bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4923: MyD88 and IL-17 have essential local and systemic functions in promoting tumors on mouse skin
Authors: Klosterman Mary , Cataisson Christophe , Salcedo Rosalba , Shibuya Kelly , Waters Jennifer , Trinchieri Giorgio , Yuspa Stuart H. 
Published: July 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 4925: Microbiome-TP53 gene interaction in human lung cancer
Authors: Greathouse Leigh , White James , Bliskovsky Valery , Vargas Ashley , Polley Eric , Bowman Elise , Khan Mohammed , Robles Ana , Ryan Brid , Dzutsev Amiran , Trinchieri Giorgio , Pineda Marbin , Bilke Sven , Meltzer Paul , Walther-Antonio Marina , Ehrlich Garth , Mell Joshua , Earl Joshua , Balashov Sergey , Bhat Archana , Valm Alex , Deming Clayton , Conlan Sean , Oh Julia , Segre Julie , Harris Curtis 
Published: July 2017

Abstract
Lung cancer is the leading cancer diagnosis worldwide and the number one cause of cancer deaths. Exposure to cigarette smoke, the primary risk factor in lung cancer, reduces epithelial barrier function and increases susceptibility to infections. Herein, we hypothesized that somatic mutations together with cigarette smoke create a dysbiotic microbiota that is associated with lung carcinogenesis. Using lung tissue from controls (n=33) or cancer cases (n=143), we conducted 16S rRNA gene sequencing (MiSeq), with RNA-seq data from lung cancer cases in The Cancer Genome Atlas (n=1112) serving as the validation cohort. We demonstrate a lower alpha diversity in normal lung as compared to non-tumor adjacent or tumor tissue, indicating a shift in the overall microbial community in lung cancer patients as compared to those without cancer. Lung cancer cases were classified by the relative abundance of two taxa, Variovorax and Streptococcus, with an increase in Variovorax abundance in tumors as compared to non-tumor adjacent paired lung tissue (FDR corrected P=0.013). The species of Variovorax was identified histologically, and also by two additional 16S rRNA strategies (Resphera Insight analysis and PacBio sequencing). A group of taxa were associated with squamous cell carcinoma (SCC), of which Acidovorax were enriched in smokers (P =0.0013). Further, these taxa, including Acidovorax, exhibited higher abundance among the subset of SCC cases with TP53 mutations, an association not seen in adenocarcinomas (AD). Therefore, we observed a microbiome-gene and a microbiome-exposure interaction in SCC lung cancer tissue. Together, these results open the door for future biomarker research that could be used to improve screening and direct mechanistic studies of lung cancer therapy.
Citation Format: Leigh Greathouse, James White, Valery Bliskovsky, Ashley Vargas, Eric Polley, Elise Bowman, Mohammed Khan, Ana Robles, Brid Ryan, Amiran Dzutsev, Giorgio Trinchieri, Marbin Pineda, Sven Bilke, Paul Meltzer, Marina Walther-Antonio, Garth Ehrlich, Joshua Mell, Joshua Earl, Sergey Balashov, Archana Bhat, Alex Valm, Clayton Deming, Sean Conlan, Julia Oh, Julie Segre, Curtis Harris. Microbiome-TP53 gene interaction in human lung 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 4925. doi:10.1158/1538-7445.AM2017-4925
Abstract 4928: Impact of E. hirae on the tumoricidal activity of cyclophosphamide
Authors: Daillere Romain , Vetizou Marie , Zitvogel Laurence 
Published: July 2017

Abstract
The tumor microenvironment is influenced by anticancer therapies, and even more so by those affecting the gut homeostasis. We previously reported that a deviated repertoire of the intestinal microbiome called « dysbiosis », caused by broad spectrum antibiotics compromised the efficacy of cyclophosphamide (CTX), an immunomodulatory alkylating agent exerting cytotoxic effects against cancer, highlighting the importance of the gut microbiota in this mechanism (Viaud, Science, 2013). CTX is responsible for disrupting the gut barrier integrity as well as intestinal homeostasis, allowing a NOD2-dependent translocation of several Gram-positive bacteria into secondary lymphoid organs. CTX breaks the intestinal tolerance towards the intestinal microbiota and leads to immunization of the host against some bacterial strains. Here, we identified a Gram positive bacteria, Enterococcus hirae, which markedly modulates the intestinal and systemic immunity through the elicitation of bacterial-specific Th1 and pathogenic Th17 cells. Moreover, we have shown that E. hirae is capable of enhancing tumor-specific CD4+ and CD8+ T cell responses against candidate tumor antigens. In parallel, we have demonstrated that intestinal epithelial cells NOD2 receptors represent ‘‘gut immune checkpoints’’ restricting the immunogenicity of E. hirae. Finally, E. hirae specific-memory Th1 immune responses selectively predicted longer progression-free survival in advanced lung or ovarian cancer patients treated with immunotherapy and chemotherapy (platinum salts- or CTX-based chemotherapy) (Daillère, Immunity, 2016). Altogether, E. hirae represents a valuable probiotic against cancer, an oncomicrobiotic ameliorating the efficacy of the most common alkylating immunomodulatory compound.
Citation Format: Romain Daillere, Marie Vetizou, Laurence Zitvogel. Impact of E. hirae on the tumoricidal activity of cyclophosphamide [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 4928. doi:10.1158/1538-7445.AM2017-4928
Abstract 4930: Genetic and epigenetic characteristics of esophageal cancer tissues with microbiome fusobacterium nucleatum
Authors: Baba Yoshifumi , Yamamura Kensuke , Nakagawa Shigeki , Mima Kosuke , Ishimoto Takatsugu , Iwatsuki Masaaki , Sakamoto Yasuo , Yoshida Naoya , Baba Hideo 
Published: July 2017

