tumor stem cells
Authors: Bozek Danielle , Hao Xiaoguang , Luchman H. Artee , Weiss Samuel 
Published: August 2018

Abstract
The median survival for patients diagnosed with Glioblastoma (GBM) is only 14 months, due to recurrence, despite current treatment options of surgery, radio- and chemo-therapies. Brain tumor stem cells (BTSCs) are thought to underlie disease recurrence and lethality as they exhibit self-renewal, multipotency and tumorigenesis. The epigenetic regulation of BTSCs are relatively un-characterized and unlike genomic mutations are potentially reversible. Disrupter of telomeric silencing-1-like (DOT1L) is the only known histone methyltransferase responsible for histone-3-lysine-79 methylation (H3K79me), an epigenetic mark associated with active gene transcription. Previous studies investigating the therapeutic implications of targeting DOT1L in cancer have shown that its inhibition in leukemia results in cancer cell death and, in solid cancers, decreases metastasis. We investigated the role of DOT1L in GBM BTSCs. We find that short-term DOT1L inhibition in BTSCs in vitro has limited effects on viability but alters growth morphology, as neurospheres become flattened and adherent. Furthermore, inhibition decreases BTSC invasion and promotes differentiation. Long-term inhibition of DOT1L had a more pronounced effect on sphere morphology and decreased BTSC proliferation and survival. Pre-treatment with the DOT1L inhibitor EPZ-5676 followed by orthotopic xenografts of BTSCs led to slowed tumor growth and improved overall survival. Initial H3K79me2 ChIP-sequencing and RNA-sequencing results show that H3K79me2 levels and gene expression are decreased for stem and progenitor cell markers SOX2 and OLIG2 respectively, in BTSCs treated with EPZ-5676. These results suggest that DOT1L may be an important regulator of GBM cancer stem cell properties and tumor progression. Current studies aim to further investigate how DOT1L regulates BTSCs by overlaying H3K79me2 ChIP-sequencing, RNA-sequencing and ATAC-sequencing in a panel of BTSCs following DOT1L inhibition and overexpression. These findings highlight the potential clinical implications of epigenetic targeted therapies for GBM.
Citation Format: Danielle Bozek, Xiaoguang Hao, H. Artee Luchman, Samuel Weiss. DOT1L epigenetically regulates cancer stem cell properties and tumor progression in glioblastoma brain tumor stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1118.
Abstract 1129: Sox2 drives ST6Gal-I expression and activity to promote a CSC phenotype in ovarian cancer
Authors: Dorsett Kaitlyn A. , Bellis Susan L. 
Published: August 2018

Abstract
This study elucidates ST6Gal-I, a sialyltransferase, as a functional driver of a cancer stem cell (CSC) phenotype regulated by the stem cell transcription factor Sox2. ST6Gal-I is upregulated in 98% of ovarian cancers (OC); it functions to add an α2-6 sialic acid, a large, negatively charged sugar, to N-glycosylated proteins bound for the cell surface. Normal differentiated epithelia have very low expression of ST6Gal-I, however, expression is turned on in stem cell compartments and transformed tissues. Furthermore, our work has shown that ST6Gal-I plays a causal role in conferring hallmark CSC properties including greater tumor-initiating capabilities, promotion of recurrence, and resistance to tumor-associated stressors like chemotherapies, serum deprivation, and hypoxia. Even given this stark upregulation and apparent functional import of ST6Gal-I in cancers, very little work has been done to identify the transcriptional driver of ST6Gal-I expression. We identified that Sox2 and ST6Gal-I are both part of one of the most commonly enriched amplicons in human cancer, amplicon 3q26. We then examined the TCGA database and found that these two genes are co-amplified in 48/73 cancer cohorts, including ovarian cancer. In addition to being genetically co-amplified, Sox2 has been shown to bind to the promoter of ST6Gal-I, though no further analyses have been performed to assess a functional link. Herein we address a novel, glycosylation-dependent mechanism that drives a CSC phenotype. We hypothesize that Sox2, a key stem-associated transcription factor in CSCs, directly induces expression of ST6Gal-I. In our ovarian cancer cell model systems, we forced overexpression or knockdown of Sox2 and found that Sox2 expression directly correlated with ST6Gal-I expression. Overexpression or knockdown of Sox2 resulted in up- or down- regulation of CSC markers Oct4 and Nanog respectively. We then forced ST6Gal-I knockdown to inhibit the Sox2-induced ST6Gal-I upregulation and found that this prevented the enhanced expression of Oct4 and Nanog. Here we show that Sox2 requires ST6Gal-I expression to promote a CSC phenotype.
Citation Format: Kaitlyn A. Dorsett, Susan L. Bellis. Sox2 drives ST6Gal-I expression and activity to promote a CSC phenotype in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1129.
Abstract 1130: The role of TET2 in mammary stem cell fate decision
Authors: Wu Meng-Ju , Chang Chun-Ju 
Published: August 2018

