bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2808: Investigating the role of macrophage-mediated suppression in the efficacy of NK cell immunotherapy for metastatic outgrowth of breast cancer cells
Authors: Brownlie Demi , Doughty-Shenton Dahlia , Pollard Jeffrey W. , Kitamura Takanori 
Published: August 2019

Abstract
Breast cancer is the leading cause of cancer-related death in females worldwide. Although 5-year survival of breast cancer patients in early stages is 89-100%, that of patients with metastatic tumours is reduced to just 21%, suggesting the requirement of more effective therapies for metastatic breast cancer (MBC). As MBC is refractory to current therapies, NK cell infusion has been suggested as an alternative therapy. However, its efficacy is modest in MBC possibly due to the suppressive nature of the tumour microenvironment, especially through the tumour-associated macrophages (TAMs) within it. Here we investigated the effects of TAMs in metastatic tumours on NK cell cytotoxicity, as well as the mechanism behind TAM-mediated NK cell suppression.
To evaluate NK cell cytotoxicity, we established a method whereby mouse breast cancer cells were cultured with splenic NK cells, and the resultant tumour cell apoptosis was determined by quantitative fluorescence microscopy. To investigate the effects of TAMs on this NK cytotoxicity, we purified them from lungs with metastatic tumours and added them to this co-culture. We also investigated the suppressive effects of bone marrow-derived macrophages cultured with M-CSF (M-BMMs). To further investigate the mechanism, we depleted TAMs in mice with metastatic tumours and detected inhibitory receptor expression on NK cells as well as NK cell inhibitory ligands on TAMs in the metastatic lung and on M-BMMs by flow cytometry.
TAMs from metastatic tumours significantly reduced NK cell cytotoxicity toward tumour cells. M-BMMs (resembling TAMs) also reduced NK cell cytotoxicity. We also found that TAMs and M-BMMs expressed high levels of NK cell inhibitory ligands. There was no difference in the expression of inhibitory receptors on NK cells between tumour bearing lungs with or without TAMs.
To conclude, we have shown that TAMs in metastatic tumours, as well as their mimetic M-BMMs, can suppress NK cell cytotoxicity towards breast cancer cells in vitro. Our data suggest that TAMs express higher levels of inhibitory ligands and thereby transmit suppressive signals possibly through direct contact with NK cells. Further investigation of mechanisms behind TAM-mediated NK suppression might lead to the improvement of NK cell-based immunotherapy for MBC.
Citation Format: Demi Brownlie, Dahlia Doughty-Shenton, Jeffrey W. Pollard, Takanori Kitamura. Investigating the role of macrophage-mediated suppression in the efficacy of NK cell immunotherapy for metastatic outgrowth of breast 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 2808.
Abstract 2812: Triple-negative breast cancer cell-intrinsic glucocorticoid receptor activity and modulation of the immune microenvironment
Authors: Dolcen Deniz N. , Szymanski Diana West , Panchamukhi Ananth , Wang Xiaomeng , Sweis Randy F. , Nanda Rita , Conzen Suzanne 
Published: August 2019

