bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-147: EMT transcription factors induce tissue factor expression and pro-coagulant properties, supporting early metastasis of circulating tumor cells
Authors: Bourcy Morgane , Skrypek Nicolas , Thompson Erik W. , Berx Geert , Hollier Brett , Polette Myriam , Gilles Christine 
Published: July 2017

Abstract
The presence of circulating tumor cells (CTCs) expressing traits of epithelial-mesenchymal transition (EMT) in cancer patients is increasingly recognized. Recently, we identified a new mechanism by which EMT induces the expression of Tissue Factor (TF, a major cell-associated initiator of coagulation), triggering a local activation of the coagulation cascade that favors the early metastatic colonization of EMT-positive CTCs (Bourcy et al., Cancer Research, 2016). Strengthening the functional contribution of EMT to TF regulation and coagulation, we further accumulated evidence that EMT transcription factors regulate TF expression. Thus, silencing ZEB1 inhibited both EMT-associated TF expression and coagulant activity. EMT-positive cells also exhibited a higher survival/persistence in lungs of mice colonized after intravenous injection, which was diminished by silencing ZEB1. Inversely, triggering de novo expression of Snail in MDA-MB-468 increased TF, coagulant properties and early metastasis in mice. Using TF promoter reporter vectors (mutated at different potential ZEB1 and Snail transcription factors) and CHIP, we further identified a binding region for ZEB1 in the proximal TF promoter encompassing a MCAT box, suggesting that ZEB1 and YAP might interact to regulate TF expression. Ongoing experiments are being performed to verify this hypothesis. We also collected data suggesting that targeting this new EMT/TF axis with anti-EMT drugs may represent an important extension to global anticoagulant strategies against cancer.
Citation Format: Morgane Bourcy, Nicolas Skrypek, Erik W. Thompson, Geert Berx, Brett Hollier, Myriam Polette, Christine Gilles. EMT transcription factors induce tissue factor expression and pro-coagulant properties, supporting early metastasis of circulating tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-147. doi:10.1158/1538-7445.AM2017-LB-147
Abstract LB-153: Lotus leaf and Cassia seed extracts, through activating Nrf2 pathway, suppress TPA-induced mouse skin cell transformation
Authors: Chan Yen-Fan , Lin Zi-Han , Chen Pei-Chun , Sung Ping-Hua , Su Zheng-Yuan 
Published: July 2017

Abstract
In traditional Chinese medicine, some Chinese herbs to be used as foods can protect and promote human health. Lotus (Nelumbo nucifera) leaves (LL) and Cassia (Cassia tora) seeds (CS) are often used as a food or an ingredient when cooking in Chinese region. LL and CS have been studied to exhibit some biological effects but there is no investigation to study their cancer chemopreventive potential. In this study, the extracts, including water extract (WE), water extraction residue ethanol extract (WREE) and ethanol extract (EE), of LL and CS were prepared. HepG2-C8 cell line, HepG2 cells stably transfected with Nrf2-ARE-luciferase plasmid, were used to screen out the extracts with cancer chemoprevetive potential. Our results showed that CS-WE, LL-WREE and LL-EE has better Nrf2-ARE-luciferase induction activity. Furthermore, we also found that these three extracts can inhibit 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced anchorage-independent cell growth of JB6 P+ cells while up-regulating Nrf2 and Nrf2 downstream antioxidant/detoxification enzymes. These results suggested that Chinese herbal Lotus leaves and Cassia seeds to be used as foods might inhibit carcinogenesis through the regulation of Nrf2 pathway.
Citation Format: Yen-Fan Chan, Zi-Han Lin, Pei-Chun Chen, Ping-Hua Sung, Zheng-Yuan Su. Lotus leaf and Cassia seed extracts, through activating Nrf2 pathway, suppress TPA-induced mouse skin cell transformation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-153. doi:10.1158/1538-7445.AM2017-LB-153
Abstract LB-165: Personalized prognostic prediction models for breast cancer recurrence and survival incorporating multidimensional data
Authors: Wu Xifeng , Ye Yuanqing , Barcenas Carlos H. , Chow Wong-Ho , Meng Qing H. , Gregor Mariana Chavez Mac , Hildebrandt Michelle , Zhao Hua , Gu Xiangjun , Deng Yang , Wagar Elizabeth A. , Esteva Francisco J. , Tripathy Debu , Hortobagyi Gabriel N. 
Published: July 2017