Abstract
Epigenetic mechanisms, including DNA methylation, has an essential role in governing the stem cell fate decision. The Ten-Eleven-Translocation (TET) protein family serves as a primary epigenetic regulator responsible for catalyzing the conversion of the modified genomic base 5-methylcytosine into 5-hydroxymethylcytosine to mediate DNA demethylation. It has been shown that loss of TET2 promotes aberrant stem cell self-renewal in hematopoietic malignancy.
Interestingly, our recent study has revealed that expression of TET2 directs the breast cancer stem cell-like population to the differentiation cell fate in vitro. Since aberrant stem cell fate is often associated with tumorigenesis, delineating the role that a critical epigenetic regulator (e.g., TET2) plays to govern the mammary stem cell (MaSC) fate will likely provide new strategies used for breast cancer treatment.
Thus, to determine the physiological and pathological roles of TET2 in the regulation of MaSC fate and mammary gland development using a mouse model with mammary specific deletion of the Tet2 gene (MMTV-Cre; Tet2fl/fl). Our data show that deletion of Tet2 in mouse mammary gland leads to disrupted mammary epithelial morphology, defective lobular-alveolar development, along with aberrant mammary stem cell fate decision, contributing to an expansion of the MaSC population and development of mammary lesions. Together, the data demonstrate that TET2 plays an important role in controlling MaSC fate decision to maintain epithelial homeostasis, and loss of TET2 may contribute to the development of mammary malignancies.
Citation Format: Meng-Ju Wu, Chun-Ju Chang. The role of TET2 in mammary stem cell fate decision [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1130.
Abstract 1147: Developing an individualized human colonic crypt cell culture as an ex vivo model for immunotherapy
Authors: Cheah Peh Yean , Low Yee Syuen , Lo Michelle , Tang See Aik , Ng Alphaeus , Tang Choong Leong , Wong Siew Heng 
Published: August 2018

Abstract
Colorectal Cancer (CRC) is the third leading cause of cancer death worldwide. Majority of mortality is attributable to metastasis to distal organs. Current treatment targeting the ERK/MAPK pathway used monoclonal anti-EGFR antibody after the first line of chemotherapy fails. However these treatments are only effective for a small percentage of patients with wild-type KRAS, and these same patients eventually develop resistance. Small molecule drugs are toxic and have limited success. A combination of antibodies is an attractive alternative. This study aims to investigate whether anti-KRAS antibody can enter live cells in an individualized ex vivo culture system and whether it can bind and inactivate KRAS. The transient culture has advantages over cell line study as it better mimics the human colonic environment and tumors can be compared to their matched normals to partially address the problem of heterogeneity. Samples were obtained from patients' resected tumour and matched mucosa, cultured ex vivo, and immunostaining performed. We show that anti-KRAS antibody is internalized in both the cultured mucosa and tumor crypt cells prior to fixation. Subcellular localization of the internalized antibody in the mucosa cells is similar in the pre-fixed and post-fixed cells. In contrast, the internal cell membrane staining observed in post-fixed tumor cells appear more cytoplasmic and 'punctated' in the pre-fixed tumors, mimicking that of the mucosa cells suggesting that the internalized anti-KRAS may have altered the sub-cellular localization and hence cycling of KRAS. Furthermore, staining with anti-keratin antibody indicates that live tumor cells treated with anti-KRAS has partial reversal of the phenotype to become more like the regular striated pattern of the matched mucosa. Preliminary double labelling of cultured tumours with monoclonal anti-KRAS prior to fixation and polyclonal anti-KRAS post-fixation revealed punctate staining of KRAS in the cytoplasm that were mainly non-overlapping suggesting that the punctate structures are in different compartments.
Citation Format: Peh Yean Cheah, Yee Syuen Low, Michelle Lo, See Aik Tang, Alphaeus Ng, Choong Leong Tang, Siew Heng Wong. Developing an individualized human colonic crypt cell culture as an ex vivo model for immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1147.
Abstract 1148: Promising preclinical platform for evaluation of immuno-oncology drugs using Hu-PBL-NSG lung cancer models
Authors: Lim Sun Min , Pyo Kyoung-Ho , Kim Jae Hwan , Lee Ji Min , Kim Seong Keun , Kim Sung Eun , Jo Ha Ni , Cho Jae Soek , Kim Hye Ryun , Cho Byoung Chul 
Published: August 2018