Abstract
Background: Variation in the infiltration of TNBC immune microenvironment is not well understood. Our lab previously demonstrated that high glucocorticoid receptor (GR; nuclear hormone receptor) activity in TNBC models is associated with tumor cell-intrinsic anti-inflammatory gene expression pathways. In addition, high GR expression in early-stage TNBC is associated with a significantly lower rate of recurrence-free survival suggesting a role for GR-associated mechanisms in TNBC progression. GR activation in lymphocytes is well known to result in their apoptosis; however, a current gap in knowledge regarding GR biology is whether tumor-cell intrinsic GR activity modulates immune cells in the microenvironment. We hypothesized that TNBC cell-intrinsic GR activity may inhibit antitumor T cell activity in the tumor microenvironment.
Methods and Results: We divided TCGA primary TNBC RNAseq expression data based on GR expression and determined enrichment for immune cells using two transcriptome parsing algorithms. We found that TNBCs with high GR expression are significantly enriched for the T cell-inflamed gene expression signature, suggesting the presence of T cells in the microenvironment. The xCell algorithm found that TNBCs with high GR expression are significantly enriched for the CD4+ naïve T cell transcriptome, which is absent in TNBCs with low GR-expression. To begin to determine whether GR activation in TNBC cells induces the secretion of cytokines and/or growth factors that result in the chemotaxis of CD4+ naïve T cells, we collected conditioned cell culture media from control versus GR-active TNBC cells and performed multiplex cytokine ELISA. We found that G-CSF secretion by TNBC cells was significantly increased following GR activation; G-CSF has been shown to promote immunosupressive Treg cell differentiation.
Conclusions: Prior data suggest that breast tumor-infiltrating immunosuppressive Tregs arise from chemotaxis of circulating naive CD4+ T cells that differentiate into Tregs in situ. Thus targeting GR in TNBC may be an important therapeutic approach to potentiate antitumor T cell responses and suppress the Treg population in the tumor microenvironment. Ongoing work is aimed at further delineating a mechanism by which GR can modulate the immune tumor microenvironment.
Citation Format: Deniz N. Dolcen, Diana West Szymanski, Ananth Panchamukhi, Xiaomeng Wang, Randy F. Sweis, Rita Nanda, Suzanne Conzen. Triple-negative breast cancer cell-intrinsic glucocorticoid receptor activity and modulation of the immune 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 2812.
Abstract 2823: Sample storage conditions alter microbiome profiles - its potential relevance for cancer patients undergoing fecal microbial transplants
Authors: Jenkins Samir V. , Vang Kieng B. , Gies Allen , Griffin Robert J. , Jun Se-Ran , Nookaew Intawat , Dings Ruud Petrus 
Published: August 2019

Abstract
Background and Objective: Fecal microbiota transplantation helps restore beneficial bacteria in cancer patients after intense antibiotics administration. Here we investigated the influence of different stabilization and storage strategies on the quality and composition of the fecal microbial community.
Methods: Same-day isolated murine DNA was compared to samples stored for one month in air at ambient temperature, with or without preservative buffers (i.e. EDTA and lysis buffer), different temperatures (i.e. 4°C, -20°C, and -80°C), and hypoxic conditions.
Results: Only storage in lysis buffer significantly reduced DNA content, yet without integrity loss. Storage in EDTA affected alpha diversity the most, which was also reflected in cluster separation. Distinct changes were also seen in the phyla and bacterial species abundance per storage strategy. Metabolic function analysis showed 22 pathways not significantly affected by storage conditions, whereas the tyrosine metabolism pathway was significantly changed in all strategies except by EDTA.
Conclusions: Overall, each long-term storage strategy introduced a unique post-collection bias, which is important to take into account when interpreting data. Funded by COBRE P20GM103625.
Citation Format: Samir V. Jenkins, Kieng B. Vang, Allen Gies, Robert J. Griffin, Se-Ran Jun, Intawat Nookaew, Ruud Petrus Dings. Sample storage conditions alter microbiome profiles - its potential relevance for cancer patients undergoing fecal microbial transplants [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 2823.
Abstract 283: Combination treatment of PARP and SRC inhibitors in BRCA2 mutated prostate cancer
Authors: Khan Nabeela , Chakraborty Goutam , Nandakumar Subhiksha , Mazzu Ying Z. , Atiq Mohammad , Yoshikawa Yuki , Lee Gwo-Shu Mary , Kantoff Philip 
Published: August 2019

