bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2328: Metabolomics pathways and biomarkers in predicting breast cancer prognosis
Authors: Hu Jennifer J. , Takita Cristiane , Reis Isildinha M. , Yang George , Zhao Wei , Lee Eunkyung 
Published: June 2022

Abstract
Breast cancer is the most frequently diagnosed cancer in women and the second leading cause of cancer death in Americans. With more than 3 million breast cancer survivors in the US, a number that is projected to increase, it is important to identify targets for precision intervention to improve breast cancer prognosis. With the rapid advancement of technology for metabolomics, the results from several recent studies have shown that metabolomics may have applications in breast cancer diagnosis and subtype analysis, characterization of heterogeneity of breast cancer, and prognosis. In the current study, we performed a global urinary metabolomic analysis of 120 breast cancer patients: 60 progression-free (PF) cases as the reference group and 60 with progressive disease (PD: recurrence, second primary, metastasis, or death). The urine samples were collected immediately after radiotherapy. Using UPLC-MS/MS and GC-MS, Metabolon Inc. identified a robust set of 1,742 biochemicals (1,258 known and 484 unknown structure). The most notable differences between PF and PD patients involved multiple pathways and metabolites include: carbohydrate metabolism (e.g., glucose, sedoheptulose, and N6-carboxymethyllysine), branch-chain amino acid metabolism (e.g., alpha-hydroxyisocaproate and beta-hydroxyisovalerylglycine), phosphatidylcholine metabolism (e.g., 1-palmitoyl-2-oleoyl-GPC (16:0/18:1) and 1-palmitoyl-2-linoleoyl-GPC (16:0/18:2)), arginine metabolism (e.g., dimethylarginine, N-acetylcitrulline, and homocitrulline), oxidative stress-related metabolites (e.g., cysteine-glutathione disulfide, gamma-glutamylisoleucine, and gamma-glutamylthreonine), androgenic steroids (Dehydroepiandrosterone sulfate (DHEA-S) and 16a-hydroxy DHEA 3-sulfate), and nucleotide metabolism. Some of these identified metabolomic differences may serve as potential predictive biomarkers of breast cancer prognosis. In summary, with increasing interest in targeting tumor metabolism in precision medicine and our pilot data suggesting multiple metabolic pathways in predicting breast cancer prognosis, future research is warranted to validate our findings and identify metabolomic targets for precision interventions.
Citation Format: Jennifer J. Hu, Cristiane Takita, Isildinha M. Reis, George Yang, Wei Zhao, Eunkyung Lee. Metabolomics pathways and biomarkers in predicting breast cancer prognosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2328.
Abstract 235: Differential polyamine expression in human pancreatic cancer supports the use of polyamine blockade therapy to modulate the in vivo pancreatic tumor microenvironment
Authors: Nakkina Sai Preethi , Gitto Sarah B. , Pandey Veethika , Parikh Jignesh , Geerts Dirk , Maurer Carlo , Olive Kenneth P. , Phanstiel Otto , Altomare Deborah A. 
Published: June 2022

Abstract
Pancreatic cancer has a poor five-year survival rate of less than 8% and is projected to be the second leading cause of cancer related deaths in the US by the year 2030. Polyamine metabolism is an underexplored therapeutic target in pancreatic ductal adenocarcinoma (PDAC). The current investigation profiled RNA expression of genes associated with polyamine metabolism, transport and homeostasis in clinical pancreatic cancer samples to reveal evidence for dysregulation of polyamine-based pathways in PDAC. Increased expression of select pro-polyamine genes was associated with poorer patient prognosis in data obtained from the TCGA dataset. Preclinical experimental data supported the use of polyamine blockade therapy (PBT) in pancreatic tumor bearing mice, and revealed that PBT increased survival and decreased tumor weights in comparison to control treatment. PBT therapeutic effects were associated with increased expression of CD86 T cell co-stimulatory marker present on antigen presenting cells in the tumor microenvironment. Collectively, polyamine dysregulation in human pancreatic cancer is associated with poorer patient prognosis, whereas PBT treatment resulted in improved in vivo therapeutic outcomes in part through immune modulation in the tumor microenvironment.
Citation Format: Sai Preethi Nakkina, Sarah B. Gitto, Veethika Pandey, Jignesh Parikh, Dirk Geerts, Carlo Maurer, Kenneth P. Olive, Otto Phanstiel, Deborah A. Altomare. Differential polyamine expression in human pancreatic cancer supports the use of polyamine blockade therapy to modulate the in vivo pancreatic tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 235.
Abstract 2379: Gender-specific metabolome in bladder cancer: Role of EPHX2 in bladder cancer
Authors: Hassan Mohammed Khurshidul , Borkar Roshan , Reddy Karthik Reddy Kami , Piyarathna Danthasinghe Waduge Badrajee , Amara Chandra Shekar , Bellman Allison , Ambati ChandraShekar R. , Putluri Vasanta , Kamal Abu Hena Mostafa , Bollag Roni J. , Terris Martha K. , Ballester Leomar Y. , Lotan Yair , Coarfa Cristian , Sreekumar Arun , Putluri Nagireddy 
Published: June 2022

