bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4373: AR signaling in concert with PP2A/B regulates YAP1 expression in prostate cancer cells
Authors: Cinar Bekir , Moreno Carlos S. 
Published: August 2018

Abstract
The transcriptional coactivator YAP1 is a key nuclear effector of the Hippo pathway. STK4/MST1 and LATS1/2 are the core kinase components of the Hippo pathway, which restricts organ size and prevents tumorigenesis by attenuating cell proliferation and inducing cell death. Previously, we have reported that STK4/Hippo-YAP1 signaling could play a critical role in prostate cancer progression and therapeutic relapse. Here, we investigated the effects of androgen hormone signaling on YAP1 expression and post-transcriptional modifications in prostate cancer cells. We demonstrated that androgen exposure reduced Ser127 phosphorylation on YAP1 in a time-dependent manner in the castration-sensitive prostate cancer cell line, LNCaP, but without altering the levels of YAP1-Ser127 phosphorylation in the C4-2 cell line, a castration-resistant subline of LNCaP cells. As demonstrated by imaging and cell fractionation methods, androgen exposure promoted the nuclear accumulation of YAP1 in LNCaP; however, regardless of androgen exposure, YAP1 was accumulated in the nucleus of C4-2 cells. In addition, we demonstrated that androgen exposure reduced YAP1-Ser127 phosphorylation that was induced by okadaic acid, a potent activator of Ser/Thr phosphatases PP1 and PP2A. Also, we demonstrated that androgen exposure increased PP2A/B protein expression. Moreover, reduction of phospho-Ser127-YAP1 was correlated with increases in total YAP1 protein, which coincided with androgen receptor (AR) nuclear accumulation by androgen. Consistent with these observation, the genetic (siRNA) or the pharmacologic (enzalutamide) inhibition of AR signaling attenuated the expression of YAP1 protein. Furthermore, our analysis of the publicly available TCGA (The Cancer Genome Atlas) set indicated that YAP1 and AR mRNA expressions were positively correlated in prostate clinical samples. These observations suggest that YAP1 is a direct target of androgen hormone signaling, implicating that the AR-PP2A/B-YAP1 axis is a viable cancer drug target.
Citation Format: Bekir Cinar, Carlos S. Moreno. AR signaling in concert with PP2A/B regulates YAP1 expression in prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4373.
Abstract 438: High-quality CNV segments from low-coverage whole genome sequencing from FFPE cancer biopsies based on an evaluation of multiple CNV tools
Authors: Lee HoJoon , Xia Li Charlie , Greer Stephanie , Bell John , Grimes Sue M. , Bouwens Christina Wood , Shin Giwon , Lau Billy TC , Johnson Lucas , Andor Noemi , Day Kenneth , Miller Mickey , Escobar Helaman , Nadauld Lincoln , Ji Hanlee P. , Hummelen Paul Van 
Published: August 2018

Abstract
Changes in DNA copy number, i.e., somatic CNVs, are common genetic aberrations in cancers. The effects of CNV include alteration in gene dosage across large segments of the cancer genome affecting the expression of cancer driver genes by amplifications, or cancer suppressor genes by deletions. In addition, CNVs are markers of underlying rearrangements within or between chromosomes and there is increasing evidence supporting a greater role for CNVs in developing and maintaining neoplastic cell population diversity.
Copy number aberrations can be estimated from next generation sequencing data, with high sensitivity and genomic resolution by sequencing the whole genome (WGS). For this study, we demonstrated that high quality CNV calls can be extracted in a fast and cost-effective way from low-coverage whole genome sequencing. Novaseq S2 flowcells (Illumina Inc) enables to obtain an average coverage of 3-4x per sample after pooling up to 96 samples per flowcell.
We examined three different copy number detection tools (CNVkit, BicSeq, and seqCBS) from paired tumor and normal WGS using microarray data as a reference. Pearson correlations were computed between the reference and CNVs from the WGS in two fashion; i) segment based and ii) gene based. The segment based comparison used sliding window of 100 K bp while gene based comparison used segments at the gene level.
We found high correlations between microarray and WGS segments. The highest correlations were obtained by CNVkit, ranging from 0.964 to 0.985 (SD: 0.973 - 0.007) and BicSeq, ranging from 0.963 to 0.986 (SD: 0.975 - 0.008). These results open the prospect of assessing large cancer cohorts of hundreds of samples at a reasonable cost. We are planning to apply this method to a large cohort of Stage III colon cancer patients and determine the clinical relevance of CNVs for survival.
Citation Format: HoJoon Lee, Li Charlie Xia, Stephanie Greer, John Bell, Sue M. Grimes, Christina Wood Bouwens, Giwon Shin, Billy TC Lau, Lucas Johnson, Noemi Andor, Kenneth Day, Mickey Miller, Helaman Escobar, Lincoln Nadauld, Hanlee P. Ji, Paul Van Hummelen. High-quality CNV segments from low-coverage whole genome sequencing from FFPE cancer biopsies based on an evaluation of multiple CNV tools [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 438.
Abstract 4380: Role of FAM3B/PANDER in inhibition of cell death and tumor growth in breast and prostate cancer
Authors: Caldeira Izabela D. 
Published: August 2018

