tbuckley/cabot-search huggingface dataset:
Abstract 5812: MIEN1 promotes breast cancer cell migration and invasion by regulating cytoskeletal dynamics via focal adhesion kinase and N-WASP
Authors: Pankaj Chaudhary, Marilyne Kpetemey, Timothy Van Treuren, Jamboor K. Vishwanatha
Journal: Cancer Research (2017)

Abstract Short Description: Migration and invasion enhancer 1 (MIEN1) is an important regulator of cell migration and invasion. MIEN1 overexpression represents an oncogenic event that promotes tumor cell dissemination and metastasis. The underlying mechanism by which MIEN1 regulates migration and invasion has yet to be deciphered. Methods: Immunofluorescence, actin polymerization, Immunoprecipitation, migration, invasion, and adhesion assays were performed using breast cancer cell lines, MDA-MB-231 and MCF10CA1a to investigate the mechanisms by which MIEN1 potentiates cell motility. Results: Our results show that MIEN1 acts as a cytoskeletal-signaling adapter protein to drive breast cancer cell migration. Knockdown of MIEN1 led to the loss of actin-protrusive structures whereas the overexpression of MIEN1 resulted in rich and thick membrane extensions. Knockdown of MIEN1 also decreased the cell-substratum adhesion, suggesting a role for MIEN1 in actin cytoskeletal dynamics. Our results show that MIEN1 supports the transition of G-actin to F-actin polymerization and stabilizes F-actin polymers. Additionally, MIEN1 promotes cellular adhesion and actin dynamics by inducing phosphorylation of FAK at Tyr-925 and reducing phosphorylation of cofilin at Ser-3, which results in breast cancer cell migration. Furthermore, we found that MIEN1 associates with cytoskeletal proteins involved in motility processes. Conclusion: Our results show that MIEN1 plays an essential role in maintaining the plasticity of the dynamic membrane-associated actin cytoskeleton, which leads to an increase in cell motility. Hence, targeting MIEN1 might represent a promising means to prevent breast tumor metastasis. Note: This abstract was not presented at the meeting. Citation Format: Pankaj Chaudhary, Marilyne Kpetemey, Timothy Van Treuren, Jamboor K. Vishwanatha. MIEN1 promotes breast cancer cell migration and invasion by regulating cytoskeletal dynamics via focal adhesion kinase and N-WASP [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 5812. doi:10.1158/1538-7445.AM2017-5812
Transdiagnostic Cognitive Behavioral Therapy and the Return of the Repressed
Authors: Peter Roy-Byrne
Journal: JAMA Psychiatry (2017)

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Abstract 4923: MyD88 and IL-17 have essential local and systemic functions in promoting tumors on mouse skin
Authors: Mary Klosterman, Christophe Cataisson, Rosalba Salcedo, Kelly Shibuya, Jennifer Waters, Giorgio Trinchieri, Stuart H. Yuspa
Journal: Cancer Research (2017)

