tbuckley/cabot-search huggingface dataset:
Abstract 4419: HER2 expression and 17β-estradiol induce ACSL4 expression in estrogen receptor positive mammary carcinoma cells
Authors: Maroua Mbarik, Anissa Belkaid, Marc E. Surette
Journal: Cancer Research (2017)

Abstract Breast cancer is a multifactorial disease involving several molecular changes and a high proliferation rate often under the activation of hormonal receptors. Therefore, cancer cells require the metabolic machinery for membrane synthesis and to promote signaling pathways. Amongst biomolecules required for efficient cell growth are polyunsaturated fatty acids, like arachidonic acid, that are essential nutrients whose cellular uptake is partly governed by long chain acyl-CoA synthetases (ACSL). In this study, we investigated the impact of 17β-estradiol and Human Epidermal growth factor Receptor 2 (HER2) on cellular uptake of polyunsaturated fatty acids and on the expression of ACSLs. The administration of 17β-estradiol in steroid-starved MCF-7 and T47D mammary carcinoma cells induced a significant increase in cellular uptake of arachidonic acid (AA) and eicosapentaenoic acid (EPA), and in ACSL4 protein content (p&amp;lt;0.05). There was no change in the expression of the ACSL1, ACSL3 and ACSL6 isoforms. Increased ACSL4 protein expression was not accompanied by changes in ACSL4 mRNA expression, but was associated with a significant increase in the protein half-life (T1/2=26±2h) compared to untreated cells (T1/2=8±0.5h). Silencing of ERα reversed the impact of 17β-estradiol on ACSL4 protein expression and half-life. Silencing of ACSL4 eliminated the 17β-estradiol-induced increase in cellular polyunsaturated fatty acid uptake, cell migration and invasion capacities. ACSL4 silencing also prevented the 17β-estradiol-induced increases in p-Akt and p-GSK3β, as well as the 17β-estradiol-induced decrease in E-cadherin expression, important events in epithelial to mesenchymal transition. In addition, the forced expression of HER2 in MCF7 cells induced an increase in cellular uptake of AA and in the expression of ACSL4 measured by both qPCR and western blots. This suggests that HER2-induces ACSL4 expression by a mechanism that differs from that of 17β-estradiol. Further investigations are planned to study the implication of ACSL4 on cellular functions induced by HER2. Overall, these results demonstrate that an induction of ACSL4 protein expression in ERα positive MCF-7 and T47D cells is implicated in 17β-estradiol-induced cellular migration and invasion capacities. Citation Format: Maroua Mbarik, Anissa Belkaid, Marc E. Surette. HER2 expression and 17β-estradiol induce ACSL4 expression in estrogen receptor positive mammary carcinoma 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 4419. doi:10.1158/1538-7445.AM2017-4419
Abstract 4889: Characterizing the viromes in pediatric cancers through whole genome sequencing
Authors: Ti-Cheng Chang, John Easton, Emilia M. Pinto, Jinghui Zhang, Gang Wu
Journal: Cancer Research (2017)

