bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4636: Oncogenic Notch triggers neoplastic-tumorigenesis in a transition-zone like tissue microenvironment
Authors: Deng Wu-Min , Yang Sheng-An 
Published: August 2019

Abstract
The “seed and soil” hypothesis proposed by Stephen Paget (1889) highlights the importance of tissue microenvironment for secondary tumor formation. The microenvironment that promotes primary tumor origination, however, remains largely unclear. Transition zones, where two types of epithelial tissue meet, have been characterized as high-risk sites for tumorigenesis. Here we show that the Drosophila salivary gland (SG) imaginal ring (ImR) can be used as a model to study tumorigenesis in transition zones. We found that constitutive activation of Notch signaling during the third larval instar drives overproliferation and tumor formation in the SG ImR. Interestingly, tumorigenesis always occurs at the posterior end of the ImR, which is a transitional area between the polyploid giant cells and diploid ImR cells. These Notch-induced tumors display disrupted epithelial organization, grow continuously and can metastasize once transplanted into the abdomen of adult flies, suggesting that they have the characteristics of malignant neoplasms. Further analyses revealed that the SG ImR transition zone possesses endogenously high levels of Janus kinase/signal transducers and activators of transcription (JAK-STAT) and c-Jun amino-terminal kinases (JNK), both of which are necessary for tumor growth. In this region, JNK signaling induces the expression of matrix metalloproteinase 1 (MMP1), which is also required for tumor formation in this model system. Furthermore, we found that ectopic MMP1 expression can transform the anterior end of the SG ImR, which is normally refractory to oncogenic Notch-induced tumorigenesis, into a tumor hotspot. Together, these studies reveal that local endogenous activation of JNK and JAK-STAT signaling creates a niche-like tissue microenvironment that is susceptible to oncogene-induced neoplastic tumor formation.
Citation Format: Wu-Min Deng, Sheng-An Yang. Oncogenic Notch triggers neoplastic-tumorigenesis in a transition-zone like tissue microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4636.
Abstract 4637: Non-stem cell-driven colonic tumors retain an intestinal differentiation hierarchy
Authors: Scurrah Cherie R. , Simmons Alan J. , Choi Eunyoung , Coffey Robert J. , Goldenring James R. , Lau Ken S. 
Published: August 2019

Abstract
Colorectal cancer (CRC) is the third leading cause of cancer mortality in the United States. Cancer stem cells (CSCs) play critical roles in therapeutic resistance, tumor recurrence, and metastasis that lead to patient death. We propose to evaluate the properties of CSCs in the context of the tumor cell-of-origin, the cell that initiates oncogenesis. We hypothesize that the tumor cell-of-origin is directly related to the CSCs present in tumors that consequently arise. To test this hypothesis, the stem-like properties of CSCs from stem cell- and non-stem cell-driven tumors, initiated from the Lrig1 and Mist1 promoters, respectively, were analyzed and compared through the use of lineage mapping and single-cell RNA-sequencing. We observed that although Mist1-expressing non-stem cells do not exhibit stem cell behavior under homeostatic or damage conditions, they can serve as tumor cells-of-origin. These tumors maintain a differentiation hierarchy that is lacking in stem cell-driven tumors. These results suggest that the origin of tumorigenesis influences tumor CSCs and thus tumor characteristics which could be utilized for the development of novel therapies.
Citation Format: Cherie R. Scurrah, Alan J. Simmons, Eunyoung Choi, Robert J. Coffey, James R. Goldenring, Ken S. Lau. Non-stem cell-driven colonic tumors retain an intestinal differentiation hierarchy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4637.
Abstract 4639: SLC7A11 expression confers cancer stem-like properties in small cell lung cancer cells
Authors: Kamenori Shohei , Suina Kentaro , Yamasaki Juntaro , Shintani Subaru , Otsuki Yuji , Hirata Yuki , Okazaki Shogo , Tsuchihashi Kenji , Sampetrean Oltea , Mitsuishi Yoichiro , Takahashi Fumiyuki , Takahashi Kazuhisa , Saya Hideyuki , Nagano Osamu 
Published: August 2019