Abstract
FAM3B/PANDER is a novel cytokine-like protein that induces apoptosis in beta-cells and regulates the effects of insulin in peripheral tissues. Since previous data revealed that FAM3B can be expressed by prostate and breast tumors, we evaluated the role of this cytokine in prostate and breast tumor progression. FAM3B expression was compared by quantitative PCR in LnCAP, PC-3 and DU145 prostate tumor cell lines and MCF-7 and MDA-MB- 231 breast tumor cell lines. After treatment with either recombinant FAM3B protein or secreted FAM3B obtained from conditioned media (CM) derived from FAM3B-overexpressing 293T cells, the cell death and viability of DU145 and MDA-MB- 231 cell lines were evaluated. DU145 and MDA-MB- 231 cells overexpressing FAM3B protein were produced by lentiviral-mediated transduction of full-length FAM3B cDNA. Cell viability and apoptosis were analyzed in DU145-FAM3B and MDA-231-FAM3B cells after treatment with cell death inducers. Anchorage-independent growth and scratch wound assays were used to evaluate in vitro tumorigenicity and cell migration, respectively. In vivo tumorigenicity and invasiveness were evaluated by tumor xenograft growth in nude mice. We observed that FAM3B was highly expressed by hormone responsive cells (LnCAP and MCF-7) and low expressed in unresponsive hormone cells (PC-3, DU145 and MDA-MB- 231). Cell viability and survival of DU145 and MDA-MB- 231 cells increased after exogenous treatment with recombinant FAM3B protein or CM containing FAM3B-secreted protein. Overexpression of FAM3B in DU145 and MDA-MB- 231 cells promoted an inhibition of apoptosis triggered by TNF-alpha and staurosporine. Cell death inhibition was accompanied by increased gene expression of the anti-apoptotic Bcl-2 and Bcl-xL genes, and by slight decrease in expression of pro-apoptotic gene Bax and with a decrease of caspases proteolytic activities. When compared to control, cells overexpressing FAM3B displayed a decreased anchorage independent growth and increased motility in vitro, as well as an increased tumor growth in xenografted nude mice. In agreement Immunohistochemistry analysis from tumor xenografts revealed similar anti-apoptotic phenotype in FAM3B overexpression, with an increase of Bcl-2. The results showed that FAM3B was capable to activates pro-survival mechanisms with an increasing of tumor growth by, activation of Bcl-2 and Bcl-xl pathways, suggesting the role of this cytokine in breast and in prostate tumors progression.
Citation Format: Izabela D. Caldeira. Role of FAM3B/PANDER in inhibition of cell death and tumor growth in breast and prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4380.
Abstract 4382: Complement system mutational landscape reveals C4BPA mutations enhance apoptosis in an immune-independent manner
Authors: Olcina Monica M. , Balanis Nikolas G. , Kim Ryan K. , Thompson Michael J. , Graeber Thomas G. , Giaccia Amato J. 
Published: August 2018