Abstract
Background: In this study, we developed integrative, personalized prognostic models for breast cancer recurrence and overall survival (OS) that consider receptor subtypes, epidemiological data, quality of life (QoL), and treatment.
Methods: 15,314 women with stage I to III invasive primary breast cancer treated at The University of Texas MD Anderson Cancer Center between 1997 and 2012 was used to generate prognostic models by Cox regression analysis including 10,809 women as discovery population (median follow-up: 6.09 years, 1,144 recurrence and 1,627 deaths) and 4,505 women as validation population (median follow-up: 7.95 years, 684 recurrence and 1,095 deaths). Model performance was assessed by calculating the area under the curve (AUC) and calibration analysis and compared with Nottingham Prognostic Index (NPI) and PREDICT.
Results: In addition to the known clinical/pathological variables, the model for recurrence included alcohol consumption while the model for OS included smoking status and physical component summary score. The AUCs for recurrence and OS were 0.813 and 0.810 in the discovery and 0.807 and 0.803 in the validation, respectively, compared to AUC of 0.761 and 0.753 in discovery and 0.777 and 0.751 in validation for NPI. Our model further showed better calibration compared to PREDICT. We also developed race-specific and receptor subtype-specific models with comparable AUC. Racial disparity was evident in the distributions of many risk factors and clinical presentation of the disease.
Conclusions: Our integrative prognostic models for breast cancer exhibit high discriminatory accuracy and excellent calibration and are the first to incorporate receptor subtype, epidemiological and QoL data.
Citation Format: Xifeng Wu, Yuanqing Ye, Carlos H. Barcenas, Wong-Ho Chow, Qing H. Meng, Mariana Chavez Mac Gregor, Michelle Hildebrandt, Hua Zhao, Xiangjun Gu, Yang Deng, Elizabeth A. Wagar, Francisco J. Esteva, Debu Tripathy, Gabriel N. Hortobagyi. Personalized prognostic prediction models for breast cancer recurrence and survival incorporating multidimensional data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-165. doi:10.1158/1538-7445.AM2017-LB-165
Abstract LB-179: Next-generation epitope prediction using mass spectrometry and integrative genomics
Authors: Rooney Michael S. , Abelin Jenn , Sarkizova Siranush , Keskin Derin , Hartigan Christine , Zhang Wandi , Sidney John , Lane William , Stevens Jonathan , Zhang Guang L. , Clauser Karl , Hacohen Nir , Carr Steve , Wu Cathy 
Published: July 2017

Abstract
Personalized neoantigen therapies for cancer require accurate epitope selection. However, most Class I prediction algorithms in common use today are based on biochemical binding assays that are difficult to scale and do not address processing steps upstream of peptide-MHC binding. Here we present an alternative approach based on the LC-MS/MS identification of MHC Class I-bound peptides. While MS-based profiling is not new, we optimized the system for rule learning by focusing on cell lines expressing only a single HLA-A or HLA-B allele and by collecting parallel transcriptomic and proteomic measurements. Identifying over 24,000 peptides across 16 individual alleles, we were able to discover novel binding motifs, which were validated biochemically, and develop novel neural network algorithms. Furthermore, we systematically interrogated processing rules - discovering a novel motif conserved across multiple cell types - and developed a principled framework for integrating epitope cleavability, expression, and MHC binding potential into an overall ranking. Validating on external datasets, we saw a doubling in positive predictive value with respect to standard approaches. We thus demonstrate a scalable strategy for systematically learning the rules of endogenous antigen presentation that can be deployed for the optimal selection of patient-specific cancer neoantigens.
Citation Format: Michael S. Rooney, Jenn Abelin, Siranush Sarkizova, Derin Keskin, Christine Hartigan, Wandi Zhang, John Sidney, William Lane, Jonathan Stevens, Guang L. Zhang, Karl Clauser, Nir Hacohen, Steve Carr, Cathy Wu. Next-generation epitope prediction using mass spectrometry and integrative genomics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-179. doi:10.1158/1538-7445.AM2017-LB-179
Abstract LB-181: Cutaneous SCC may escape immune surveillance by secreting complement factor H
Authors: Loomis Ellise , Pulford Christopher , Uppalapati Chandana , Pascual Agnes , Montgomery McKale , Leyva Kathryn J. , Hull Elizabeth E. 
Published: July 2017