Abstract
Small Cell Lung Cancer (SCLC) which accounts for 15 % of primary lung cancers is known to grow fast and metastasize easily to whole body at early stages. However, the standard care of SCLC has not been changed for over 10 years and effective treatment remains to be developed. System xc(-) comprises xCT (SLC7A11) and CD98hc subunits and is a major plasma membrane antiporter responsible for the cellular uptake of cystine in exchange for intracellular glutamate. Recently, we studied the impact of xCT inhibitor sulfasalazine (SSZ) in various cancers and found that SCLC cells manifest low level of xCT and are highly sensitive to SSZ treatment compared with non-small cell lines. Furthermore, we found that xCT expression in SCLC cells is regulated by the cellular density and the tumorsphere culture which is known to enhance the cancer stem cell properties also enhances the xCT expression in these cells. To examine the functional relevance of xCT expression to cancer stem-like properties in SCLC cells, we established the stably xCT-expressing SBC-5 cells (SBC5-xCT). Similar to other SCLC cell lines, parental SBC5 cells were not able to proliferate from single-cell level, however, SBC5-xCT cells were found to possess an ability to proliferate from single-cell level. Furthermore, SBC5-xCT cells manifested higher resistance to an anticancer agent cisplatin and higher ability of tumor-initiation than parental SBC5 cells. Our findings establish a new functional role for xCT in the promotion of cancer stem-like properties in SCLC cells.
Citation Format: Shohei Kamenori, Kentaro Suina, Juntaro Yamasaki, Subaru Shintani, Yuji Otsuki, Yuki Hirata, Shogo Okazaki, Kenji Tsuchihashi, Oltea Sampetrean, Yoichiro Mitsuishi, Fumiyuki Takahashi, Kazuhisa Takahashi, Hideyuki Saya, Osamu Nagano. SLC7A11 expression confers cancer stem-like properties in small cell lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4639.
Abstract 4642: RNA interference reveals tumor promoting roles of integrin alpha 6 (ITGA6) in hepatocellular carcinoma
Authors: Zheng Guixi , Zeballos Carla , Bouamar Hakim , Cserhati Matyas , Cigarroa Francisco G , Sun Lu-zhe 
Published: August 2019

Abstract
Introduction: Hepatocellular carcinoma (HCC) is the sixth most common malignancy worldwide and the third leading cause of cancer related mortality. The incidence and mortality rates of HCC are two times higher in Latinos than in the general population in the US and are the highest in Latinos from the South Texas region. The genetic and epigenetic events associated with the increased incidence of HCC in this population are still unclear. Increasing evidence suggests that integrins are one of the most important receptors for cell metastasis including integrin α6β1 and α6β4. However, few studies have focused on the function of integrin alpha 6 (ITGA6) in the tumorigenesis and progression of HCC. We aim to investigate the expression and potential roles of ITGA6 in HCC.
Materials and Methods: Paired HCC tissues and adjacent non-tumor tissues were collected for RNA sequencing. ITGA6 RNA and protein expression levels were evaluated by RNA sequencing, RT-qPCR, Western blot and immunohistochemistry. HCC cell lines (SNU398 and Huh7) were transiently transfected with two ITGA6siRNAs and stably transfected with an ITGA6 shRNA lentivector. These cell lines were used for assays testing the effects of ITGA6 knockdown on HCC cell proliferation, migration and anchorage independent growth.
Results: Analysis of RNA sequencing data indicated that the expression of ITGA6 increased 4-fold in HCC tumor tissues compared to adjacent non-tumor tissues, which was validated by RT-qPCR. Western blotting also confirmed increased expression of ITGA6 in the tumor tissues. The knockdown of ITGA6 by siRNAs and shRNA was confirmed with Western blot and qRT-PCR. ITGA6 knockdown significantly decreased proliferation, migration and anchorage independent growth of HCC cell lines.
Conclusions: ITGA6 is upregulated in HCC tumors in Latinos patients. ITGA6 may play a malignant-promoting role in HCC cells. Our studies provided new insights into the molecular mechanisms that drive HCC progression and potential therapeutic targets for treating patients with HCC including South Texas Latino patients.
Citation Format: Guixi Zheng, Carla Zeballos, Hakim Bouamar, Matyas Cserhati, Francisco G Cigarroa, Lu-zhe Sun. RNA interference reveals tumor promoting roles of integrin alpha 6 (ITGA6) in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4642.
Abstract 4643: Mutant ASXL1 collaborates with HHEX to promote myeloid leukemogenesis
Authors: Asada Shuhei , Takeda Reina , Inoue Daichi , Goyama Susumu , Kitamura Toshio 
Published: August 2019