Abstract
Bladder cancer (BLCA) is the fourth most common cancer diagnosed in American men. In the U.S., men are four times more likely to be diagnosed with bladder cancer than women. Our research group has previously identified alterations in xenobiotic metabolism in BLCA. In this study, using a metabolomics approach, we identified alterations in the arachidonic acid pathway in bladder tumors from male versus female patients. Included within this altered arachidonic acid pathway was downregulation of EPHX2, an enzyme that converts epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acids (DiHETs). Consistent with this, levels of EETs were significantly elevated in bladder tumors derived from male versus female patients. Cox proportional hazard regression analysis further revealed that reduced expression of EPHX2 was significantly associated with poor clinical outcome across multiple publicly available datasets only in male BLCA patients but not in females. Mechanistic studies revealed that EPHX2 over-expression in male-derived BLCA cell line reduced cell growth in vitro and tumor growth in vivo. Overall, these studies nominate EPHX2 as a potential tumor suppressor in male patients with BLCA.
Citation Format: Mohammed Khurshidul Hassan, Roshan Borkar, Karthik Reddy Kami Reddy, Danthasinghe Waduge Badrajee Piyarathna, Chandra Shekar Amara, Allison Bellman, ChandraShekar R. Ambati, Vasanta Putluri, Abu Hena Mostafa Kamal, Roni J. Bollag, Martha K. Terris, Leomar Y. Ballester, Yair Lotan, Cristian Coarfa, Arun Sreekumar, Nagireddy Putluri. Gender-specific metabolome in bladder cancer: Role of EPHX2 in bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2379.
Abstract 2391: Alterations in metformin mediated metabolism in chemoresistant ovarian cancer cells
Authors: Jenkins Brenita Colette , Roy Debarshi , Maner-Smith Kristal , Shridhar Viji 
Published: June 2022

Abstract
Ovarian cancer (OVCA) is the fifth leading cause of death in post-menopausal women in comparison to all other gynecologic malignancies. Late detection of OVCA is common as screening is done mostly in women over 63. This delay in screening coupled with poor prognosis presents the need for novel treatment measures. Repurposing of Metformin (Met), a biguanide used to increase insulin responses in the body, has been identified as a promising approach for therapeutic treatment in OVCA patients. The purpose of this study is to isolate metabolic pathways used by Met to alter OVCA onset. Preliminary results show that Met inhibits cell proliferation and clonogenic growth in both HeyA8 and HeyA8MDR which are drug-sensitive and drug-resistant cell lines, respectively. In combination with carboplatin, Met treatment enhanced chemosensitivity in both cell lines. In addition, lipidomic analysis was done to monitor the impact of lipid metabolites on OVCA cells. Our analysis showed differences in neutral lipid composition in drug-sensitive and resistant cells which indicates the role of various lipid species play in mediating drug-resistance. Furthermore, Met treatment triggered anti-cancerous pathways through syntheses of lipid metabolites. This data indicates that cell proliferation, along with clonogenic growth are inhibited dose dependently by Met treatment in drug-resistant and drug-sensitive cell lines. Chemosensitivity is enhanced by Met treatment in combination with carboplatin in HeyA8 and HeyA8MDR cell lines. Together, the data suggests that autophagy and lipid biogenesis can be altered through metabolic pathways by Met treatment. Through the use of repurposed Metformin, this approach shows promising results of a treatment regimen and potential prevention of OVCA.
Citation Format: Brenita Colette Jenkins, Debarshi Roy, Kristal Maner-Smith, Viji Shridhar. Alterations in metformin mediated metabolism in chemoresistant ovarian cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2391.
Abstract 2401: Investigating the role of type II IL4 receptor in breast cancer brain metastasis
Authors: Bindeman Wendy , Williams Demond , Hargrove-Wiley Ebony , Fingleton Barbara 
Published: June 2022