Abstract
Background: Research into the microbiome is a rapidly advancing field in human cancers. The gut microbiome has recently been shown to play an important role in health, as well as in diseases such as obesity, inflammatory bowel disease, diabetes, non-alcoholic fatty liver disease, and several types of cancers. Fusobacterium nucleatum is a component of the human microbiome that primarily inhabits the oral cavity. It causes periodontal disease and has also been implicated in the development of human cancers. We have recently reported that Fusobacterium nucleatum in esophageal cancer tissues was associated with shorter survival, suggesting a potential role as a prognostic biomarker. In addition, our KEGG enrichment analysis using microarray data showed that Fusobacterium nucleatum might also contribute to aggressive tumor behavior through activation of chemokines such as CCL20. Nonetheless, molecular features of Fusobacterium nucleatum-positive esophageal cancers have been still unknown. Methods: Using 325 esophageal cancers, we detected Fusobacterium nucleatum DNA in 74 tumors (23%). We assessed other genetic and epigenetic events including mutations in KRAS, BRAF, PIK3CA gene, p53 expression, phosphorylated-AKT expression, LINE-1 methylation level (global DNA methylation level), IGF2 DMR0 methylation, MGMT methylation, and MLH1 methylation. Results: The LINE-1 methylation levels of Fusobacterium nucleatum-positive tumors was significantly lower compared with that of Fusobacterium nucleatum-negative tumors (P&lt;0.0001). In addition, Fusobacterium nucleatum was significantly associated with PIK3CA wild type (P=0.010). There was no relationship of Fusobacterium nucleatum with KRAS, BRAF mutation, p53 expression, p-AKT expression, IGF2 DMR0 methylation, MGMT methylation, or MLH1 methylation. Conclusion: Fusobacterium nucleatum was related with LINE-1 hypomethylation and PIK3CA wild type. Our findings may shed lights on understanding the mechanism by which Fusobacterium nucleatum affects aggressive tumor behavior. .
Citation Format: Yoshifumi Baba, Kensuke Yamamura, Shigeki Nakagawa, Kosuke Mima, Takatsugu Ishimoto, Masaaki Iwatsuki, Yasuo Sakamoto, Naoya Yoshida, Hideo Baba. Genetic and epigenetic characteristics of esophageal cancer tissues with microbiome fusobacterium nucleatum [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 4930. doi:10.1158/1538-7445.AM2017-4930
Abstract 4932: Oxygen sensing by T cells establishes an immunologically favorable metastatic niche
Authors: Clever David , Restifo Nicholas 
Published: July 2017

Abstract
Cancer cells must evade immune responses at distant sites to establish metastases. The lung is a frequent site for metastasis. We hypothesized that lung-specific immunoregulatory mechanisms create an immunologically permissive environment for tumor colonization. We found that T-cell-intrinsic expression of the oxygen-sensing prolyl-hydroxylase (PHD) proteins is required to maintain local tolerance against innocuous antigens in the lung but powerfully licenses colonization by circulating tumor cells. PHD proteins limit pulmonary type helper (Th)-1 responses, promote CD4(+)-regulatory T (Treg) cell induction, and restrain CD8(+) T cell effector function. Tumor colonization is accompanied by PHD-protein-dependent induction of pulmonary Treg cells and suppression of IFN-γ-dependent tumor clearance. T-cell-intrinsic deletion or pharmacological inhibition of PHD proteins limits tumor colonization of the lung and improves the efficacy of adoptive cell transfer immunotherapy. Collectively, PHD proteins function in T cells to coordinate distinct immunoregulatory programs within the lung that are permissive to cancer metastasis.
Note: This abstract was not presented at the meeting.
Citation Format: David Clever, Nicholas Restifo. Oxygen sensing by T cells establishes an immunologically favorable metastatic niche [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 4932. doi:10.1158/1538-7445.AM2017-4932
Abstract 4938: A vicious cycle between osteoblasts-derived WISP-1 and mesenchymal-like cancer cells is essential to prostate cancer metastasis
Authors: Chang An-Chen , Chuang Show-Mei , Tang Chih-Hsin 
Published: July 2017

