tbuckley/cabot-search huggingface dataset:
Abstract 3966: Targeting integrin αvβ3-expressing cancer stem cells to manipulate tumor-associated macrophages
Authors: Hiromi I. Wettersten, Toshiyuki Minami, Megan M. Kaneda, Laetitia Seguin, Judith A. Varner, Sara M. Weis, David A. Cheresh
Journal: Cancer Research (2017)

Abstract Tumor associated macrophages are involved in regulation of cancer growth and aggressiveness. Whereas M1 macrophages trigger an inflammatory response and inhibit tumor growth, M2 macrophages secrete pro-tumor cytokines into the microenvironment to support tumor progression. A macrophage switch from M1 to M2 has been associated with lung cancer progression, and cancer stem cells have been implicated as a driver of this reprogramming. We recently reported that integrin αvβ3 expression is induced on lung adenocarcinoma cells during drug resistance and is both necessary and sufficient to reprogram these tumors to a stem-like state. Given the role that cancer stem cells play in switching M1 to M2 macrophages, we asked whether αvβ3 expression on lung adenocarcinoma cells account for this macrophage conversion. The M1/M2 macrophage ratio in αvβ3-positive tumors was markedly decreased relative to tumors lacking αvβ3. We next treated mice bearing αvβ3-positive tumors with a monoclonal antibody (LM609) targeting this receptor to assess its ability to alter the macrophage phenotype within these tumors. LM609 was able to selectively eliminate the αvβ3-positive cancer stem cells via antibody-dependent cell-mediated cytotoxicity (ADCC), and this not only increased the M1 macrophage population, but also markedly enhanced the sensitivity of these tumors to the effects of therapy. These findings reveal that αvβ3-expressing cancer stem cells favor the pro-tumor M2 macrophage phenotype. Eliminating αvβ3-positive cancer stem cells via ADCC serves to both increase pro-inflammatory macrophages within the tumor microenvironment and prolong tumor sensitivity to therapy. Citation Format: Hiromi I. Wettersten, Toshiyuki Minami, Megan M. Kaneda, Laetitia Seguin, Judith A. Varner, Sara M. Weis, David A. Cheresh. Targeting integrin αvβ3-expressing cancer stem cells to manipulate tumor-associated macrophages [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 3966. doi:10.1158/1538-7445.AM2017-3966
Abstract 2301: Genital use of talc and risk of ovarian cancer: A meta-analysis
Authors: Paolo Boffetta, Wera Berge
Journal: Cancer Research (2017)

Abstract Some epidemiological studies suggest an association between genital use of talc powders and increased risk of ovarian cancer, but the evidence is not consistent. We performed a meta-analysis of epidemiologic studies to formally evaluate this suspected association. A systematic search was conducted in Medline, Embase and Scopus, leading to the identification of 24 case-control studies and 3 cohort studies, including 302,705 women with ovarian cancer. In the meta-analysis, we used a random-effect model to calculate summary estimates of the association between genital use of talc and occurrence of ovarian cancer. We assessed potential sources of between-study heterogeneity and presence of publication bias. The summary relative risk (RR) for ever use of genital talc and ovarian cancer was 1.22 (95% confidence interval [CI] 1.13-1.30). The RR for case-control studies was 1.26 (95% CI 1.17-1.35) and for cohort studies was 1.02 (95% CI 0.85-1.20, p heterogeneity=0.007). Serous carcinoma was the only histologic type for which an association was detected (RR 1.24; 95% CI 1.15-1.34). There was no trend in RR with either duration or frequency of genital talc use. This meta-analysis resulted in a weak but statistically significant association between genital use of talc and ovarian cancer, which appears to be limited to serous carcinoma. The heterogeneity of results by study design and the lack of a trend for duration and frequency of use, however, detract from a causal interpretation of this association. Note: This abstract was not presented at the meeting. Citation Format: Paolo Boffetta, Wera Berge. Genital use of talc and risk of ovarian cancer: A meta-analysis [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 2301. doi:10.1158/1538-7445.AM2017-2301
Abstract 3475: Inhibitory effects of ZFP36L1 and ZFP36L2 on the cell proliferation in human colorectal cancer cells
Authors: Fat-Moon Suk, Ya-Ting Chen, Yu-Chih Liang
Journal: Cancer Research (2017)