Abstract
The complement system is an important pathway in immunity. When dysregulated in the tumor microenvironment, complement is associated with suppression of antitumor immunity and tumorigenesis promotion. While complement has been reported to have important intracellular functions in immune cells, the role of intracellular complement in cancer has remained poorly understood to date. In this study we investigated the prevalence and significance of pathway-wide complement mutations as well as their role with respect to intracellular complement in cancer. We describe mutations in both individual genes as well as within functional groups that are significantly associated with altered survival outcomes. Analyzing mutations occurring across multiple TCGA cancer types highlighted the potential clinical significance of certain mutations that would otherwise not have surfaced at a single cancer level. As an example, we test the significance of mutations in complement regulator C4BPA in vitro and in vivo in a single cancer type. This approach allowed us to uncover a new immune-independent biologic function of the complement system with potential clinical implications for colorectal cancer patients. Specifically, we find that colorectal cancer cells with specific C4BPA mutations display increased oxaliplatin-induced intracellular C4BPA stabilization. By studying the mechanistic basis of this association we report novel crosstalk between intracellular complement and apoptosis signaling, occurring in an NFκB/RelA-dependent manner. Based on both experimental and patient outcome data, we therefore propose that assessing complement mutation status might facilitate patient stratification. In the case of C4BPA mutations, this would be particularly relevant to improve accuracy of prognosis assessment in stage II colorectal patients where TNM staging alone does not accurately predict outcome in patients who might benefit from adjuvant chemotherapy.
Citation Format: Monica M. Olcina, Nikolas G. Balanis, Ryan K. Kim, Michael J. Thompson, Thomas G. Graeber, Amato J. Giaccia. Complement system mutational landscape reveals C4BPA mutations enhance apoptosis in an immune-independent manner [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4382.
Abstract 4387: Triplet nucleotide repeat-based siRNAs are highly toxic to cancer cells
Authors: Murmann Andrea E. , Putzbach Will , Gao Quan , Patel Monal , Bartom Elizabeth T. , Law Calvin , Bridgeman Bryan , Chen Siquan , McMahon Kaylin M. , Thaxton Shad C. , Peter Marcus E. 
Published: August 2018

Abstract
Triplet nucleotide repeat (TNR) expansions in the genome cause a number of degenerative diseases. A prominent TNR expansion involves the triplet CAG in the huntingtin (HTT) gene responsible for Huntington's disease (HD). Pathology is caused by both protein and RNA generated from the TNR regions including small siRNA-sized repeat fragments. An inverse correlation between the length of the repeats in HTT and cancer incidence has been reported for HD patients. We now show that siRNAs based on the CAG TNR can be used to kill cancer cells by targeting genes containing reverse complimentary long TNRs in their open reading frames. Of the 60 siRNAs based on the different TNRs, the 6 members in the CAG/CUG family of related TNRs are the most toxic to both human and mouse cancer cells. siCAG/CUG-induced cell death occurs in vitro in all tested cancer cell lines and in a preclinical mouse model of ovarian cancer with no signs of toxicity to the mice. We propose to explore TNR-based siRNAs as a novel form of anticancer reagents.
Citation Format: Andrea E. Murmann, Will Putzbach, Quan Gao, Monal Patel, Elizabeth T. Bartom, Calvin Law, Bryan Bridgeman, Siquan Chen, Kaylin M. McMahon, Shad C. Thaxton, Marcus E. Peter. Triplet nucleotide repeat-based siRNAs are highly toxic to cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4387.
Abstract 4391: CD95L mRNA is toxic to cancer cells
Authors: Putzbach William , Haluck-Kangas Ashley , Gao Quan , Sarshad Aishe A. , Bartom Elizabeth , Stults Austin , Qadir Abdul S. , Scholtens Denise M. , Hafner Markus , Peter Marcus 
Published: August 2018

Abstract
CD95/Fas ligand (CD95L) is best characterized for its role in activating extrinsic apoptosis through binding to its receptor, CD95. However, we recently reported that the CD95L mRNA is enriched in sequences that when converted to si- or shRNAs kill cancer cells through an RNAi-dependent mechanism. When loaded into the RNA Induced Silencing Complex (RISC), CD95L-derived small RNAs downregulate genes critical for cancer cell survival, eliciting a unique form of cell death we call Death Induced by Survival Gene Elimination (DISE). We now report that expression of full-length CD95L mRNA itself is toxic to cells. Acute expression of either wild-type CD95L mRNA in CD95-deficient cells or a CD95L mRNA with a premature stop codon in CD95 wild-type cells induces cell death. RNA-Seq analysis of small RNA reveals that CD95L mRNA is specifically processed into discrete clusters ~19-25 nucleotides long that map along the CD95L ORF. These clusters of CD95L sequences were bound by AGO proteins in cells about to die, suggesting that the mRNA may be killing cells through an RNAi-dependent mechanism. Generation of AGO-bound CD95L mRNA sequences does not appear to be dependent on the canonical miRNA biogenesis pathway, as clusters of CD95L mRNA were detectable in both Drosha and Dicer deficient HCT116 cells. We propose that CD95L mRNA is toxic to cells through processing and loading of small CD95L-derived RNA sequences into the RISC.
Citation Format: William Putzbach, Ashley Haluck-Kangas, Quan Gao, Aishe A. Sarshad, Elizabeth Bartom, Austin Stults, Abdul S. Qadir, Denise M. Scholtens, Markus Hafner, Marcus Peter. CD95L mRNA is toxic to cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4391.
Abstract 4393: Electrochemotherapy with irreversible electroporation and FOLFIRINOX improves survival in murine pancreatic adenocarcinoma by increasing apoptosis and decreasing tumor cell proliferation
Authors: Bhutiani Neal , Pandit Harshul , Zheng Qianqian , Li Suping , Li Yan , Martin Robert C. 
Published: August 2018