Abstract NF-kB has been causally implicated with cancer-associated inflammation. In the skin, ligands of the Toll-like receptor/IL-1 receptor superfamily induce the recruitment of MyD88 (Myeloid differentiation primary response gene 88), ultimately leading to NF-kB activation. We previously reported that MyD88 is required for two stage chemical carcinogenesis on mouse skin, and that MyD88 exerts a cell-intrinsic function in RAS-mediated transformation of keratinocytes (Ras-keratinocytes). Now, we explore the role of MyD88 during tumor promotion with 12-O-tetradecanoyl-phorbol-13-acetate (TPA). Epidermal hyperplasia is reduced in MyD88 deficient mice relative to controls after multiple applications of TPA. Furthermore, the upregulation of the chemokines Cxcl1 and S100a8 in response to TPA was deficient in MyD88 null cultured keratinocytes revealing a necessary role for MyD88 in the intrinsic response of keratinocytes to phorbol ester. We also uncovered a systemic requirement for MyD88 in carcinogenesis since lineage specific ablation of MyD88 in T cells conferred significant resistance to skin tumorigenesis and reduced infiltration of IL-17 positive T cells in TPA treated MyD88 null mouse skin. IL-17 treatment of normal primary keratinocytes increased their proliferation while reducing their response to calcium-induced differentiation but had no effect on the proliferation of RAS-keratinocytes. The atypical nuclear IkBzeta protein can act as an activator of so-called secondary NF-kB response genes. IkBzeta deficiency blocked the keratinocyte proliferative response to IL-17 but had no effect on altered differentiation. Finally, both IL-17 and oncogenic RAS required IkBzeta to upregulate the expression of S100a8, lipocalin2 and Steap4 mRNAs. Collectively, these results demonstrate that MyD88 plays a pro-tumorigenic function during tumor promotion in both epithelial and T-cell compartments and that IL-17/IkBzeta could play a facilitating role on keratinocytes during tumor promotion beyond its pro-inflammatory activity. Citation Format: Mary Klosterman, Christophe Cataisson, Rosalba Salcedo, Kelly Shibuya, Jennifer Waters, Giorgio Trinchieri, Stuart H. Yuspa. MyD88 and IL-17 have essential local and systemic functions in promoting tumors on mouse skin [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 4923. doi:10.1158/1538-7445.AM2017-4923
Abstract 1550: Epigenetic downregulation and growth inhibition of IGFBP7 in gastric cancer
Authors: Jin Kim, Min A Kim, Sun-Ju Byeon, Woo Ho Kim
Journal: Cancer Research (2017)

Abstract Insulin-like growth factor-binding protein 7 (IGFBP7) has been found to be a tumor suppressor in several human cancers, but the role of IGFBP7 in gastric cancer has not yet been fully investigated. In this study, we examined the epigenetic downregulation of IGFBP7 expression in gastric cancer. Analysis by qRT-PCR, western blot, and methylation specific-PCR revealed that DNA methylation was inversely correlated with IGFBP7 expression, and the expression of IGFBP7 was restored after treatment with 5-aza-2'-deoxycytidine. Immunohistochemistry showed that IGFBP7 expression was downregulated in 47.5% of advanced gastric cancer patients. Univariate and multivariate analysis showed that IGFBP7 expression and tumor stage were independent prognostic factors. In cell culture, IGFBP7 knockdown increased gastric cancer cell growth, invasion, and migration, whereas IGFBP7 overexpression in gastric cancer cells showed cell growth inhibition and apoptosis. Our data suggest that IGFBP7 functions as a tumor suppressor in gastric cancer via an epigenetic pathway. Citation Format: Jin Kim, Min A Kim, Sun-Ju Byeon, Woo Ho Kim. Epigenetic downregulation and growth inhibition of IGFBP7 in gastric cancer [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 1550. doi:10.1158/1538-7445.AM2017-1550
Abstract 3113: Knockdown of cell division cycle-associated 8 (CDCA8) suppresses hepatocellular carcinoma growth via the upregulation of tumor suppressor ATF3
Authors: Tae-Won Jeon, Min Ji Ko, Yu-Ri Seo, In Hye Baik, Ilseon Hwang, Hun-Mo Ryoo, Jin Young Kim, Keon Uk Park, Yun-Han Lee
Journal: Cancer Research (2017)