Abstract ZFP36 family members include ZFP36 (also named TTP and TIS11), ZFP36L1 (also called BRF1, ERF1 or TIS11B) and ZFP36L2 (also called BRF2, ERF2 and TIS11D), which belong to the CCCH-type zinc finger protein with 2 tandem zinc finger region (TZF). These ZFP36 family proteins can function as RNA-binding protein through binding to AU-rich elements (AREs) in the 3’ untranslated region (3’ UTR) of mRNA, which promote the mRNA degradation or translation repression. Previously, ZFP36 has been found to inhibit cell proliferation through p53-dependent manner. In this study, we’d like to investigate whether ZFP36L1and ZFP36L2 have anti-proliferative activity as same as ZFP36 work. Tetracycline-inducible (Tet-On) system was used to induce the overexpression of ZFP36L1 or ZFP36L2 proteins in T-REx-293 cells by doxycycline (Dox) treatment. While ZFP36L1 or ZFP36L2 was overexpressed, we found that cell proliferation was dramatically inhibited, but didn’t cause cell death significantly. The importance of TZF was confirmed by using TZF mutants, and found that cell proliferation was deprived in HEK-293 cells with overexpression of ZFP36L1 mutant (C135/173R). Using western blot analysis, it was revealed that expression level of p53 protein was increased after the overexpression of ZFP36L1 or ZFP36L2 protein. Whereas, the levels of cell cycle-related proteins including cyclin B1, cyclin D1, cyclin A2 and p21 were decrease. Next, three human colorectal cancer cells HCT116 p53+/+, HCT116 p53-/- and SW620 (mutated p53) cells were used and ZFP36L1 or ZFP36L2 gene was transduced into these three cells by lentivirus. Overexpression of ZFP36L1 or ZFP36L2 also inhibited the cyclin D1 protein expression and cell proliferation in these three cells, however, increased the p53 and p21 protein expression in HCT116 p53+/+ cells, and decreased the c-Myc expression only in SW620 cells. On the other hand, knockdown of ZFP36L1 or ZFP36L2 increased cell proliferation, and mutation in TZF of ZFP36L1 (C135/173R) or ZFP36L2 (C174/212R) lost their anti-proliferative abilities in these three cells. Taken together, the results suggest that ZFP36L1 and ZFP36L2 play a negative role in cell proliferation of human colorectal cancer cells, and the underlying mechanisms might be mediated through downregulation of cyclin D1 and p53-independent pathway. Citation Format: Fat-Moon Suk, Ya-Ting Chen, Yu-Chih Liang. Inhibitory effects of ZFP36L1 and ZFP36L2 on the cell proliferation in human colorectal 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 3475. doi:10.1158/1538-7445.AM2017-3475
Abstract 5161: Inhibition of TBK1/IKBKE impacts tumor growth of KRAS-mutant colorectal cancers
Authors: Susanna Stinson, Jianhua He, Zhiheng Jia, Katie S. Walker, Zhi-Hua Cui, Joshua A. Kaplan, Chandrasekar Venkataramani, Yujin Wang, Fatima Guevara, Timothy Nelson, Ewa Sicinska, Kimmie Ng, Charles S. Fuchs, David Dornan
Journal: Cancer Research (2017)