Abstract
Background: Recently, poly (adenosine diphosphate [ADP]-ribose) polymerase inhibitors (PARPi) have shown promise in metastatic castration resistant prostate cancers (mCRPC) patients harboring DNA repair defects due to mutations of BRCA1/2 and ATM. Despite responses, resistance is common and treatment modalities for PARPi-resistant patients are limited. We hypothesized that combining PARPi with other agents in BRCA2 altered tumors would create synergy and greater response rate and durability.
Methods: We established a transcriptomic profile associated with genomic deletion of BRCA2 (homozygous and heterozygous) using publicly available datasets from mCRPC patient tumors. To identify the significantly unregulated oncogenic signaling pathways associated with BRCA2 loss, we used gene-set enrichment analysis (GSEA). We also analyzed this transcriptomic profile by Toppgene suite to identify potential drug targets for BRCA2 deleted tumors. We used experimental human prostate cancer cell lines to validate our current observations from human clinical datasets and pathway analysis.
Results: Our GSEA analysis showed significant enrichment of the SRC signaling pathway in BRCA2-altered tumors, and based on the Toppgene suite, we also identified dasatinib (pharmacological inhibitor of SRC) as a potential agent for BRCA2-deleted tumors. Similarly, we observed significant up regulation of SRC phosphorylation in human prostate cancer cells (LNCaP-abl and PC3M) that harbor genomic deletion of BRCA2. We performed cell growth assays in these BRCA2 deleted cells treated with PARPi (olaparib, talazoparib), and dasatinib alone or in combination and calculated drug synergy based on the Chou-Talay Method. PC3M and LNCaP-abl prostate cancer cell lines showed different sensitivities to olaparib and talazoparib. We used olaparib for PC3M and talazoparib for LNCaP-abl cells. Co-administration of the PARPi and SRCi showed significant synergy in both cell lines compared to either inhibitors alone. We will develop the rationale for combining PARPi and SRCi in CRPC patients who harbor defects of BRCA2 after completion of our study in xenograft models.
Conclusion: Our study reveals the synergistic effect of PARPi and SRCi in prostate cancer cell lines. We believe this shows great potential for future clinical trials in patients with mCRPC harboring BRCA2 deletions.
Citation Format: Nabeela Khan, Goutam Chakraborty, Subhiksha Nandakumar, Ying Z. Mazzu, Mohammad Atiq, Yuki Yoshikawa, Gwo-Shu Mary Lee, Philip Kantoff. Combination treatment of PARP and SRC inhibitors in BRCA2 mutated prostate cancer [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 283.
Abstract 2833: Alterations in intestinal microbiota of colorectal cancer patients receiving radical surgery combined with adjuvant CapeOx therapy
Authors: Kong Cheng , Gao Renyuan , Qin Huanlong 
Published: August 2019

Abstract
Background: An intricate relationship exists and interactions occur between gut microbiota and colorectal cancer (CRC). Radical surgery combined with adjuvant chemotherapy (AC) serves as the mainstream therapeutic scheme for most CRC patients. However, the impact of surgery or chemotherapy on gut microbiota remains elusive.
Methods: Forty-three CRC patients who received radical surgery and AC were enrolled in the present study. Fecal samples of these patients were collected preoperatively, postoperatively, and after the first to fifth cycles of postoperative chemotherapy. The microbial community of each sample was analyzed using high throughput 16S rRNA amplicon sequencing.
Results: Compared with preoperative samples, fecal samples collected postoperatively exhibited a significant decrease of obligate anaerobes (Bacteroides, Parabacteroides, Faecalibacterium, Prevotella_9 and Bifidobacterium), tumor-related bacteria (Enterococcus and Fusobacterium), and butyric acid-producing bacteria (Bacillus, Bilophila, Barnesiella and Enterococcus). However, a significant increase of some conditional pathogens was observed (Escherichia-Shigella, Enterobacteriaceae_unclassified, Veillonella, Morganella, Streptococcus, and Proteus). In addition, the AC regimen (CapeOx) was found to alter intestinal microbiota dramatically. In particular, several changes were observed after chemotherapy including an increase of pathogenic bacteria (Collinsella, Anaerostipes, Bilophila, Comamonas, Weissella, and Eggerthella), the “rebound effect” of chemotherapy-adapted bacteria (Dorea, Ruminococcaceae_UCG-010, Streptococcus, Prevotella_9, Mogibacterium and Roseburia), the shift of lactate-utilizing microbiota from Veillonella to Butyricimonas and Butyricicoccus, as well as the decrease of probiotics (such as Lactobacillus).
Conclusions: Both radical surgery and CapeOx chemotherapy exert a non-negligible effect on the gut microbiota of CRC patients. Microbiota-based intervention may be beneficial for these patients during postoperative clinical management.
Citation Format: Cheng Kong, Renyuan Gao, Huanlong Qin. Alterations in intestinal microbiota of colorectal cancer patients receiving radical surgery combined with adjuvant CapeOx therapy [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 2833.
Abstract 284: Combination therapies to prevent resistance to androgen deprivation therapies in prostate cancer
Authors: Li Zhenghong , Sun Carrie Qi , Arnold Rebecca , Petros John A. , Moreno Carlos S. 
Published: August 2019