Abstract
Breast-to-brain metastasis is a devastating disease complication for which there are currently few treatment options. Among breast cancer subtypes, patients with triple-negative breast cancer (TNBC) and HER2+ breast cancer experience elevated rates of brain metastasis. The cytokines IL4 and IL13 are overexpressed by many human solid tumors. Both are associated with invasive and metastatic phenotypes; IL13 is additionally consequential in primary brain tumors. These cytokines signal through type I (IL4 only) and type II (IL4/IL13) IL4 receptors (IL4R). Importantly, expression of type II IL4R correlates with poor patient prognosis in basal-like (i.e., triple-negative) breast cancer, and HER2+ tumors display elevated type II IL4R expression. Our laboratory has shown that genetic loss of IL4R signaling in tumor cells attenuates lung and liver metastasis in mice. Additionally, we recently identified a role for IL4R signaling in modulating glycosylation in tumor cells. We hypothesize that IL4R signaling influences TNBC brain metastasis at least in part via modulating glycosylation. In a pilot mouse study, pharmacological blockade of IL4R after intracardiac injection of syngeneic TNBC cells resulted in attenuation of brain metastatic growth and circulating tumor cell burden. We have also observed significant changes in the expression of a sialyltransferase (ST8SIA1) that has been implicated in primary brain tumors, as well as in the abundance of several sialic acid-containing protein species in breast cancer cells following treatment with IL4 or IL13. Further, IL4 stimulation increases the overall glycosylation of several proteins of interest, including a glucose transporter and a glutamine transporter, without altering gene expression. Overall, our data suggest that type II IL4R signaling promotes metastasis, potentially through a mechanism involving protein glycosylation. Blockade of this receptor may be a useful therapeutic approach for patients with breast cancer brain metastases.
Citation Format: Wendy Bindeman, Demond Williams, Ebony Hargrove-Wiley, Barbara Fingleton. Investigating the role of type II IL4 receptor in breast cancer brain metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2401.
Abstract 2407: Transmembrane chloride intracellular channel 1 (tmCLIC1) protein is a key regulator of colorectal cancers' metastasis
Authors: Cianci Francesca , Verduci Ivan , Carlini Valentina , Tacconi Carlotta , Ranucci Matteo , Fantin Alessandro , Florio Tullio , Mazzanti Michele 
Published: June 2022

Abstract
Colorectal cancer (CRC) is the third most common tumor worldwide and the fourth cause of cancer-related death. The presence of distal metastasis at the time of the first diagnosis represents a worst prognosis factor for patients’ long-term survival. Therefore, finding new targets to arrest the metastatic process is a main challenge for successful CRC therapy. Our laboratory focused its attention on the Chloride Intracellular Channel 1 (CLIC1), a metamorphic protein able to switch from a cytoplasmic to a transmembrane form associated to ion channel activity. Previous experiments demonstrate that tmCLIC1 functional activity is negligible in normal colon cells, while increases proportionally to CRC cells’ aggressiveness. Moreover, we also reveal that tmCLIC1 supports CRC cells abnormal proliferation rate. Here, we show that tmCLIC1 pharmacological inhibition or its stable downregulation led to a significative reduction of CRC cells migrative and invasive potential, in vitro. To further confirm our hypothesis, we analysed downregulation of metalloproteinase-7 (MMP-7) protein and p38 mitogen-activated protein kinase (MAPK) signalling, both involved in migration and metastatic processes. Moreover, we demonstrate in murine model that CLIC1 knock-down impairs tumor growth and limits cancer cells dissemination. We tried to investigate the alteration of metastatic pathways after CLIC1 silencing. We obtained that many different genes are downregulated when CLIC1 protein is absent; in particular, genes regulated by Reactive Species of Oxygen (ROS) levels. In this scenario, we tried to define the mechanism of action in which CLIC1 is involved. Altogether, all the results obtained in the present work could be considered a starting point to design a new therapeutic strategy to counteract against metastatic colorectal cancer.
Citation Format: Francesca Cianci, Ivan Verduci, Valentina Carlini, Carlotta Tacconi, Matteo Ranucci, Alessandro Fantin, Tullio Florio, Michele Mazzanti. Transmembrane chloride intracellular channel 1 (tmCLIC1) protein is a key regulator of colorectal cancers' metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2407.
Abstract 2409: EGFR-phosphorylated GDH1 harmonizes with RSK2 to drive CREB activation and tumor metastasis in EGFR mutated cancers
Authors: Kang JiHoon , Hwang Jung Seok , Boese Austin , Malin Courteney , Kang Sumin 
Published: June 2022