Abstract Mutations in RAS occur in an estimated one third of all human cancers. While direct targeting of RAS remains challenging, targeting downstream RAS effector molecules has been shown to impact the oncogenic function of RAS and elicit anti-tumor activity. TANK Binding Kinase 1 (TBK1) and I-Kappa B Kinase Epsilon (IKBKE) serine/threonine kinases are non-canonical IKK family members. TBK1 is directly downstream of the RAS effector Ral Guanine Nucleotide Dissociation Stimulator (RALGDS) and may be required for RAS to elicit its full oncogenic potential. To explore this possibility, we identified a potent and selective TBK1/IKBKE inhibitor to determine whether inhibition of TBK1 impacts the growth of RAS-mutant cancer models. KRAS-mutant cancer cell lines showed preferential sensitivity to TBK1/IKBKE inhibition over KRAS wild-type cell lines. The TBK1/IKBKE inhibitor was then evaluated in vivo with two KRAS-mutant colorectal cancer patient-derived xenograft (PDX) models, one of which harbors co-occurring PIK3CA and KRAS mutations. The TBK1/IKBKE inhibitor caused moderate tumor growth inhibition in comparison to vehicle in both PDX models. Since RAS exerts its oncogenic effects via additional effectors, such as RAF, and that inhibition of MEK1/2 resulted in compensatory activation of TBK1 in a KRAS-mutant cancer cell line, we tested if inhibition of TBK1/IKBKE in combination with the MEK inhibitor, trametinib, would result in superior efficacy in PDX models. The combination of a TBK1/IKBKE inhibitor and trametinib resulted in greater than 90% tumor growth inhibition within both of these KRAS mutant PDX models compared to either single agent alone. We also tested TBK1/IKBKE inhibition in a KRAS wild-type colorectal PDX model containing a BRAF mutation. In this model, TBK1/IKBKE did not inhibit tumor growth and, although there was significant tumor growth inhibition with trametinib alone, there was no further enhancement of efficacy with the addition of a TBK1/IKBKE inhibitor. Together, these data suggest that a TBK1/IKBKE inhibitor in combination with a MEK inhibitor may impact KRAS-mutant cancers. Citation Format: Susanna Stinson, Jianhua He, Zhiheng Jia, Katie S. Walker, Zhi-Hua Cui, Joshua A. Kaplan, Chandrasekar Venkataramani, Yujin Wang, Fatima Guevara, Timothy Nelson, Ewa Sicinska, Kimmie Ng, Charles S. Fuchs, David Dornan. Inhibition of TBK1/IKBKE impacts tumor growth of KRAS-mutant colorectal cancers [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 5161. doi:10.1158/1538-7445.AM2017-5161
Abstract 5351: A simple yet powerful method to purify NGS compatible RNA from formalin fixed paraffin embedded tissues using FormaPure DNA
Authors: Jung H. Doh
Journal: Cancer Research (2017)

Abstract Extensive archives of formalin-fixed, paraffin-embedded (FFPE) cancer tissues and next generation sequencing (NGS) capabilities provide rich resources for identifying and validating new cancer biomarkers. However, the ability to conduct FFPE-NGS studies has been limited by poor nucleic acid purification methods that are generally difficult and cumbersome to perform, particularly with RNA. FormaPure DNA was recently launched to provide a simplified workflow to extract DNA from FFPE curls. Its nucleic acid binding chemistry employs Beckman Coulter's proprietary SPRI (solid phase reversible immobilization) technology, which purifies nucleic acids without centrifugation or vacuum manifold. The SPRI technology ensures stronger binding and higher quality purification than other silica-coated bead methods that typically lead to lower quality results due to instances of nucleic acid shearing. Here, we present a modified FormaPure DNA workflow to purify RNA from FFPE samples, offering the flexibility to examine both genomic and transcriptomic roles in cancer biomarkers studies. We show that our extractions yield significantly more RNA (up to 2.5 µg per FFPE curl) and take a fraction of the time to perform compared to other benchmarks. Furthermore, we demonstrate that purified RNA can be used to generate high quality NGS data. Lastly, our extraction method can be automated on a variety of Beckman Coulter’s Biomek liquid handling workstations to offer an integrated solution for high-throughput FFPE-RNA-NGS experiments: RNA from 96 FFPE samples can be purified for NGS in less than 5 hours with minimal hands-on time. Citation Format: Jung H. Doh. A simple yet powerful method to purify NGS compatible RNA from formalin fixed paraffin embedded tissues using FormaPure DNA [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 5351. doi:10.1158/1538-7445.AM2017-5351
Evidence-based management of adult patients with diffuse glioma – Authors' reply
Authors: Michael Weller, Martin van den Bent, Jörg C Tonn, Roger Stupp, Matthias Preusser, Elizabeth Cohen-Jonathan-Moyal, Roger Henriksson, Emilie Le Rhun, Carmen Balana, Olivier Chinot, Martin Bendszus, Jaap C Reijneveld, Frederic Dhermain, Pim French, Christine Marosi, Colin Watts, Ingela Oberg, Geoffrey Pilkington, Brigitta G Baumert, Martin J B Taphoorn, Monika Hegi, Manfred Westphal, Guido Reifenberger, Riccardo Soffietti, Wolfgang Wick
Journal: The Lancet Oncology (2017)