Abstract
Introduction: Combining gemcitabine (gem) with irreversible electroporation (IRE) has been shown to result in increased tumor cell apoptosis in a murine model of pancreatic adenocarcinoma (PDAC). However, it remains unclear whether this effect can be augmented locally and systemically by utilizing more active chemotherapies. The objective of this study was to evaluate the efficacy of IRE+FOLFIRINOX (FOL: 5-FU, leucovorin, irinotecan, and oxaliplatin).
Methods: Athymic nude mice underwent intrapancreatic injection with S2-013 PDAC cells. After 7-10 days, tumors were confirmed with ultrasound and mice were treated with chemotherapy (gem or FOL), IRE, or chemotherapy+IRE. Four hours after last chemotherapy, pancreas was evaluated histologically. Levels of irinotecan and its active metabolite (SN-38) were evaluated in organs of mice treated with FOL and IRE+FOL. Experiments were repeated and survival analyses performed to evaluate long-term efficacy. Pancreas was harvested for histology and evaluation of apoptotic machinery, cell cycle proteins, and tumor cell proliferation.
Results: IRE+FOL (ECT) resulted in increased tumor cells apoptosis compared to gem, gem+IRE, or FOL (apoptotic index (AI) 34.6% vs. 3.8%, 7.3%, 5.8%, respectively, p&lt;0.001). High performance liquid chromatography (HPLC) demonstrated a 1.5-2-fold increase in irinotecan and SN-38 in the pancreas and a 4-fold increase of both compounds in the liver in mice treated with ECT vs. FOL. ECT significantly improved overall survival when compared to mice treated with IRE or FOL (median 7 days ECT vs. 4 days IRE vs. 3 days FOL, p=0.03). Histology demonstrated increased tumor cell apoptosis at time of death (AI = 34.2% ECT vs. 13.2% IRE vs. 4.4% FOL, p=0.026). Western blot demonstrated an increase in active caspase 3 (0.14 ECT vs. 0.00 IRE vs. 0.03 FOL fold change/GAPDH, p=0.02). ECT resulted in lower cell proliferation compared to IRE or FOL (0.2% vs. 0.3% vs. 0.9, p&lt;0.001).
Conclusions: ECT with IRE and FOL causes significant tumor cell apoptosis, decreases tumor cell proliferation, enhances systemic FOL exposure, and improves overall survival. Human Phase 1 trials have been initiated to evaluate safety and efficacy of this therapeutic modality.
Citation Format: Neal Bhutiani, Harshul Pandit, Qianqian Zheng, Suping Li, Yan Li, Robert C. Martin. Electrochemotherapy with irreversible electroporation and FOLFIRINOX improves survival in murine pancreatic adenocarcinoma by increasing apoptosis and decreasing tumor cell proliferation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4393.
Abstract 4407: Targeting BMP4 and miR-139-5p in EGFR-mutant non-small cell lung cancer cells
Authors: Bach Duc-Hiep , Luu Thi-Thu-Trang , Kim Dong-Hwa , An Yong Jin , Park Hyen Joo , Park Sunghyouk , Lee Sang Kook 
Published: August 2018