Abstract Viral infections have been associated with the development of adult cancers such as cervical carcinomas and head/neck cancers. However, there is lack of clear understanding of the composition of virome in pediatric cancers. Here, we made the first attempt to identify differentially enriched viral communities in biological material from pediatric cancer patients, and to predict virus integration sites that may be associated with etiology or tumor progression of pediatric cancers. The Pediatric Cancer Genome project (PCGP) has previously generated whole-genome sequencing (WGS) data of matched cancer-normal samples for over 600 pediatric patients from three classes of cancers: leukemia, solid tumors, and central nervous system (CNS) cancers. We re-constructed the virome composition profiles in each sample based on the unmapped and partially mapped Illumina reads extracted from the PCGP WGS data. Taxonomic assignments of the extracted read data were conducted using the Kraken metagenomic pipeline and virus integration sites were predicted by the VyPER pipeline. Custom scripts were used for downstream comparative analyses. A comparison of the alpha diversity of each virome indicated that the tumor samples in general have a lower diversity compared to the normal samples across all tumor types. This trend holds true in leukemia, where both tumor and normal samples were blood derived, suggesting that this is not due to different origins of the tumor samples. Ordination analyses based on the viral composition identified distinct clusters in the three classes of cancers. These clusters were formed mainly by samples of medulloblastoma for CNS, T-ALL and hypodiploid B-ALL for leukemia, retinoblastoma and rhabdomyosarcoma for solid tumors. Viruses, such as phages, herpesviraidae and several sarcoma viruses, were differentially enriched in these clusters. Potential integration with retroviruses or herpesviruses was predicted at a high frequency. Less frequent integration events were also detected with known oncogenic viruses, such as simian virus 40 and human adenovirus C, which were under deep sequencing validation. In summary, our comprehensive characterization of the virome in a wide spectrum of pediatric cancers revealed a potential connection between specific viral communities and integration sites in certain distinct types of pediatric cancers. Our findings highlight a possible mechanism underlying the tumor progression in pediatric patients. Citation Format: Ti-Cheng Chang, John Easton, Emilia M. Pinto, Jinghui Zhang, Gang Wu. Characterizing the viromes in pediatric cancers through whole genome sequencing [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 4889. doi:10.1158/1538-7445.AM2017-4889
Abstract 1439: Genetic profiling of colitis-associated cancer indicates <i>de novo</i> carcinogenesis and the impact of chronic inflammation
Authors: Masashi Fujita, Nagahide Matsubara, Kazuhiro Maejima, Tomoki Yamano, Ikuo Matsuda, Seiichi Hirota, Hiroki Ikeuchi, Naohiro Tomita, Hidewaki Nakagawa
Journal: Cancer Research (2017)

Abstract Background: Chronic inflammation is one of the major causes of carcinogenesis. Ulcerative colitis (UC) and Crohn’s disease (CD) increase the risk of colitis-associated cancer (CAC) development, and its biological and pathological characters are also distinct. However, the genetic mechanism of how chronic inflammation leads to CACs is still unclear. Methods: We obtained frozen tumor tissues from 21 CAC patients and performed exome or whole-genome sequencing of the matched tumor-normal samples. We enumerated recurrently mutated genes and selected 43 genes among them for target capture. We then performed targeted resequencing of 84 FFPE specimens from CAC tissues. Totally, we made genomic profiles of 105 CACs. Results: The most frequently mutated gene was TP53, whose mutation was found in 70 of 105 samples (67%), which is more prevalent in CACs than common colorectal cancers (CRCs). Somatic mutations of APC and KRAS were less prevalent (17 and 13 samples, respectively). Genes in the Wnt signaling pathway (APC, FBXW7, TCF7L2, and RNF43) were mutated in 31 samples, whereas those in the TGFβ pathway (TGFBR2, ACVR1B, SMAD2, SMAD4, LTBP4) were mutated in 25 samples. Mutational signature of CACs shows some differences from common CRCs. Conclusion: Our results confirmed genetic differences for cancer development between CACs and common CRCs. Frequent TP53 mutations and less frequent APC mutations are consistent with the idea of “de novo” carcinogenesis than adenoma-carcinoma sequence. The association between the mutations and clinical information are also discussed. Citation Format: Masashi Fujita, Nagahide Matsubara, Kazuhiro Maejima, Tomoki Yamano, Ikuo Matsuda, Seiichi Hirota, Hiroki Ikeuchi, Naohiro Tomita, Hidewaki Nakagawa. Genetic profiling of colitis-associated cancer indicates de novo carcinogenesis and the impact of chronic inflammation [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 1439. doi:10.1158/1538-7445.AM2017-1439
Abstract 922: Delta133p53 represses p53-inducible senescence genes and enhances the generation of human induced pluripotent stem cells
Authors: Izumi Horikawa, Kye-yoon Park, Han Li, Kazunobu Isogaya, Yukiharu Hiyoshi, Katsuhiro Anami, Ana I. Robles, Abdul M. Mondal, Kaori Fujita, Manuel Serrano, Curtis C. Harris
Journal: Cancer Research (2017)