We appreciate the interest of our colleagues representing the European Low-Grade Glioma Network in the updated European Association for Neuro-Oncology (EANO) guidelines. 1 Weller M van den Bent M Tonn JC et al. for the European Association for Neuro-Oncology (EANO) Task Force on GliomasEANO guideline on the diagnosis and treatment of adult astrocytic and oligodendroglial gliomas. Lancet Oncol. 2017; 18: e315-e329 Google Scholar Such guidelines often represent a multidisciplinary consensus that aims at providing guidance also in areas where evidence from conclusive clinical studies is limited or absent. Our colleagues miss a specific reference to the value of radiological growth rates. European Association for Neuro-Oncology (EANO) guideline on the diagnosis and treatment of adult astrocytic and oligodendroglial gliomasThe European Association for Neuro-Oncology guideline provides recommendations for the clinical care of adult patients with astrocytic and oligodendroglial gliomas, including glioblastomas. The guideline is based on the 2016 WHO classification of tumours of the central nervous system and on scientific developments since the 2014 guideline. The recommendations focus on pathological and radiological diagnostics, and the main treatment modalities of surgery, radiotherapy, and pharmacotherapy. In this guideline we have also integrated the results from contemporary clinical trials that have changed clinical practice. Full-Text PDF Evidenced-based medicine in glioma: molecular biology is only part of the storyRecently, Weller and colleagues1 proposed the new European Association for Neuro-Oncology (EANO) guidelines for adult gliomas. They have to be congratulated for their efforts in building recommendations based on the 2016 revision of the WHO classification, translating the integrated histomolecular diagnosis into algorithmic decision making. They confirm that maximal safe surgical resection in high-volume specialist centres has to be proposed whenever feasible, independent of the grade of malignancy and the histomolecular profile. Full-Text PDF
Abstract 1978: Identification of the metastatic cell populations in a spontaneous mouse model of melanoma
Authors: Xiaoshuang Li, Raul Torres, Lidia Kos
Journal: Cancer Research (2017)

Abstract Melanoma is the deadliest form of skin cancer due to its high propensity to metastasize and resistance to current therapies. We have created a spontaneous mouse model of metastatic melanoma (Dct-Grm1/K5-Edn3) where metastasis to the lungs is 80% penetrant. The primary tumors of these mice present cellular heterogeneity with cells at varying levels of differentiation. The main goal of this study is to determine the metastatic potential of the primary tumor resident Tyrosinase positive cells and evaluate the dynamic pattern of gene expression as those cells move from the primary tumors to the sites of metastasis. To accomplish this aim we crossed the Dct-Grm1/K5-Edn3 mice to CreERT2/ ROSAmT/mG mice to indelibly label Tyrosinase cell populations within the primary tumor by topical application of 4-hydroxytamoxifen at the tumor site. In vivo lineage tracing and characterization of those labeled cells was performed in the metastatic lesions. We found that Tyrosinase positive cells enter the circulation before the appearance of any noticeable tumor or nevus and establish close interactions with the vasculature as single cells. Metastatic cells in close association with the inner wall of the vasculature lose pigmentation and do not express melanocytic markers. Interestingly, those intravascular cells mimic endothelial cell properties with the expression of platelet endothelial cell adhesion molecule (PECAM-1, also known as CD31). In the lung tissue, the primary tumor derived Tyrosinase positive cells or their progeny can survive and establish successful metastases with pigmentation. This in vivo lineage tracing system in mouse will be a powerful model to evaluate and help us understand the etiology and pathogenesis of melanoma metastasis. Further characterization of those more aggressive cells in melanoma will allow for the development of new prognostic tests and novel therapeutic strategies to eliminate metastasis. Citation Format: Xiaoshuang Li, Raul Torres, Lidia Kos. Identification of the metastatic cell populations in a spontaneous mouse model of melanoma [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 1978. doi:10.1158/1538-7445.AM2017-1978
Abstract 235: Probiotics ameliorate <i>Porphyromonas gingivalis</i>-promoted pancreatic cancer progression in oncogenic <i>Kras</i> transgenic mice
Authors: Ming-Shiou Jan, Wan-Ting Chen, Yu-Jen Chen, Chia-Wei Lin, Wen-Wei Chang, Chung-Hung Tsai, Jia-Shiou Peng, Li-Jin Hsu
Journal: Cancer Research (2017)