Abstract Background: Hepatocellular carcinoma (HCC) is the third most lethal cancer worldwide which remains a major challenge due to poor prognosis and limited treatment options. Cell division cycle associated 8 (CDCA8) is known as a component of a chromosomal passenger complex required for stability of the bipolar mitotic spindle and it is commonly overexpressed in human HCC. However, the functional role of CDCA8 in HCC progression remains to be clarified. In this study, we hypothesized if targeting of CDCA8 with small interfering (si) RNA could alter the course of HCC progression. We also investigated the molecular mechanism that mediates HCC cell death caused by CDCA8 silencing. Methods: Human HCC cell lines, Huh1 and Huh7, were transfected with CDCA8 siRNA and tested for growth inhibition and apoptotic induction using MTS, FACS and microscopic analysis. To obtain insights into the molecular changes in response to CDCA8 knockdown, global changes in gene expression were examined using RNA sequencing. Results: siRNA silencing of CDCA8 inhibited HCC cell growth and long-term colony formation by blocking cell cycle progression and by inducing apoptotic cell death. RNA sequencing data showed that, representatively, the anti-proliferative effects were driven by a subset of molecular alterations including the upregulation of tumor suppressive ATF3 and GADD34 genes and the downregulation of BGLAP, a key regulator of cell growth and invasiveness. Subsequent Western blot analysis affirmed that CDCA8 silencing induces the increase in the levels of ATF3 and GADD34 and the decrease in phosphorylated Akt in both Huh1 and Huh7 cells. Also, the same condition decreased the levels of PARP-1 and pro-caspase 3, accelerating apoptosis. Of importance, silencing of CDCA8 expression effectively suppressed HCC tumor growth in a murine xenograft model. Conclusion: These findings suggest that targeting CDCA8 could be an attractive option for molecular therapy of HCC. Citation Format: Tae-Won Jeon, Min Ji Ko, Yu-Ri Seo, In Hye Baik, Ilseon Hwang, Hun-Mo Ryoo, Jin Young Kim, Keon Uk Park, Yun-Han Lee. Knockdown of cell division cycle-associated 8 (CDCA8) suppresses hepatocellular carcinoma growth via the upregulation of tumor suppressor ATF3 [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 3113. doi:10.1158/1538-7445.AM2017-3113
Abstract 2025: A distinct role of RhoB in simvastatin-induced cytotoxicity in breast cancer cells
Authors: Serena Seah, Tingting Wang, Soo Chin Lee
Journal: Cancer Research (2017)

Abstract Purpose Statins, a class of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, are initially developed as cholesterol-lowering drugs by inhibiting the mevalonate pathway. They have recently gained attention for their potential anticancer properties, but the mechanisms of their anticancer effects remain elusive. This study aims to investigate the antiproliferative effects of statins in breast cancer cell lines. Methods We screened a panel of breast cancer cell lines (Estrogen receptor positive (ER+): CAMA1, MCF7, T47D, ZR-75-1 and Hcc1428; triple negative (TNBC): MDA MB231, MDA MB468, BT549, Hs578T and Hcc1806) and assessed the sensitivity of these cells to simvastatin in relation to their hormone receptor status using cell proliferation assay. Next, to elucidate the mechanisms underlying simvastatin sensitivity, we evaluated the (i) expression of key enzymes in the mevalonate pathway using qPCR and western blot analysis and (ii) the role of sterol biosynthesis metabolites by exogenously adding these compounds and testing their effects on simvastatin-induced cytotoxicity. Finally, we performed functional assays following siRNA knockout to identify the key small GTPase involved. Results We found TNBC cell lines to be more susceptible to simvastatin compared to ER+ cell lines (mean IC50 of 7.98μM [95%CI 2.75-13.22] versus 41.74μM [95%CI 6.71-76.78]). Simvastatin treatment induced robust apoptosis in TNBC but not the ER+ cells. There was no significant difference in mRNA expression of HMGCR, HMGCS, MVK, MVD, IDI1 enzymes involved in the mevalonate pathway between TNBC and ER+ breast cancer cell lines. Supplementation with geranylgeranyl pyrophosphate but not farnesyl pyrophosphate, inhibited simvastatin-mediated cell death, suggesting the involvement of geranylgeranylated proteins such as Rho family of GTPases. Here, we identified RhoB to be a key player in simvastatin-mediated cytotoxicity. RhoB showed a significant increase in transcript and protein levels in response to simvastatin treatment in the TNBC cells. Interestingly, the increase in protein expression was not associated with an increase in its prenylation as the accumulation of RhoB was observed only in the cytosolic fraction. Finally, silencing RhoB was able to abrogate the cytotoxic effects mediated by simvastatin in TNBC cells. Conclusions Taken together, our data reveals a critical role of RhoB in the anticancer activity of simvastatin, which appears to be exclusive to TNBC cells suggesting that HMG-CoA reductase inhibitors may provide new therapeutic strategies for TNBC treatment. Citation Format: Serena Seah, Tingting Wang, Soo Chin Lee. A distinct role of RhoB in simvastatin-induced cytotoxicity in breast cancer 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 2025. doi:10.1158/1538-7445.AM2017-2025
Abstract 859: Epigenetic regulation of epithelial-mesenchymal transition in esophageal squamous cell carcinoma
Authors: Chen Chen, Ming Zhao, Xiaojie Huang, Xiang Wang, Wenliang Liu, Mingjiu Chen, Bangliang Yin, Zhi Li, Yunchang Yuan, Qianjin Lu, Fenglei Yu
Journal: Cancer Research (2017)