Abstract p53 functions to induce cellular senescence and apoptosis, which can be incompatible with self-renewal of pluripotent stem cells such as induced pluripotent stem cells (iPSC) and embryonic stem cells (ESC). On the other hand, p53 regulates DNA damage response and repair and thus plays an essential role in maintaining genomic integrity and suppressing malignant transformation in iPSC and ESC. It remains to be elucidated whether and how p53 and its regulators contribute to balanced regulation between the self-renewing capacity and the genomic and functional integrity in these pluripotent stem cells. We hypothesized the involvement of Δ133p53, a physiological p53 protein isoform that inhibits the activity of full-length p53 (FL-p53), and here examined 12 lines of human iPSC and their original fibroblasts, as well as 3 human ESC lines, for endogenous protein levels of Δ133p53 and FL-p53, and mRNA levels of p53 target genes of different functions. While FL-p53 levels in iPSC and ESC widely ranged from below to above those in the fibroblasts, all iPSC and ESC lines expressed elevated levels of Δ133p53. The p53-inducible genes that mediate cellular senescence (e.g., p21WAF1 and miR-34a), but not those for apoptosis and DNA repair, were downregulated in iPSC and ESC. Consistent with these endogenous expression profiles, overexpression of Δ133p53 in human fibroblasts preferentially repressed the p53-inducible senescence mediators and significantly enhanced their reprogramming to iPSC. The iPSC clones derived from Δ133p53-overexpressing fibroblasts, when injected into immunodeficient mice, formed well-differentiated, benign teratomas, suggesting that Δ133p53 overexpression is non- or less oncogenic than total inhibition of p53 activities. Overexpressed Δ133p53 prevented FL-p53 from binding to the regulatory regions of p21WAF1 and miR-34a, providing a mechanistic basis for its dominant-negative inhibition. This study supports the hypothesis that upregulation of Δ133p53 is an endogenous mechanism that facilitates human somatic cells to become pluripotent without malignant transformation. Citation Format: Izumi Horikawa, Kye-yoon Park, Han Li, Kazunobu Isogaya, Yukiharu Hiyoshi, Katsuhiro Anami, Ana I. Robles, Abdul M. Mondal, Kaori Fujita, Manuel Serrano, Curtis C. Harris. Delta133p53 represses p53-inducible senescence genes and enhances the generation of human induced pluripotent stem 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 922. doi:10.1158/1538-7445.AM2017-922
Abstract 2034: LSD1 inhibition alone and in combination with chemotherapy in Ewing sarcoma cell lines
Authors: Darcy Welch, Elliot Kahen, Christopher L. Cubitt, Damon R. Reed
Journal: Cancer Research (2017)

Abstract Background: Ewing Sarcoma (ES) is the second most common primary bone cancer affecting children and young adults. Despite advances in treatment that have led to survival rates of approximately 73% for localized disease, outcomes for patients with metastatic or recurrent ES remain poor. A distinguishing feature of ES is the presence of the EWS/FLI1 fusion in 85% of cases. The fusion has been shown to alter expression of a number of oncogenic genes. Mechanistic studies have demonstrated that the NuRD co-repressor complex interacts with EWS/FLI1. The associated protein LSD-1 contributes to the repressive function by histone modifications. While reversible LSD1 inhibitors demonstrate single agent activity, in preclinical models, a system to evaluate combinations may be needed for optimizing effect in clinical trials. Methods: Here, we seek to confirm promising single drug activity and evaluate combination therapies using active chemotherapies currently utilized in ES care (4-HC, etoposide, SN-38, vincristine and doxorubicin) along with the LSD1 Inhibitors SP2509 and SP2577 and romidepsin, an HDAC inhibitor. We evaluated these combinations in high-throughput screening platforms and well-established cell line models for ES (A-673, TC-32, RD-ES, TC-71). Taking into consideration past lessons learned from in vitro experiments, we designed stringent screening conditions that assess the candidate compounds and combinations at clinically-relevant concentrations and exposure times that mimic the in vivo pharmacokinetics in an effort to maximize the translational potential of these results to the clinical setting. All combinations of agents were studied in two-drug combinations to evaluate for synergy in addition to efficacy. Results: IC50 for SP2509 was found to be in the submicromolar range across cell lines with SP2577 being more potent. A-673 and TC-71 were 5-10 fold less sensitive than RD-ES and TC-32. Agents currently utilized in clinic were universally active at clinically achievable concentrations and exposure times. Combinations showed additivity frequently and demonstrated promising activity that can be used to inform further decision making once LSD1 inhibition toxicities are better known. These findings suggest potentially promising opportunities for developing combination clinical trials to maximize development of LSD1 inhibitors. Citation Format: Darcy Welch, Elliot Kahen, Christopher L. Cubitt, Damon R. Reed. LSD1 inhibition alone and in combination with chemotherapy in Ewing sarcoma cell lines [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 2034. doi:10.1158/1538-7445.AM2017-2034
Abstract 3703: A genomic characterization of testicular germ cell tumor immune microenvironment
Authors: Daniel P. Hollern, Katie Hoadley, Benjamin Vincent, Charles M. Perou, TCGA Testicular Germ Cell Tumor Analysis Working Group
Journal: Cancer Research (2017)