Abstract
Prostate cancer (PCa) is the most commonly diagnosed malignancy in the United States and other Western countries. It is well established that tumor microenvironment plays an important role in cancer progression and metastasis. Wnt-induced secreted protein-1 (WISP-1) belongs to the CCN family (CTGF/CYR61/NOV) that plays a key role in osteogenesis and tumor growth. We found that osteoblast-conditioned media (OBCM) stimulated migration and invasion in human PCa cells. Furthermore, the medium was collected 2 days after treatment of osteoblasts with PCa conditioned media which were designed as PCa-OBCM. The results showed that treatment of PCa cells with PCa-OBCM further increased the migration and invasion activity, as well as epithelial-mesenchymal transition (EMT), including the epithelial marker (E-cadherin) down-regulation and mesenchymal marker (N-cadherin and twist) up-regulation. Moreover, human cytokine array was used to measure the secretion of 32 Cytokines into PCa-OBCM. The data showed that WISP-1 is highly up-regulated with PCa-OBCM treatment compared to OBCM. Stimulation of osteoblasts with PCa conditioned media induced WISP-1 expression. In contrast, knockdown WISP-1 in osteoblasts impacted PCa-OBCM-mediated cancer migration, invasion, and EMT. In addition, conditioned media from PCa cells was incubated with another cytokine array membranes. The data showed that ADAM-9 and cathepsinL were overexpressed in PCa conditioned media but only ADAM-9 could regulate WISP-1 expression in osteoblasts. Taken together, these results demonstrated that primary PCa-secreted ADAM-9 promotes osteoblasts-derived WISP-1 up-regulation, which in turn enhances primary PCa cells migration, invasion, and EMT, resulting in cancer metastasis. Our study suggests that inhibition of osteoblasts-derived WISP-1 is a new therapeutic target for treating metastasis in human PCa patients.
Citation Format: An-Chen Chang, Show-Mei Chuang, Chih-Hsin Tang. A vicious cycle between osteoblasts-derived WISP-1 and mesenchymal-like cancer cells is essential to prostate cancer metastasis [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 4938. doi:10.1158/1538-7445.AM2017-4938
Abstract 4939: Activation of GSK3β/β-catenin pathway promotes organ-specific metastasis in prostate cancer
Authors: Qin Siyuan , Song Qiong , Dai Jinlu , Tong Haibo , Keller Evan , Zhang Jian , Lu Yi 
Published: July 2017

Abstract
Metastasis is the major cause of treatment failure in various malignancies, including prostate cancer (PCa). Accumulating data has suggested that primary cancer cells prefer to spread to certain distant organs. To explore the mechanisms of different cancer cells preferentially metastasizing to certain organs, we established a prostate cancer lung metastasis model. Murine prostate cancer cells (RM1), which labeled with luciferase, were used in this study. RM1 cells were injected into left tibia of mouse (C57BL/6J), and monitored the tumor growth and metastasis every week by Bioluminescence Imaging. The mice would be sacrificed when metastatic tumor appeared in multi-organs. We isolated the lung metastatic tumor, made single cell suspension and amplified. The lung metastatic tumor cells were specifically metastasized to lung when the tumor cells were injected intratibially again. After several cycles we obtained highly lung metastatic tumor cells, named RM1-LM cells. Further, we investigated property and function changes in RM1-LM cells compared to parental cells (RM1) using in vitro assays. We firstly found the highly lung metastatic tumor cells showed more mesenchymal properties. Western blot results showed that hallmarks of EMT including E-cadherin, vimentin, snail, and ZO-1 were altered significantly in RM1-LM cells. Then, we observed that the highly lung metastatic tumor cells exhibited increased proliferative, colony formation, migratory and invasive abilities. Mechanistic analyses indicated that prostate cancer organ-specific metastasis mediated by the activation of GSK-3β/β-catenin pathway. The current study may provide potential therapeutic targets and diagnostic biomarkers of PCa metastasis. This work was supported by Natural Science Foundation of China (NSFC) Key Project (81130046); NSFC (81171993; 81272415); Guangxi Projects of China (2013GXNSFEA053004; 2012GXNSFCB053004).
Note: This abstract was not presented at the meeting.
Citation Format: Siyuan Qin, Qiong Song, Jinlu Dai, Haibo Tong, Evan Keller, Jian Zhang, Yi Lu. Activation of GSK3β/β-catenin pathway promotes organ-specific metastasis in prostate 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 4939. doi:10.1158/1538-7445.AM2017-4939
Abstract 494: Frequent NRG1 genomic rearrangements in invasive mucinous adenocarcinoma from caucasian patients
Authors: Trombetta Domenico , Rossi Giulio , Sparaneo Angelo , Fabrizio Federico P. , Manzorra Maria C. , Maiello Evaristo , Fazio Vito M. , Graziano Paolo , Muscarella Lucia A. 
Published: July 2017