Abstract
Cancer metastasis process involves dysregulated oncogenic kinase signaling, but the precise mechanism by which this orchestrates metabolic networks and signal cascades for metastasis is largely unclear. Here we report that pharmacological inhibition of a glutaminolytic enzyme glutamate dehydrogenase 1 (GDH1) and ribosomal S6 kinase 2 (RSK2) synergistically attenuates cell invasion, anoikis resistance, and immune escape more evidently in tumors harboring EGFR activating or EGFR inhibitor-resistant mutations. Mechanistically, GDH1 is activated by EGFR through phosphorylation at tyrosine 135, and together with RSK2 enhances transcriptional activity of CREB via CaMKIV signaling fostering metastasis. Moreover, GDH1, RSK2, and CREB phosphorylation positively correlate with EGFR mutation status and metastatic cancer progression in primary patient tumors. Our finding reveals a crosstalk between kinase, metabolic, and transcription machinery in metastasis and offers an alternative combinatorial therapeutic strategy to target EGFR therapy-resistant metastatic cancers.
Citation Format: JiHoon Kang, Jung Seok Hwang, Austin Boese, Courteney Malin, Sumin Kang. EGFR-phosphorylated GDH1 harmonizes with RSK2 to drive CREB activation and tumor metastasis in EGFR mutated cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2409.
Abstract 2425: Mechano-response via ATP alters calcium signaling in breast epithelial cells with oncogenic KRas mutation
Authors: Mull Makenzy , Pratt Stephen , Lee Rachel , Gad Abanoub , Chang Katarina , Annis David , Thompson Keyata , Vitolo Michele , Boyman Liron , Martin Stuart 
Published: June 2022

Abstract
The majority of breast cancer patient deaths occur when tumor cells migrate away from the primary tumors and disseminate metastatically. Cancer cells at the invasive front mimic the behaviors of non-tumorigenic epithelial cells at wound edges but show less coordinated migration comparatively. While most wound healing studies use a timeframe of 24-48 hours, our previous studies have shown that ATP released from wounded cells initiates a calcium (Ca2+) signal within seconds that spreads to neighboring cells through activation of the P2Y2 surface receptor. RNAseq data of MCF10A mammary epithelial cells with stepwise mutations of PTEN knockout and KRas activation alone or in combination, demonstrate that P2Y2 is downregulated specifically by active KRas. Fluorescence microscopy was used to measure Ca2+ signaling and mitochondrial membrane potential in parental and mutant MCF10A cells. Change in total fluorescence was measured and compared to baseline using Fluo-4, a Ca2+ fluorescent indicator, and TMRM (tetramethylrhodamine, methyl ester), a fluorescent mitochondrial membrane potential dye on Nikon analysis software. We show that KRas activation disrupts ATP stimulation and Ca2+ signaling. This change was further quantified using a FlexStation III plate reader with Fluo-4 to read specific fluorescent changes in Ca2+ after ATP addition. ATP-stimulated Ca2+ was also disrupted in other breast tumor cell lines harboring Ras activating mutations, MDA-MB-231 and MDA-MB-436, both showing a similar decrease in P2Y2 expression. These data show that ATP stimulation can be used to further understand the differences in Ca2+ signaling and mechanical-response between normal breast epithelial cells and cancer cells. Clarifying these molecular mechanisms could reveal targets for new cancer treatments, especially since 90% of human tumors are epithelial carcinomas.
Citation Format: Makenzy Mull, Stephen Pratt, Rachel Lee, Abanoub Gad, Katarina Chang, David Annis, Keyata Thompson, Michele Vitolo, Liron Boyman, Stuart Martin. Mechano-response via ATP alters calcium signaling in breast epithelial cells with oncogenic KRas mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2425.
Abstract 2528: PDLIM2 expression in triple negative breast cancer stromal macrophages
Authors: Cox Orla T. , Ward Stephanie , Tresse Emilie , O'Connor Rosemary 
Published: June 2022