Abstract
Androgen receptor (AR) signaling is a distinctive feature of prostate cancer (PCa) and represents a major therapeutic target for treating metastatic prostate cancer (mPCa). Thus, androgen deprivation therapy (ADT) is a first-line treatment for mPCa. Although initially highly effective as a treatment for mPC, ADT is characterized by the frequent emergence of resistance, a disease state termed castration-resistant prostate cancer (CRPC) and is generally incurable after progression to metastatic disease. Therefore, understanding the mechanisms underlying CRPC and subsequent progression to metastatic disease is critical. In our previous study, which was mainly focused on how transcriptional networks change in response to ADT and lead to metastasis, we analyzed matched pre-ADT and post-ADT tissue samples via RNAseq analysis of 40 formalin-fixed paraffin-embedded (FFPE) patient-matched pre-ADT biopsy (Bx) and post-ADT radical prostatectomy (RP) prostate cancer samples. We observed strong upregulation of components of the MAPK pathway including FOS, FOSB, and JUN, as well as downstream targets of MAPK signaling. These data suggest that ADT may induce a compensatory increase in MAPK signaling in response to the decrease in androgen signaling. Thus, we hypothesize that combination therapies targeting AR and the MAPK pathway may synergistically kill prostate cancer cells and prevent recurrence and progression to CRPC. In the current study, we have tested the effects of the MEK inhibitors PD0325901 and GSK1120212, ERK1/2 inhibitor GDC-0994, and the JNK inhibitor AS602801 alone and in combination with enzalutamide in androgen-sensitive LNCaP and MDA-PCa-2b cells. Cell viability assays indicated that enzalutamide combined with MEK and JNK inhibitors synergistically killed LNCaP and MDA-PCa-2b cells, and decreased migration and invasion of LNCaP cell more than any of the drugs alone. We therefore propose that combination therapy targeting AR and MEK and/or JNK signal pathways may be an effective treatment for recurrent prostate cancer. We are currently investigating the most promising combinations of enzalutamide with JNK inhibitors for anti-tumorigenic effects in vivo using a mouse xenograft model.
Citation Format: Zhenghong Li, Carrie Qi Sun, Rebecca Arnold, John A. Petros, Carlos S. Moreno. Combination therapies to prevent resistance to androgen deprivation therapies in prostate cancer [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 284.
Abstract 2846: Chemerin, as a serum biomarker, promotes tumorigenesis and metastasis in oral squamous cell carcinoma
Authors: Wang Anxun 
Published: August 2019

Abstract
Chemerin encoded by retinoic acid receptor responder 2 (RARRES2) has been found to be related with malignant tumors, but its causal role in the development of oral squamous cell carcinoma (OSCC) is largely unexplored. In the present study, clinical data showed that higher serum levels of chemerin were observed in OSCC patients compared to the healthy and significantly decreased after tumor resection, and were positively associated with advanced tumor stage and lymph node metastasis. The expression level of chemerin was positive correlated with the migration and invasion of OSCC cell lines. Recombinant chemerin dose-dependently enhanced the migration, invasion and proliferation of OSCC cells in vitro, and shRNA targeting RARRES2 inhibited chemerin expression, OSCC cells metastasis and proliferation in vitro and vivo. Additionally, Chemerin activated the Manganese superoxide dismutase (SOD2) activity and increased intracellular H2O2, led to a significant decrease of E-cadherin expression and a dramatically increasing expression of p-ERK1/2, Slug, Vimentin and N-cadherin. This study suggested that chemerin was a novel biomarker for OSCC patients. Chemerin promoted the tumorigenesis and metastasis of OSCC and would be a new therapeutic target for OSCC.
Keywords: Chemerin; Oral squamous cell carcinoma; Tumorgenesis; Metastasis; SOD2
Citation Format: Anxun Wang. Chemerin, as a serum biomarker, promotes tumorigenesis and metastasis in oral squamous cell 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 2846.
Abstract 2849: Axl: A promising therapeutic target that leads to multimodal inhibition of the metastatic pathway
Authors: Tanaka Mai , Siemann Dietmar W. 
Published: August 2019