Abstract
Developing tumors evade elimination by the immune system using a variety of mechanisms. Evidence suggests that cutaneous squamous cell carcinomas (cSCCs) may evade immune system surveillance by secreting complement factor H (CFH), a regulatory protein of the complement system. As part of its normal function, CFH binds to glycosaminoglycans on the surface of host cells where it acts as a cofactor for Factor I mediated C3b cleavage and accelerates the decay of the C3-convertase C3bBb. This mechanism for protecting self-cells also involves shifting the immune response from a pro-inflammatory T-helper-1 cell to an anti-inflammatory regulatory T-cell response. Data presented here suggest that some cSCCs have the ability to upregulate expression of CFH and studies have shown that this could be in response to the pro-inflammatory cytokine interferon-γ. We suggest that, in our cSCC samples, a potential negative-feedback loop exists in which the initial immune response to the developing tumor triggers expression of an immunosuppressive molecule, allowing the cancer to create an environment conducive to evading immune surveillance mechanisms.
Note: This abstract was not presented at the meeting.
Citation Format: Ellise Loomis, Christopher Pulford, Chandana Uppalapati, Agnes Pascual, McKale Montgomery, Kathryn J. Leyva, Elizabeth E. Hull. Cutaneous SCC may escape immune surveillance by secreting complement factor H [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-181. doi:10.1158/1538-7445.AM2017-LB-181
Abstract LB-189: Blockade of stearoyl CoA desaturase 1 promotes immunogenic clearance of tumors
Authors: Roemeling Christina Anna Elizabeth Von , Caulfield Thomas , Qie Yaqing , Radisky Derek C. , Liu Xiujie , Chen Yuanxin , Knight Joshua , Copland John , Kim Betty 
Published: July 2017

Abstract
Metabolic reprogramming plays a critical role in carcinogenesis, in part due its ability to promote immune suppressive properties within tumors. Agents that specifically target crucial metabolic enzymes utilized by cancer are been actively investigated. However, it is unclear whether inhibition of fatty acid metabolism in tumors affects their immunogenicity. Here, we show for the first time that inhibition of stearoyl-CoA desaturase 1 (SCD1), a key enzyme involved in fatty-acid synthesis and a potential prognostic marker for human cancers, increases the immunogenicity of poorly immunogenic tumors. The enhanced immune activation is accompanied by upregulated endoplasmic reticulum (ER) stress and is dependent on the translocation of ER protein calreticulin to the tumor cell surface. Inhibition of SCD1 increased both recruitment and activation of immune cells in vivo, which when combined with PD-1 blockade resulted in potent and durable anti-tumor T cell responses. Together, our results indicate that inhibition of tumorigenic de novo lipogenesis represents a novel approach to enhance T cell based cancer immunotherapy.
Citation Format: Christina Anna Elizabeth Von Roemeling, Thomas Caulfield, Yaqing Qie, Derek C. Radisky, Xiujie Liu, Yuanxin Chen, Joshua Knight, John Copland, Betty Kim. Blockade of stearoyl CoA desaturase 1 promotes immunogenic clearance of tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-189. doi:10.1158/1538-7445.AM2017-LB-189
Abstract LB-206: Indicators of responsiveness to immune checkpoint inhibitors
Authors: Shields Bradley D. , Mahmoud Fade , Taylor Erin M. , Byrum Stephanie D. , Sengupta Deepanwita , Koss Brian , Baldini Giulia , Ransom Seth , Cline Kyle , Mackintosh Samuel , Edmondson Ricky , Shalin Sara C. , Tackett Alan J. 
Published: July 2017