Abstract
Introduction: With the advance of immunotherapy, treatment of non-small-cell lung cancer (NSCLC) has revolutionized by having anti-PD-1 therapy in front-line setting. In this era of cancer immunotherapy, humanized mouse models which recapitulate human immune system, are needed for predicting immunotherapy response in patients. We established a Hu-PBL-NSG mouse model which can be used as a preclinical testing platform for assessing efficacy of different immunotherapeutic agents.
Methods: Hu-PBL-NSG mouse model was established by engrafting human peripheral blood lymphocytes (PBLs) into NOD-scid (NSG) mice. The 6-7 week-old NSG mouse was transfused with 1 x 107 cells of PBL via tail vein, and human immune cells were characterized after 24 hours, and weekly thereafter. Cytokine array was performed to assess serological similarity between patient and the Hu-PBL-NSG mouse, and microscopic immune cell infiltration was observed in various organs mouse model. Human anti-PD-1 therapy was treated for assessing drug efficacy in patient-derived tumor.
Results: hCD3+hCD45+ T-cells and antigen presenting cells (dendritic cells, macrophages, and MDSC) increased in the serum of Hu-PBL-NSG mouse 24 hour after the transfusion of human PBLs, and CD3+ T cells were observed in lung, liver, kidney, spleen sections. Cytokine arrays of human and Hu-PBL-NSG mouse revealed high similarity of Th1, Th2, Th17-related cytokines. A tumor xenograft was engrafted from an EML4-ALK patient, and Hu-PBL-NSG mouse was sacrificed for histological analyses. hCD3+ T cells were infiltrated within the tumor, and CD11c+ cells, which represent antigen-presenting capability, were seen in spleen, lung, liver and kidney. When anti-PD-1 Ab was treated intraperitoneally, xenograft tumor showed significant reduction in volume after day 6, and increased expression of immune response-related genes on microarray analysis in the tumor. Mostly IFN-gamma and its related gene sets were significantly changed (FDR &lt; 0.25, GSEA).
Conclusion: Hu-PBL-NSG mouse model which highly resembles human immune system was successfully established. This model could be a strong preclinical model for testing efficacy of immunotherapeutic agents, and also for pursuing novel immunotherapy treatment strategies in advanced NSCLC.
Citation Format: Sun Min Lim, Kyoung-Ho Pyo, Jae Hwan Kim, Ji Min Lee, Seong Keun Kim, Sung Eun Kim, Ha Ni Jo, Jae Soek Cho, Hye Ryun Kim, Byoung Chul Cho. Promising preclinical platform for evaluation of immuno-oncology drugs using Hu-PBL-NSG lung cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1148.
Abstract 1149: Humanized knock-in mouse models for evaluating in vivo efficacy of immune-oncology drugs targeting inhibitory immune checkpoint molecules
Authors: Zhang Baozhu , Guo Chaoshe , Shen Yuelei , Guo Yanan 
Published: August 2018