Abstract
Cancer is the second leading cause of death in the United States and approximately 90% of cancer-related deaths result from metastasis, the spread of cancer cells to secondary sites. In tumors, the upregulation of certain signaling pathways promotes the metastatic phenotypes of cancer cells characterized by enhanced invasion, migration, survival, proliferation and induction of angiogenesis. A key pathway involved in metastasis is the receptor tyrosine kinase Axl. Axl is expressed in a variety of tumor types and is associated with poor prognosis, metastasis, and outcome. The purpose of the current study was to evaluate the efficacy of genetic and pharmacologic inhibitions of Axl on the metastatic phenotypes, specifically cell migration, invasion and angiogenesis.
Human breast and prostate cancer cell lines (MDA-MB-231 and PC3-ML, respectively), and human lung microvascular endothelial cell (HMVEC-L) were used in this study. Stable Axl short hairpin RNA (shRNA) knockdown MDA-MB-231 and PC3-ML cell lines were generated by Mission Lentiviral transduction particles (Sigma). The efficacy of genetic and pharmacologic inhibition of Axl on tumor cell migration and invasion was evaluated by transwell migration and invasion assays. The effect of Axl knockdown on prostate cancer cell metastasis in vivo was evaluated by an intracardiac bone metastasis model. Conditioned media of Axl knockdown or control MDA-MB-231 cells were analyzed for angiogenic factors using the human angiogenesis array. The effect of Axl knockdown conditioned medium on angiogenic properties in vitro were assessed by endothelial cell tube formation and sprouting. Induction of angiogenesis in vivo was measured by performing intradermal assay.
Genetic and pharmacologic inhibition of Axl decreases tumor cell migration and invasion. Axl knockdown inhibits metastatic disease burden of prostate cancer. Axl knockdown conditioned medium secretes less pro-angiogenic factors compared to its scramble control cells, suggesting that tumor cells utilize Axl pathway to promote the induction of angiogenesis. Axl knockdown conditioned medium impairs angiogenic properties, including endothelial cell tube formation and sprouting. Axl knockdown of tumor cells suppress tumor cell-induced angiogenesis in vivo. Collectively, these data indicate that Axl is involved in multiple steps of the metastatic pathway and that Axl is a promising anti-metastatic agent to inhibit tumor cell dissemination and initiation of angiogenesis. Further studies are ongoing to understand the downstream molecular signaling of Axl.
Citation Format: Mai Tanaka, Dietmar W. Siemann. Axl: A promising therapeutic target that leads to multimodal inhibition of the metastatic 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 2849.
Abstract 2852: PKM2 phosphorylates and stabilises Matrin 3 which promotes FOXC2-mediated tumorigenesis
Authors: Kumari Richa , Das Sanjeev 
Published: August 2019

Abstract
PKM2 is tumor specific isoform of Pyruvate kinase essential for Warburg effect. Apart from its well-known function in aerobic glycolysis, it has non-metabolic functions as well. Under oncogenic/mitogenic stimulation conditions it can translocate into the nucleus and acts as co-transactivator or kinase and promotes tumorigenesis. In order to explore its interactome we carried out a proteomic screen and found several interacting proteins. However, in vitro and in vivo studies confirmed Matrin 3 as a novel interacting partner of PKM2. Kinase assays revealed Matrin 3 as novel substrate of the PKM2-mediated phosphorylation. Further, we mapped the site of phosphorylation to the highly conserved T239 residue in Matrin 3. Intriguingly; this phosphorylation is inhibitory in nature as it prevents Matrin 3 degradation by abrogating K48-linked ubiquitylation. Moreover, the expression of a phospho-dead mutant of Matrin 3 or kinase-dead mutant of PKM2 increases ubiquitylation and leads to reduced level of Matrin 3.We also identified K132 as site of ubiquitylation which is conserved across species. Further, we screened a shRNA library targeting nuclear E3 ubiquitin ligases and identified FBXO11 as the cognate E3 ligase involved in this degradation. Matrin 3 is a RNA binding protein which mediates post-transcriptional regulation of various mRNAs. Further studies using qPCR array for EMT related genes and RNA immunoprecipitation assays established that Matrin 3 binds to FOXC2 and promotes post-transcriptional stability of FOXC2. FOXC2 is a transcription factor which regulates EMT, angiogenesis, invasion/migration by regulating Integrin β-3, ZEB1 and c-MET. Decreased Matrin 3 level leads to reduced proliferation capacity, migration and invasiveness of tumor cells. Furthermore, mouse tumor models confirmed that Matrin 3 promotes tumorigenesis, metastasis and invasion in FOXC2 dependent manner. Taken together, our findings add to the substrate repertoire of nuclear PKM2 kinase and provide key insights into FOXC2-mediated tumorigenesis.
Citation Format: Richa Kumari, Sanjeev Das. PKM2 phosphorylates and stabilises Matrin 3 which promotes FOXC2-mediated tumorigenesis [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 2852.