Abstract
Non-small cell lung cancer (NSCLC) cells with harboring EGF receptor (EGFR) mutations are sensitive to EGFR tyrosine kinase inhibitors (EGFR-TKIs). Recent studies suggest that bone morphogenetic proteins (BMPs) and microRNAs (miRNAs) might act as oncogenes or suppressors in tumor microenvironment. We identified the potential roles of BMPs and miRNAs involved in EGFR TKIs resistance by analyzing datasets from a pair of NSCLC-sensitive and NSCLC-resistant cells. BMP4 was found to be significantly over-expressed in EGFR-TKI resistant cells and its underlying mechanism was highly associated with induction of energy metabolism for cancer cells through modulating Acyl-CoA synthetase long-chain family member 4. In addition, miR-139-5p was found to be importantly down-regulated in the resistant NSCLC cells. The combination of miR-139-5p and yuanhuadine, a natural product-derived antitumor agent, synergistically suppressed the BMP4 expression in the resistant cells. We furthermore confirmed that LDN-193189, a small molecule BMP receptor 1 inhibitor inhibited the tumor growth in a xenograft nude mouse model implanted with drug resistant cells. These findings suggest a role of BMP4-mediated tumorigenesis in the progression of acquired drug resistance in EGFR-mutant NSCLC cells.
Key words: microRNAs, bone morphogenetic proteins, drug resistance, metabolism, EGFR-TKIs, NSCLC.
Acknowledgements
This study was funded by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2015R1D1A1A02062012).
Citation Format: Duc-Hiep Bach, Thi-Thu-Trang Luu, Dong-Hwa Kim, Yong Jin An, Hyen Joo Park, Sunghyouk Park, Sang Kook Lee. Targeting BMP4 and miR-139-5p in EGFR-mutant non-small cell lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4407.
Abstract 4410: miRNA-34a sensitizes triple-negative breast cancer cells to paclitaxel reducing cancer stem cell population and lung colonization
Authors: Climent Montserrat , Bonetti Paola , Nicassio Francesco 
Published: August 2018

Abstract
Background: Cancer stem cells (CSCs) have inherent or developed drug resistance for which chemotherapy fails to eliminate all tumor cells, a property that is critically contributing to recurrence and metastasis. Here, we combine miR-34a, a well-known tumor suppressor miRNA that controls proliferation, apoptosis and self-renewal, with Paclitaxel (PTX), a commonly used first-line chemotherapy drug. Based on our preliminary observations (Bonetti et al., manuscript under revision), we hypothesized a combinatorial approach, coupling miRNA- and chemo- treatment, aimed at reducing CSCs in vitro and recurrence in vivo using triple-negative breast cancer (TNBC) as a model. Methodology: As a model, we exploited SUM159pt cells (TNBC mesenchymal-like, with CSC features) to mimic aggressive breast cancer, which harbor a vector for pLUC, which is induced by luciferin in vivo, to monitor tumor growth in real time. Furthermore, we used i) pSlik34a, with tunable expression of miR-34a by doxycycline; ii) treatment with PTX to select for resistant cells (RC); and combined the two, by treating RC with doxycycline. CSC content was evaluated by ALDH (Aldehyde Dehydrogenase) activity, sphere-forming efficiency (SFE) and qRT-PCR of known markers. A similar approach was followed for in vivo studies, with NSG female injected through tail vein injection with 500,000 SUM159/pLUC/pSlik34a cells, and separated into three groups: not treated (NT), PTX alone, and PTX+34a. Results: As observed for aggressive breast cancer, treatment of SUM159 with PTX generated resistant cells (RC) with increased CSC content (ALDH activity and spheres forming ability). When miR-34a was induced in the RC, cells changed morphology, slowed proliferation rate, and decreased CSC content (ALDH activity and spheres). Moreover, a second PTX treatment almost completely abolished the ALDH activity and SFE. The combined effect was evaluated in vivo, following by luminescence the growth of metastases after lung colonization, with PTX+34a mice reducing lung colonization than the PTX treatment or miR-34a treatment alone. Conclusions: Overall, these results indicate that miR-34a sensitize PTX-resistant cells reducing cancer stem-cell capacities, and in this preclinical setting limited the aggressive phenotype of breast cancer, including proliferation, drug resistance, relapse and metastasis causing in delay of lung colonization in vivo.
Citation Format: Montserrat Climent, Paola Bonetti, Francesco Nicassio. miRNA-34a sensitizes triple-negative breast cancer cells to paclitaxel reducing cancer stem cell population and lung colonization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4410.