Abstract
Invasive Mucinous Adenocarcinoma (IMA) accounts for 2-5% of lung adenocarcinomas and it is associated with an unfavorable clinical course, mainly due to lack of effective treatments. Current knowledge of the molecular alterations involved in IMAs is limited. Recently, the NRG1 genomic rearrangement was identified as a subtype-specific molecular feature of Asiatic IMA cohorts since it acts as a strong inductor of the aberrant tyrosine kinase activity of ErbB2/ErbB3 heterodimers through PI3K–AKT and MAPK cellular cascades.
In light of these premises we explored the occurrence and frequency of NRG1 fusions in a cohort of 90 Formalin Fixed Paraffin Embedded (FFPE) lung adenocarcinoma from Caucasian patients (35 non-IMAs and 55 IMAs) by performing FISH analysis to study the NRG1 genomic region (β-III isoform, chr 8p12). In total, 16 out of 55 (29%) IMAs showed NRG1 rearrangements, whereas in non-mucinous lung adenocarcinoma group it was found with a frequency of 3% (1/35). The functional effect of the genomic rearrangement was confirmed by RT-PCR and sequencing in three cases with available RNA, where NRG1-CD74 fusion transcripts were identified. An aberrant expression of pErbB3 was also observed in these three NRG1 rearranged cases by performing immunohistochemistry analysis, thus confirming the ErbB3 cascade activation.
Our results strongly confirm NRG1 rearrangements as potentially treatable oncogenic driver alterations associated with a definite lung adenocarcinoma subtype in Caucasian population and support a clear molecular rationale to novel therapeutic opportunity for these aggressive tumors.
Note: This abstract was not presented at the meeting.
Citation Format: Domenico Trombetta, Giulio Rossi, Angelo Sparaneo, Federico P. Fabrizio, Maria C. Manzorra, Evaristo Maiello, Vito M. Fazio, Paolo Graziano, Lucia A. Muscarella. Frequent NRG1 genomic rearrangements in invasive mucinous adenocarcinoma from caucasian patients [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 494. doi:10.1158/1538-7445.AM2017-494
Abstract 4944: Modeling tumor dormancy by using EMT lineage tracing under chemotherapy
Authors: Lopez Jay , Bednarczyk Robert , Altorki Nasser , Mittal Vivek , Gao Dingcheng 
Published: July 2017

Abstract
Tumor dormancy and recurrence after initial effective treatment arose as one of most challenging questions in cancer research. Up to now, there is still no established animal model of tumor dormancy, which significantly hurdles our exploration in this field. In an effort to trace the phenotypic changes of metastatic tumor cells in vivo, we found that the dormant tumor cells were derived through a mechanism of epithelial to mesenchymal transition (EMT). We established an EMT lineage tracing model in triple transgenic mice (Tri-MMTV) carrying Fsp1-cre, Rosa26-RFP-GFP and MMTV-PyMT alleles. Tumor cells from these mice are able to switch their fluorescent marker from RFP to GFP due to the specific activation of CRE recombinase during the EMT process. Using this EMT lineage tracing model, we confirmed that within a predominantly epithelial primary tumor, a small portion of tumor cells undergo EMT. Strikingly, lung metastases were mainly derived from non-EMT tumor cells maintaining their epithelial phenotype. However, under chemotherapy condition, EMT cells significantly contributed to recurrent lung metastasis. The EMT tumor cells survived the chemotherapy due to reduced proliferation and apoptotic tolerance, which are common characters of dormant tumor cells. More interestingly, the GFP+ EMT tumor cells reversed back to epithelial phenotype through mesenchymal to epithelial transition (MET) and formed recurrent metastatic lesions in the lung. These results suggest that our EMT lineage tracing model may provide a unique tool to study tumor dormancy and recurrence. The EMT process may represent a major mechanism for tumor dormancy under chemotherapy condition, while MET is a driving mechanism for tumor recurrence.
Citation Format: Jay Lopez, Robert Bednarczyk, Nasser Altorki, Vivek Mittal, Dingcheng Gao. Modeling tumor dormancy by using EMT lineage tracing under chemotherapy [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 4944. doi:10.1158/1538-7445.AM2017-4944