Abstract
Modulation of the immune system can produce anti-tumor responses in various cancer types, including melanoma. Recently, immune checkpoint inhibitors, in single agent and combination regimens, have produced durable and long-lasting clinical responses in a subset of metastatic melanoma patients. These monoclonal antibodies, developed against CTLA-4 and PD-1, block immune-inhibitory receptors on activated T-cells, amplifying the immune response. However, even when using anti-CTLA-4 and anti-PD-1 in combination, approximately half of patients exhibit innate resistance and suffer from disease progression. Currently, it is impossible to predict therapeutic response. Here, we report the first proteomic and histone epigenetic analysis of patient metastatic melanoma tumors taken prior to immune checkpoint inhibitor therapy, which revealed specific biological signatures that can stratify metastatic melanoma patients as responders or non-responders. Furthermore, our findings provide the first evidence of epigenetically-driven epithelial-mesenchymal transition, a known mechanism of immune-escape, in non-responding melanoma tumors. We identified elevated histone H3 lysine (27) trimethylation (H3K27me3), decreased E-cadherin, and other protein features indicating a more mesenchymal phenotype in non-responding tumors. Furthermore, we show E-cadherin is transcriptionally regulated by the EZH2-catalyzed H3K27me3 epigenetic mark in non-responding tumors. The repressive epigenetic mark H3K27me3, has known roles in melanoma pathogenesis and progression, but not in response to immunotherapies. Here, we provide the first report of an epigenetic program directly linking elevated levels of H3K27me3 to non-responding tumors. Our results have broad implications for immune checkpoint inhibitor therapy in a variety of carcinomas as patient specific responsiveness can be predicted through readily assayable proteins and histone epigenetic marks, and specific pathways activated in non-responders have been identified for therapeutic development to enhance responsiveness.
Citation Format: Bradley D. Shields, Fade Mahmoud, Erin M. Taylor, Stephanie D. Byrum, Deepanwita Sengupta, Brian Koss, Giulia Baldini, Seth Ransom, Kyle Cline, Samuel Mackintosh, Ricky Edmondson, Sara C. Shalin, Alan J. Tackett. Indicators of responsiveness to immune checkpoint inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-206. doi:10.1158/1538-7445.AM2017-LB-206
Abstract LB-209: RON kinase: a target for treatment of cancer-induced bone destruction and osteoporosis
Authors: Andrade Kelsi , Fornetti Jaime , Zhao Ling , Miller Scott C. , Randall Lor R. , Anderson Neysi , Waltz Susan E. , McHale Mark , Welm Alana L. 
Published: July 2017

Abstract
Bone destruction occurs in aging and numerous diseases, including osteoporosis and cancer. Many cancer patients have bone osteolysis that is refractory to state-of-the-art treatments, which block osteoclast activity with bisphosphonates or by inhibiting the RANKL pathway. We previously showed that macrophage-stimulating protein (MSP) signaling, which is elevated in approximately 40% of breast cancers, promotes osteolytic bone metastasis, but it was unknown whether this was due to activation of the MSP signaling pathway in the tumor cells or in the bone microenvironment. Here we show that MSP signals through host expression of its receptor, RON tyrosine kinase, to directly activate osteoclasts by a previously undescribed pathway that is complementary to RANKL signaling and converges on SRC. Genetic or pharmacologic inhibition of RON kinase blocked cancer-mediated bone destruction and osteoporosis in several mouse models. Furthermore, the RON kinase inhibitor BMS-777607/ASLAN002 altered markers of bone turnover in a first-in-human clinical cancer study, indicating potential for normalizing bone loss in patients. These findings uncover a new therapeutic target for pathogenic bone loss and provide a rationale for treatment of bone destruction in various diseases with RON inhibitors.
Citation Format: Kelsi Andrade, Jaime Fornetti, Ling Zhao, Scott C. Miller, Lor R. Randall, Neysi Anderson, Susan E. Waltz, Mark McHale, Alana L. Welm. RON kinase: a target for treatment of cancer-induced bone destruction and osteoporosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-209. doi:10.1158/1538-7445.AM2017-LB-209
Abstract LB-211: Phenotypic change specific to tumor-infiltrating regulatory T cells by LFPRLR knockdown
Authors: Chen Kuan-Hui E. , Walker Ameae 
Published: July 2017