Abstract
An epigenetic modulator Additional sex combs-like 1 (ASXL1) is recurrently mutated in myeloid neoplasms and its mutations are associated with poor prognosis. Recently, we generated mutant Asxl1 conditional knock-in (Asxl1-MT KI) mice mimicking human ASXL1 E635RfsX15 mutation, one of the most common mutations in myeloid neoplasms (Nagase et al. JEM 2018). Retrovirus-mediated insertional mutagenesis study exhibited susceptibility of Asxl1-MT KI bone marrow cells to myeloid leukemia, and we identified Hematopoietically expressed homeobox (Hhex) gene as one of the common retrovirus integration sites. In this study, we investigated the potential cooperation between the mutant ASXL1 and HHEX in myeloid leukemogenesis. We first performed colony-forming assay and found that forced expression of HHEX enhanced colony replating activity and blocked myeloid differentiation in bone marrow hematopoietic stem progenitor cells (HSPCs) derived from ASXL1-MT KI mice, while it showed only modest effect in normal HSPCs. The synergistic effect between the mutant ASXL1 and HHEX in blocking myeloid differentiation was also observed in human HL-60 cells. We next evaluated the role of endogenous Hhex in the mutant ASXL1-expressing cells. Depletion of endogenous Hhex using CRISPR-Cas9 system ameliorated mutant ASXL1-induced differentiation block in 32Dcl3 cells. Depletion of endogenous Hhex in murine mutant ASXL1-expressing leukemia cells [cSAM cells: cells with combined expression of SETBP1 and ASXL1 mutations (Inoue et al. Leukemia 2015), cRAM cells: cells with combined expression of RUNX1 and ASXL1 mutations (Nagase et al. JEM 2018)] also promoted differentiation and increased apoptosis. Furthermore, Hhex deletion profoundly attenuated the colonogenicity of cSAM and cRAM cells and leukemogenicity of cSAM cells. We then investigated target genes of the mutant ASXL1 and HHEX in myeloid neoplasms using public database and our previous RNA-Seq data. Among the potential target genes of the mutant ASXL1 and HHEX, we found that Myb, Etv5 and Oraov1 genes were upregulated by the mutant ASXL1 and HHEX in murine HSPCs. Conversely, Hhex depletion resulted in downregulation of these genes both in cSAM and cRAM leukemic cells. In addition, depletion of Myb, Etv5 or Oraov1 genes significantly abrogated the colonogenicity of cSAM cells. These data suggest that mutant ASXL1 and HHEX cooperatively induce myeloid leukemogenesis via dysregulating Myb, Etv5 and Oraov1.
Citation Format: Shuhei Asada, Reina Takeda, Daichi Inoue, Susumu Goyama, Toshio Kitamura. Mutant ASXL1 collaborates with HHEX to promote myeloid leukemogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4643.
Abstract 4646: Loss of nuclear HoxA10 is associated with proliferation of testicular germ cell tumors
Authors: Chen RuiQi , Li Haolong , Li Yinan , Fazli Ladan , Gleave Martin , Nappi Lucia , Dong Xuesen 
Published: August 2019