Abstract Testicular germ cell tumors (TGCT) are a histologically diverse set of tumors and the most common cancer type in young men. As part of the TCGA effort, we analyzed tumors from 133 patients including 4 patients with asynchronous double primary TGCTs (137 primary tumors) by histopathologic, genomic, epigenomic, transcriptomic, and proteomic methods. We noted molecular signatures of various immune cells were greater in seminomas than other histologies. Specifically, we find seminomas show elevation of expression signatures for B-Cells, Cytotoxic T-Cells, Th17 Cells, and T-regulatory cells. This increase in immune cells were accompanied by high expression of specific cytokines and key immune checkpoint molecules such as CTLA4, LAG3, and PD-L1. Strong positive correlations were identified between immune cell signatures and increases in T-Cell and B-Cell receptor diversity measures. Interestingly, increases in receptor diversity also showed strong positive associations to gene expression signatures for anti-tumor immune responses. This indicates that anti-tumor immune responses in seminomas may be polyclonal. We found no evidence for relationships between immune cells and mutation load, neoantigen load, or detected viruses. We do observe that seminomas have significantly high expression of the testis specific antigens, yet the contribution of these antigens to the immune response did not show strong or uniform statistical indications. Instead, the strongest association between expanded immune cells populations in seminomas were the presence of activating mutations in KIT accompanied by elevation of gene expression of signatures associated with KIT and expression of MHC class I and II genes. Together, these data describe the immune microenvironment of seminomas and suggest alterations and events in the kit pathway as being critical to the nature of the immune microenvironment in seminomas. Citation Format: Daniel P. Hollern, Katie Hoadley, Benjamin Vincent, Charles M. Perou, TCGA Testicular Germ Cell Tumor Analysis Working Group. A genomic characterization of testicular germ cell tumor immune microenvironment [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 3703. doi:10.1158/1538-7445.AM2017-3703
Abstract 2850: A systems genetics approach reveals Rnaseh2c-immune response axis that affects metastasis severity in breast cancer
Authors: Sarah Deasy, Kent Hunter
Journal: Cancer Research (2017)

Abstract Metastatic breast cancer is a devastating disease with a 5-year survival rate of only 26%. This is due to a lack of effective therapies against established metastases and an inability to identify high risk patients who would benefit from specific adjuvant therapies to prevent metastatic progression. We have shown in mouse models that spontaneously arising tumors metastasize with different severity based on the mouse genetic background. Using systems genetics approaches we have identified genes correlated with metastasis and survival in both mice and humans. Rnaseh2c was identified as a novel candidate metastasis susceptibility gene. This gene encodes a scaffolding subunit of the Ribonuclease H2 enzyme which removes ribonucleotides misincorporated into the DNA. Experimentally modulating Rnaseh2c expression in a murine mammary cancer cell line resulted in significant changes in pulmonary metastasis, confirming this gene as a metastasis modifier. Mutations in Rnaseh2c are known to cause Aicardi-Goutieres Syndrome, a neurological autoinflammatory disorder that overlaps clinically with congenital viral infections and the autoimmune disease Systemic Lupus Erythematosus. Given this, we hypothesized that altered expression of Rnaseh2c in breast cancer cells affects metastasis by engaging the immune system. To investigate immune system involvement, we analyzed metastasis in immunocompromised mice. T cell deficiency ablated the effect of reduced Rnaseh2c expression on metastasis, revealing for the first time an Rnaseh2c-immune response axis in metastasis. Gene ontology pathway analysis following mRNA-sequencing of Rnaseh2c knockdown and overexpression tumors revealed that 20% of the genes with altered expression are involved in immune system-related pathways, including T cell signaling and antigen presentation. Furthermore, genes with significant changes included Type I interferons, T cell markers, and immune regulators. These results confirm that Rnaseh2c is a novel metastasis modifier gene and validate our hypothesis that the immune system is mediating the effect of Rnaseh2c on metastasis. This mechanism highlights a potential new target for combination with immune modulatory therapies to combat this devastating disease and adds to a panel of genes we identified that together could determine patients with high risk for metastasis. Citation Format: Sarah Deasy, Kent Hunter. A systems genetics approach reveals Rnaseh2c-immune response axis that affects metastasis severity in breast 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 2850. doi:10.1158/1538-7445.AM2017-2850
TREM2 in Neurodegenerative Diseases
Authors: Taylor R. Jay, Victoria E. von Saucken, Gary E. Landreth
Journal: Molecular Neurodegeneration (2017)