Abstract
The clinical relevance and prognostic significance of tumor-infiltrating Tregs in different types of cancers makes them appealing therapeutic targets. However, targeting all Tregs initiates autoimmune disease. In the current study, we have found that knockdown of the long form of the prolactin receptor (LFPRLR) inhibits the function of tumor Tregs with no functional change in peripheral Tregs. Knockdown of the LFPRLR was by splice modulating oligomer (SMO), tested in the syngeneic 4T1-Balb/c immune-competent breast cancer model. Similar effects would be predicted to occur in prostate and ovarian cancer. Knockdown reduced tumor output of CCL17, a chemokine regulated by the major LFPRLR signaling Jak2/Stat5 pathway. Reduced CCL17 output in turn resulted in impaired Treg recruitment into tumors, allowing enhanced CD4+ and CD8+ T cell activities within the tumor and reducing metastasis to distal organs. Also observed was a reduction in Tregs at metastatic sites. RNAseq transcriptomic analysis of LFPRLR SMO-treated tumor Tregs revealed that among immune-suppressive cytokines, expression of IL-10 and TGF-β was not affected, but EBI3, a component of IL-35, became undetectable. Of cytokines known to promote metastasis, IL-6, IL23a and IL34 were reduced. When tumor Tregs, isolated from LFPRLR SMO-treated animals, were co-cultured with 4T1 breast cancer cells, they failed to drive epithelial to mesenchymal transition, while tumor Tregs isolated from control SMO-treated animals did transform 4T1 cells into a more mesenchymal phenotype. Although tumor T regs were reduced by treatment, other major components of the tumor microenvironment, including B cells, CD8+ T cells, macrophages, NK T cells, dendritic cells, myeloid-derived suppressor cells, and fibroblasts were not changed by LFPRLR knockdown, while effector CD4+ T cells were increased and tumor endothelial cells were decreased. Although the population of CD8+ T cells was not changed, their activity was enhanced, as determined by their production of IL-2 and IFN-γ when stimulated. Examination of splenic Tregs from animals treated with LFPRLR- or control SMO for 28 days showed normal suppressive activity of anti-CD3-stimulated T cell proliferation. In conclusion, systemic LFPRLR knockdown has direct and indirect effects on tumor Tregs that modify their cytokine profile and reduce their suppressive capability and ability to drive epithelial to mesenchymal transition of tumor cells.
Citation Format: Kuan-Hui E. Chen, Ameae Walker. Phenotypic change specific to tumor-infiltrating regulatory T cells by LFPRLR knockdown [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-211. doi:10.1158/1538-7445.AM2017-LB-211
Abstract LB-212: Antioxidant therapy reprograms macrophages from protumor M2 to antitumor M1
Authors: Griess Brandon , Datta Kaustubh , Teoh-Fitzgerald Melissa 
Published: July 2017

Abstract
Macrophages (Mϕ) have high plasticity and can polarize to two extremes, pro-inflammatory M1 Mϕ and immuno-suppressive M2 Mϕ. In triple negative breast cancer, tumor-associated Mϕ (TAM) have a pro-tumor M2-like phenotype and are associated with decreased survival. Thus, it is vital to develop treatments to reprogram TAM away from protumor M2 Mϕ toward antitumor M1 Mϕ. A recent study reported a lipid peroxide scavenger selectively inhibits M2 Mϕ markers and cytokines. However, little is known about the differences in ROS metabolism between M1 Mϕ and M2 Mϕ. Our hypothesis is pro-tumorigenic M2 Mϕ possess a distinct profile of pro- and anti-oxidant enzymes, as well as a different sensitivity to ROS modulation versus the anti-tumor M1 Mϕ. Our results show M2 Mϕ, derived from primary human monocytes, have a significant 20-30% reduction in intracellular ROS levels versus M1 Mϕ by DCFH and DHE staining. Extracellular ROS synthesis was dramatically reduced by ~70% in M2 Mϕ, in part due to reduced mRNA expression of Nox2, Nox5, and their accessory protein CYBA in M2 Mϕ. Another contributing factor to lower ROS levels is that M2 Mϕ have significantly increased Catalase and Gpx4 mRNA expression, as well as increased Cu/ZnSOD and Gpx1 protein and activity. These data suggest M2 Mϕ have increased ROS metabolism versus M1 Mϕ, which may provide an advantage in the oxidative tumor microenvironment. Furthermore, EcSOD re-expression in MB231, a triple negative breast cancer cell line, inhibited the MB231-mediated increase in M2 Mϕ markers and decrease in M1 Mϕ markers. We moved forward utilizing Mn(III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin (MnTE), a small molecule SOD mimetic, shown to have anti-tumor effects. MnTE treatment increased M1 Mϕ markers, IL-12b and CD86, while concurrently decreasing M2 Mϕ markers, IL-10, CD163, and CD206. MnTE also inhibited the ability of M2 Mϕ to inhibit T cell activation suggesting ROS is required for M2 Mϕ polarization and function. Increasing ROS levels by addition of exogenous H2O2, lead to increased M2 markers and decreased M1 markers, which implicates the oxidative tumor microenvironment in promoting a M2-like TAM phenotype. These studies provide the rationale for antioxidant treatment of breast cancer to reprogram TAM from pro-tumorigenic M2-like TAM phenotype to a more tumoricidal M1-like phenotype.
Citation Format: Brandon Griess, Kaustubh Datta, Melissa Teoh-Fitzgerald. Antioxidant therapy reprograms macrophages from protumor M2 to antitumor M1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-212. doi:10.1158/1538-7445.AM2017-LB-212