Abstract
Recently, increasingly attention has been paid to the development of immuno-oncology (IO) drugs, due to the promising clinical results acquired by CTLA-4, PD-1 and PD-L1 antibodies. However, along the IO drug development process, in vivo efficacy models have always been a rate-limiting step. Mouse surrogate antibodies were often used in immune-competent mice with murine syngeneic tumor models to evaluate in vivo efficacy of the IO drugs. However, the efficacy of a surrogate antibody cannot fully represent the human drug in the clinical scenario. In most cases, a human monoclonal antibody does not have mouse cross-reactivity. Therefore, we generated humanized knock-in mouse to evaluate the in vivo efficacy of human IO antibodies. For example, human PD-1 knock-in (B-hPD-1) mice were generated with a chimeric PD-1 receptor, which is recognizable by human PD-1 antibodies, and can be used to test human PD-1 antibody in vivo efficacy. Mouse cancer cell lines including colon cancer MC38, melanoma B16F10 and lung cancer LLC1 were genetically modified with over-expression of hPD-L1 and knock-out of mPD-L1, and used to evaluate the in vivo efficacy of human PD-L1 antibodies. Additionally, more knock-in mice targeting inhibitory immune checkpoint molecules were developed, such as B-hPD-L1, B-hCTLA-4, B-hLAG3, B-hTIM3, B-hTIGIT, B-hBTLA, B-hSIRPa et al,. Humanized knock-in mice, pairing with genetically modified mouse cancer cells, represent a promising in vivo efficacy model for the development of IO drugs, and contribute to the clinical translation of animal studies.
Citation Format: Baozhu Zhang, Chaoshe Guo, Yuelei Shen, Yanan Guo. Humanized knock-in mouse models for evaluating in vivo efficacy of immune-oncology drugs targeting inhibitory immune checkpoint molecules [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1149.
Abstract 1156: New spontaneous and carcinogen-induced mouse-derived isograft (MDI) tumor models for immune therapeutic approaches
Authors: Jantscheff Peter , Beshay Janette , Lemarchand Thomas , Obodozie Cynthia , Schaechtele Christoph , Weber Holger 
Published: August 2018

Abstract
First findings in the late 1990s and the early 2000s, that blockade of immune checkpoint inhibitors (ICI) by antibodies could induce rejection of established tumors and induce immunity also to secondary exposure with these tumor cells, led again to a stronger focus of experimental studies on syngeneic tumor models in immunocompetent animals. The availability of such models, however, is mainly limited by the small number of genetically-modified (GEM) or long-term passaged cell line-derived tumor models. We here describe establishment and first characterization of a new type of animal tumor models, named Mouse-Derived-Isografts (MDI), from spontaneously appearing or carcinogen-induced syngeneic tumors in both sexes of various mouse strains (C3H/HeN, CBA/J, BALB/C, DBA/2N and C57BL/6N). The tumors were obtained from animals during long-term observation (≥ 1-2 years) of normally fed, otherwise untreated animals (spontaneous - sMDI) or during short-term observation (3-9 month) of once subcutaneously, intramuscularly, intraperitoneally or orally methylcholanthrene (MCA) or methyl-nitroso-urea (MNU) treated animals (carcinogen - cMDI). Criteria to perform a primary necropsy were critical weight loss, bad general conditions or externally observable tumor growth in monitored animals. At this first step, tissues were assessed only macroscopically, and conspicuous ones were transplanted (in PDX-like manner) as small pieces into sex-matched syngeneic animals. If possible tissue/tumor pieces were also frozen and stored in 10% DMSO freezing medium at -80°C. In a second step these re-transplanted, outgrowing tumors were amplified once again in syngeneic mice for freeze storing, and then the models were finally established by re-transplantation and testing outgrowth of the frozen stored tumor pieces in the syngeneic animals. The tumors appear phenotypically stable, as far as routine standard HE stained sections could show. General characteristics of these models are; they are primary spontaneous or carcinogen-induced tumors, of low passage number (&lt;10), propagated as tissue pieces only in mice without tissue culturing, and thus with conserved original tumor characteristics as assessed microscopically and intra-tumoral immune cell populations analyzed by flow cytometry.
Citation Format: Peter Jantscheff, Janette Beshay, Thomas Lemarchand, Cynthia Obodozie, Christoph Schaechtele, Holger Weber. New spontaneous and carcinogen-induced mouse-derived isograft (MDI) tumor models for immune therapeutic approaches [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1156.