TREM2 variants have been identified as risk factors for Alzheimer's disease (AD) and other neurodegenerative diseases (NDDs). Because TREM2 encodes a receptor exclusively expressed on immune cells, identification of these variants conclusively demonstrates that the immune response can play an active role in the pathogenesis of NDDs. These TREM2 variants also confer the highest risk for developing Alzheimer's disease of any risk factor identified in nearly two decades, suggesting that understanding more about TREM2 function could provide key insights into NDD pathology and provide avenues for novel immune-related NDD biomarkers and therapeutics. The expression, signaling and function of TREM2 in NDDs have been extensively investigated in an effort to understand the role of immune function in disease pathogenesis and progression. We provide a comprehensive review of our current understanding of TREM2 biology, including new insights into the regulation of TREM2 expression, and TREM2 signaling and function across NDDs. While many open questions remain, the current body of literature provides clarity on several issues. While it is still often cited that TREM2 expression is decreased by pro-inflammatory stimuli, it is now clear that this is true in vitro, but inflammatory stimuli in vivo almost universally increase TREM2 expression. Likewise, while TREM2 function is classically described as promoting an anti-inflammatory phenotype, more than half of published studies demonstrate a pro-inflammatory role for TREM2, suggesting that its role in inflammation is much more complex. Finally, these components of TREM2 biology are applied to a discussion of how TREM2 impacts NDD pathologies and the latest assessment of how these findings might be applied to immune-directed clinical biomarkers and therapeutics.
Abstract 2187: A pro-nanodrug with intratumoral reconstitution and intracellular delivery beyond therapy-resistance molecular pumps
Authors: Rong Xu, Mauro Ferrari, Haifa Shen
Journal: Cancer Research (2017)

Abstract Tumor metastases to distant organs pose a serious challenge to cancer treatment. The metastatic tumor lesions are less accessible to cancer drugs and the malignant cells often quickly develop therapy resistance. To address both biological and drug transport concerns in cancer treatment, we have developed a novel composite pro-nanodrug to provide sustained intra-tumoral assembly of nanotherapeutics, and tested its anti-cancer efficacy in murine models of breast cancer metastases to the lung and liver. Specifically, large payloads of polymeric doxorubicin (pDox) pro-drug were packaged as single molecules into a porous silicon microparticles that can be enriched in tumor tissue in the forms of vascular and cellular depots. Once inside the tumor, the pDox molecules self-assemble into nanoparticles that are released into the tissue where they are effectively internalized by tumor cells. The nanoparticulate prodrug is transported through the vesicular system, and doxorubicin is cleaved from the polymer and released in the immediate proximity of the nucleus beyond the reach of the drug efflux pumps. In vivo efficacy studies demonstrated that the pro-nanodrug was effective in treating metastatic tumors with or without expression of the multi-drug resistant genes. Citation Format: Rong Xu, Mauro Ferrari, Haifa Shen. A pro-nanodrug with intratumoral reconstitution and intracellular delivery beyond therapy-resistance molecular pumps [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 2187. doi:10.1158/1538-7445.AM2017-2187