Abstract Periodontal disease has been shown to play important roles in the pathogenesis of many chronic diseases. Recent epidemiological studies and microbiome analysis have suggested that periodontal disease may be associated with the progression of pancreatic cancer. Our recent study has demonstrated that oral-smear of a periodontitis pathogen Porphyromonas gingivalis (P. gingivalis) significantly induced pancreatic cancer deterioration in the KrasG12D/-Pdx-1-Cre transgenic mouse model. Higher expression levels of epithelial-mesenchymal transition (EMT) markers, such as N-Cadherin, αSMA, SNAIL-1, Vimentin and ZEB1, were observed in P. gingivalis-treated KrasG12D/-Pdx-1-Cre mice than the untreated controls. In an attempt to develop a prophylactic treatment for pancreatic cancer, the mice were fed with a combination of two probiotics, Lactobacillus reuteri and Lactobacillus paracasei, for four consecutive weeks after oral-smear of P. gingivalis. These probiotic strains have been demonstrated to have the efficacy of either anti-inflammation or enhancement of cell-mediated immunity, respectively. Our results demonstrated that oral administration of the probiotics significantly suppressed oncogenic Kras-induced pancreatic cancer development and reversed P. gingivalis-stimulated cancer deterioration in mice. Significantly reduced expression of the aforementioned EMT markers in pancreatic cancer tissues was observed in KrasG12D/-Pdx-1-Cre transgenic mice treated with the probiotics. Our results suggest that the microbiota profile is very important for pancreatic cancer development. The manipulation of microbiota for enhancing antitumor immunity may be an emerging strategy for cancer prevention. Citation Format: Ming-Shiou Jan, Wan-Ting Chen, Yu-Jen Chen, Chia-Wei Lin, Wen-Wei Chang, Chung-Hung Tsai, Jia-Shiou Peng, Li-Jin Hsu. Probiotics ameliorate Porphyromonas gingivalis-promoted pancreatic cancer progression in oncogenic Kras transgenic mice [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 235. doi:10.1158/1538-7445.AM2017-235
Abstract 3481: Leveraging protein coding gene expression profiles to accurately impute lncRNA transcriptome of cancer cells
Authors: Aritro Nath, Paul Geeleher, R. Stephanie Huang
Journal: Cancer Research (2017)

Abstract Long noncoding RNAs (lncRNAs) represent a large, diverse and tissue-specific class of transcripts that are involved in gene regulation. Recent large-scale cancer sequencing efforts indicate that lncRNAs are an important component of the cancer transcriptome, and may play a critical role in carcinogenesis and drug sensitivity. Accurate profiling of lncRNAs however remains a challenge owing to significantly lower expression levels than mRNA, requiring deep paired-end total RNA sequencing, which can be prohibitively expensive. Additionally, previous generation microarrays that constitute a vast majority of GEO and ArrayExpress datasets do not provide comprehensive lncRNA coverage. Here we propose a lncRNA expression imputation (LEXI) framework to reconstruct the lncRNA transcriptome of cancer cells using their mRNA expression profiles. Our goal is to provide a tool that enables the harnessing of enormous wealth of publicly available cancer mRNA datasets and discover novel lncRNAs associated with carcinogenesis and drug sensitivity. The LEXI approach is based on learning patterns of mRNA expression associated with each lncRNA across a diverse cohort of cancer cells and then predict lncRNA expression profile of uncharacterized cells. We developed LEXI by evaluating the performance of various machine-learning algorithms benchmarked in a cross-validation study across a cohort of 675 cancer cell lines and 9755 pan-cancer tissues. We adapted the LEXI framework based on optimal performance and computation time and show that LEXI accurately predicts lncRNA expression profiles in both cell lines and tissues. To demonstrate the utility of LEXI, we reconstruct the lncRNA transcriptome of over 1000 cell lines and 2000 TCGA samples, and compare with RNAseq measured lncRNA levels in corresponding samples. We further show expression levels of MALAT1, HOTAIR, CCAT1 and other established cancer-associated lncRNAs are accurately predicted across cancer types, and can be used to discover novel associations in uncharacterized phenotypes. LEXI will be available as a free resource for researchers to easily obtain lncRNA profiles using their own mRNA data. Citation Format: Aritro Nath, Paul Geeleher, R. Stephanie Huang. Leveraging protein coding gene expression profiles to accurately impute lncRNA transcriptome of 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 3481. doi:10.1158/1538-7445.AM2017-3481