Abstract Epithelial-mesenchymal transition (EMT) is a developmental program, which is associated with tumor progression and metastasis. Here we investigated the DNA methylation and histone modifications in the regulation of EMT in esophageal squamous cell carcinoma (ESCC). The RNA-Seq analysis identified a total of 6150 differentially expressed genes (3423 up-regulated and 2727 down-regulated). The GO terms showed that these genes belonged to several molecular functions and biological pathways. The abnormal expression of key EMT genes, some of Sox family genes and EZH2 significantly related to patient survival. The MeDIP-Seq analysis identified differentially methylated regions (DMRs) on the whole genome level with focal hypermethylation and widespread global DNA hypomethylation. The gene ontology analysis showed that the DMRs related genes belonged to several different ontological domains, such as EMT progression, cell cycle, adhesion, proliferation, and apoptosis. The results of the bisulfite-sequencing confirmed the EMT gene DMRs identified by MeDIP-Seq. However, further analyses showed that the EMT gene DMRs only related to gene expression, but not the patient survival. ChIP-Seq was then performed to observe the relationship between histone methylation and gene expression. A total of 295 genes were found to correlate with H3K27 tri-methylation (H3K27me3) , and a certain number of key EMT genes, such as ZEB1/2,AREG, GATA4,and CDH8 were identified. Further study showed that Ezh2-mediated H3K27me3 regulate the expression of key EMT genes. Ablation of Ezh2 expression prevents EMT, whereas forced expression of Ezh2 restores EMT. Sox4 gene could directly regulate Ezh2 expression, tri-methylated H3K27me3 for EMT gene repression. Taken together, our results suggest that both of the DNA methylation and H3K27me3 modification involved in the regulation of EMT in ESCC. Sox4-Ezh2-mediated H3K27me3 marks associate with key EMT gene regulation, representing an important epigenetic EMT signature. Note: This abstract was not presented at the meeting. Citation Format: Chen Chen, Ming Zhao, Xiaojie Huang, Xiang Wang, Wenliang Liu, Mingjiu Chen, Bangliang Yin, Zhi Li, Yunchang Yuan, Qianjin Lu, Fenglei Yu. Epigenetic regulation of epithelial-mesenchymal transition in esophageal squamous cell carcinoma [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 859. doi:10.1158/1538-7445.AM2017-859
Vasopressin deletion is associated with sex-specific shifts in the gut microbiome
Authors: Christopher T. Fields, Benoit Chassaing, Matthew J. Paul, Andrew T. Gewirtz, Geert J. de Vries
Journal: Gut Microbes (2017)

Brattleboro rats harbor a spontaneous deletion of the arginine-vasopressin (Avp) gene. In addition to diabetes insipidus, these rats exhibit low levels of anxiety and depressive behaviors. Recent work on the gut-brain axis has revealed that gut microbiota can influence anxiety behaviors. Therefore, we studied the effects of Avp gene deletion on gut microbiota. Since Avp gene expression is sexually different, we also examined how Avp deletion affects sex differences in gut microbiota. Males and females show modest but differentiated shifts in taxa abundance across 3 separate Avp deletion genotypes: wildtype (WT), heterozygous (Het) and AVP-deficient Brattleboro (KO) rats. For each sex, we found examples of taxa that have been shown to modulate anxiety behavior, in a manner that correlates with anxiety behavior observed in homozygous knockout Brattleboro rats. One prominent example is Lactobacillus, which has been reported to be anxiolytic: Lactobacillus was found to increase in abundance in inverse proportion to increasing gene dosage (most abundant in KO rats). This genotype effect of Lactobacillus abundance was not found when females were analyzed independently. Therefore, Avp deletion appears to affect microbiota composition in a sexually differentiated manner.
Abstract 678: A strategy to overcome the interfering problem of tissue embedding OCT compound in activity based multiplex profiling of tyrosine kinase substrates
Authors: Stephan Arni, Claudio Caviezel, Walter Weder, Sven Hillinger
Journal: Cancer Research (2017)