Abstract
Background: HOXA10 is a key transcriptional factor that regulates testis development as reported from previous transgenic mouse models and human inherited diseases. However, whether it also plays important roles in promoting the development of testicular cancer is not well understood.
Objective: To study the expression of HOXA10 and its regulated signaling pathways in testicular cancers.
Design, Setting, and Participants: A tissue microarray was constructed with benign and cancerous testis. TCam2, NT-2, and NCCIT cell models were applied in this study.
Intervention: Immunohistochemistry and immunofluorescence were performed to measure the expression and cellular localization of HOXA10 in testicular cancer tissues and cell models. Cell proliferation and cell cycling rates were determined by BrdU incorporation and flow cytometry assays. HOXA10 transcriptomes were profiled with Ampliseq RNA-seq in testicular cancer cells. Immunoblotting assays were used to detect HOXA10-regulated signaling.
Results: HOXA10 is a nuclear protein in benign spermatocytes. Reduced nuclear expression and increased cytoplasmic expression of HOXA10 are associated with testicular cancers. These changes are consistent in both seminoma and non-seminoma. Enhanced HOXA10 expression in testicular cancer cell models inhibits cell proliferation and delays cell cycle progression through G2/M phases. These functions of HOXA10 mainly affect the TP53, cKit, STAT3, AKT and ERK signaling pathways.
Conclusions: Loss of nuclear functions of HOXA10 enhances proliferation of testicular cancer cells, suggesting that downregulation of HOXA10 transcription activity may promote the development of testicular cancers.
Citation Format: RuiQi Chen, Haolong Li, Yinan Li, Ladan Fazli, Martin Gleave, Lucia Nappi, Xuesen Dong. Loss of nuclear HoxA10 is associated with proliferation of testicular germ cell tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4646.
Abstract 465: Molecular classification of endometrial cancer provides complementary information but does not outperform current predictive models: The Karolinska and Bern experience
Authors: Nastic Denis , Imboden Sara , Ghaderi Mehran , Rydberg Filippa , Olsson Daniel , Mueller Michael , Rau Tilman T. , Epstein Elisabeth , Carlson Joseph 
Published: August 2019

Abstract
Purpose: The purpose of this study was to evaluate the performance of a proposed prognostic molecular classification of endometrial cancer in a retrospective cohort of n=604 patients. A secondary goal was to compare the performance to existing prognostic models.
Methods: All cases were analysed using 1) sequencing of the exonuclease domain of the POLE gene, 2) microsatellite instability by immunohistochemistry, and 3) TP53 mutation, as evaluated by immunohistochemistry. Additionally, complete histopathological and clinical data was available. The cases were classified using the molecular markers analyzed.
Results: The assembled cohort largely resembled the typical unselected distribution of FIGO grade and stage. Analysis of clinicopathologic variables showed that FIGO grade and stage, LVSI, tumor histotype, depth of myometrial invasion, ESMO 2013 and 2016 risk group, recurrence and survival all were significantly associated with molecular subgroups. A large number of patients showed multiple molecular aberrations (so called multiple classifiers, n=50, 8.4%). Mutation in P53 was a statistically prognostic marker for overall survival (OS) in the univariable Cox regression (p-value 0.003 for OS, and &lt;0.001 for DSS and PFS, HRs of 1.61, 1.83 and 1.72). The POLE mutated cases showed a trend towards favorable prognosis. By contrast, histotype (endometrioid vs. non-endometrioid) was a highly significant predictor of OS, DSS and PFS (HR=2.23, p=&lt;0.001). Both ESMO 2013 and 2016, which represent an aggregate of the various clinicopathologic factors, were highly significant in predicting outcome and especially so for the high and advanced risk groups with HRs up to 70.1 (CI 23.9-206.8) and all p-values of &lt;0.001. In the multivariable Cox regression analysis, however, none of the molecular markers remained significant. The Harrell C-index for 2016 ESMO risk groups was 0.76. Adding molecular markers did not show improved discriminatory ability.
Conclusions: In this retrospective cohort, molecular markers provided important biological information that may be helpful in therapeutic decision making. However, the molecular markers did not outperform current prognostic models.
Citation Format: Denis Nastic, Sara Imboden, Mehran Ghaderi, Filippa Rydberg, Daniel Olsson, Michael Mueller, Tilman T. Rau, Elisabeth Epstein, Joseph Carlson. Molecular classification of endometrial cancer provides complementary information but does not outperform current predictive models: The Karolinska and Bern experience [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 465.
Abstract 4655: Association of a new germline variant in the MUTYH DNA glycosylase gene with colorectal adenoma transformation into malignancy
Authors: Mahasneh Amjad A. , Al-Shaheri Fawaz , Banihani Mohamemd N. 
Published: August 2019