Abstract Introduction: The analysis of clinically relevant human tissue preserved in optimal cutting temperature (OCT) medium with activity based proteomic approaches are promising for the discovery of novel druggable disease biomarkers for the diagnosis, prognosis and prediction of response to therapeutic interventions. Nonetheless, and for many different proteomic approaches, there are important signal interferences observed in the presence of the OCT compound. Methods: We tested activity based multiplex profiling tyrosine kinase substrates in a large batch of neoplastic and non-neoplastic lung resection specimen embedded with or without OCT. We observed significant differences in overall phosphorylation levels and searched for reasons explaining such a large effect. Results: We ruled out the implication of either short versus long storage time after sample extraction or of nonhomogeneous batch processing of samples. We documented that the clear downward shift in overall phosphorylation levels coincided with the introduction of OCT as an improved embedding medium for resection specimen. For all the kinomes extracted, we developed a corrective procedure where a median centering was performed on the values of each peptide, separately for the with or without OCT samples. Conclusions: We applied corrective filtering of data to the multiplex profiling approach of well characterised tyrosine kinase substrates obtained in lung resection specimen embedded with or without OCT. With the OCT correction parameters applied, the quantitation of molecular prognosis signature based on tyrosine kinase activity differences found in lung adenocarcinoma resection specimens may result in the identification of novel targets for future anti-lung cancer therapies. Citation Format: Stephan Arni, Claudio Caviezel, Walter Weder, Sven Hillinger. A strategy to overcome the interfering problem of tissue embedding OCT compound in activity based multiplex profiling of tyrosine kinase substrates [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 678. doi:10.1158/1538-7445.AM2017-678
Abstract 2917: High complexity molecular indexing reveals that time-dependent cell plasticity underpins response to EGFR targeted therapy
Authors: Aaron Boudreau, Richard Bourgon, Marie Evangelista
Journal: Cancer Research (2017)

Abstract Non-small-cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR)-mutant tumors often receive erlotinib, a 1st generation EGFR inhibitor, as a frontline therapy. Although many patients initially experience positive response with erlotinib treatment, resistance invariably occurs in the majority of cases - however, it remains unclear the full extent by which resistance is pre-determined by genomic aberration, stochastic by potentially epigenetic mechanisms, or a combination thereof. Using a lentiviral DNA barcode library to molecularly index PC-9, an EGFR mutant (exon 19 del. E746-A750) cell line model, we used next-generation DNA sequencing to trace the fate of over 1.6 million individual cells following erlotinib treatment. Similar to previous reports, we show that multiple subpopulations are present in PC-9 cells - those that are exquisitely sensitive to erlotinib, and those that are inherently resistant, representing ~2% of the population. Surprisingly, in the absence of erlotinib treatment, we show that cells cultured over time transitioned between these two states while maintaining population equilibrium. Using mathematical modeling, we identified several parameters of state switching or flux that were required to maintain this dynamic equilibrium. Understanding the molecular basis by which cells maintain cell state plasticity may enable new strategies to limit intra-tumor heterogeneity and may ultimately improve recurrence-free survival in NSCLC following erlotinib therapy. Citation Format: Aaron Boudreau, Richard Bourgon, Marie Evangelista. High complexity molecular indexing reveals that time-dependent cell plasticity underpins response to EGFR targeted therapy [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 2917. doi:10.1158/1538-7445.AM2017-2917