Abstract
Background: Germline mutations in mutY homolog (E.coli) (MUTYH)DNA glycosylase gene have been associated with recessive inheritance of multiple s adenoma. Several studies revealed that germline mutations in this gene are ethnicity related. This study aimed to identify the germ-line mutations in MUTYH gene and determine their prevalence among Jordanian patients with colorectal adenoma.
Methods: 150 colorectal adenoma patients and 150cancer free individuals with no previous history of polyps were recruited. Sanger DNA sequencing of the MUTYH genewas carried out using 3130xL Genetic Analyzer. Sequencing results were analyzed by ChromasPro and mutational effects were predicted by online bioinformatics tools(accession number for the transcript used as reference isNG_008189.1).
Results: Two novel variants, g.87C&gt;T and c.1264G&gt;C, have been identified. G.87C&gt;T was found in 60 (40%) patients and 10 (6.7%) controls.C.1264G&gt;C was found in 90 (60%) patients and 7 (4.7%) controls. Thus, a significant association between g.87C&gt;T and c.1264G&gt;C variants and colorectal adenoma was found (p value for both variants was &lt;0.0001). Moreover, the newly identified germline variant, c.1264G&gt;C, was found to be significantly associated with colorectal adenoma transformation into malignancy (p&lt; 0.0001).
Conclusion: The data showed high prevalence of two germline mutations in MUTYH gene among Jordanians with colorectal adenoma, which may make them as potential early biomarkers for diagnosis of colorectal adenoma.
Citation Format: Amjad A. Mahasneh, Fawaz Al-Shaheri, Mohamemd N. Banihani. Association of a new germline variant in the MUTYH DNA glycosylase gene with colorectal adenoma transformation into malignancy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4655.
Abstract 4659: Cadmium induced malignant transformation involves activation of the Erk/MAPK pathway
Authors: Dasgupta Pritha , Kulkarni Priyanka , Bhat Nadeem S. , Gupta Ravi , Hashimoto Yutaka , Saini Sharanjot , Dar Altaf A. , Shahryari Varahram , Yamamura Soichiro , Tanaka Yuichiro , Shiina Marisa , Dahiya Rajvir , Majid Shahana 
Published: August 2019

Abstract
Cadmium (Cd) is a chemical pollutant of the natural and occupational environment and is reported to be associated with human carcinogenesis. The molecular mechanisms associated with Cd-induced prostate cancer remain elusive. This study provides evidence that Erk/MAPK signaling is a carcinogenic molecular fingerprint for Cd induced prostate cancer. Cd exposed RWPE1 (Cd-RWPE1) cells robustly formed tumors in nude mice. Functionally, chronic Cd exposure of RWPE1 cells promoted cell survival, proliferation and colony formation with inhibition of apoptosis. RT2 PCR array analysis of 84 genes involved in the Erk/MAPK pathway revealed induction of gene expression in Cd-RWPE1 cells compared to RWPE1. This was confirmed by individual TaqMan gene expression analysis. Gene Set Enrichment Analysis (GSEA) for differentially expressed genes in Cd-RWPE1 showed an enrichment of the Erk/MAPK pathway along with other pathways such as KEGG-ERBB, KEGG-Cell Cycle, KEGG-VEGF, KEGG-Pathways in cancer and KEGG-prostate cancer pathway. We randomly selected upregulated genes from the Erk/MAPK pathway and performed profile analysis in a prostate adenocarcinoma data set (n=534) from the TCGA/GDC data base. We observed upregulation of these genes in prostate cancer compared to normal prostate samples. Taken together, these data reveal that Erk/MAPK signaling is a major pathway involved in Cd-induced malignant transformation of normal prostate epithelial cells. Understanding the dominant oncogenic pathways involved in the malignant transformation of normal prostate epithelial cells may help develop optimal therapeutic strategies for prostate cancer.
Citation Format: Pritha Dasgupta, Priyanka Kulkarni, Nadeem S. Bhat, Ravi Gupta, Yutaka Hashimoto, Sharanjot Saini, Altaf A. Dar, Varahram Shahryari, Soichiro Yamamura, Yuichiro Tanaka, Marisa Shiina, Rajvir Dahiya, Shahana Majid. Cadmium induced malignant transformation involves activation of the Erk/MAPK pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4659.