Abstract
PDLIM2 is a PDZ-LIM domain protein expressed in hematopoietic and epithelial cells that regulates the stability of transcription factors including NFΚB, STATs and beta catenin. PDLIM2 function is associated with tumour suppression and also with the acquisition of a metastatic or epithelial mesenchymal transition (EMT) phenotype. We recently showed that PDLIM2 is more highly expressed in Triple Negative Breast Cancer (TNBC) tumours than in other breast cancer types or normal breast tissue, and that this is associated with active beta catenin in TNBC (1). Interestingly, in PDLIM2-positive TNBC tumours, PDLIM2 was also present in the tumour-associated stroma. However, whether stromal PDLIM2 expression contributes to TNBC cancer progression is unknown.
To investigate this further we assessed the phenotype of PDLIM2-expressing stromal cells and determined that they most strongly represented a M2-like macrophage population. We then investigated the requirement for PDLIM2 in polarization towards either the M1 and M2-like macrophage phenotype using cultured bone marrow-derived macrophages from PDLIM2 knockout mice compared with wild type. This demonstrated that PDLIM2 is required for full adoption of IL-4-induced M2 macrophage polarization and function, including cell adhesion and migration. M1 polarization was less dependent on PDLIM2, although potential for activation of STATs and NFKB was similar in both macrophage populations.We conclude that high expression of PDLIM2 in TNBC influences the tumour microenvironment through the presence of an M2 macrophage population.
Reference: (1) Cox, O. T., Edmunds, S. J., Simon-Keller, K., Li, B., Moran, B., Buckley, N. E., Bustamante-Garrido, M., Healy, N., O'flanagan, C. H., Gallagher, W. M., Kennedy, R. D., Bernards, R., Caldas, C., Chin, S. F., Marx, A. & O'Connor, R. 2019. Pdlim2 Is A Marker Of Adhesion And Beta-Catenin Activity In Triple-Negative Breast Cancer. Cancer Res, 79, 2619-2633.
Citation Format: Orla T. Cox, Stephanie Ward, Emilie Tresse, Rosemary O'Connor. PDLIM2 expression in triple negative breast cancer stromal macrophages [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2528.
Abstract 2534: Neural control of glioma infiltration
Authors: Huang-Hobbs Emmet J. , Cheng Yi-Ting , Ko Yeungjun , Woo Junsung , Harmanci Akdes , Rao Ganesh , Deneen Benjamin 
Published: June 2022

Abstract
Adult glioblastoma multiforme (GBM) is the most common and deadly form of malignant brain cancer. A broad relationship between tumor progression and neuronal stimulation in the microenvironment is known in peripheral tumors, but only a few interactions between neuronal cues and GBM cells have been characterized. By combining in utero electroporation (IUE) with CRISPR/Cas9 and piggyBac transposase genetics, we have developed an endogenous, immunocompetent, in vivo model with which to study these interactions in a native tumor context. Combining this model with Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) we interrogated tumor-neuron interactions. We assessed molecular and physiological changes in tumors during neural stimulation through tumor development with single cell sequencing and spatial transcriptomics. We examined expression data in populations present under stimulation that did not appear or appeared later in control tumors. These data showed axon guidance genes, a family of genes associated with directed cell motility, were upregulated in these populations. To functionally test these findings, we performed a barcoded screen of axon guidance genes in the IUE model followed by individual confirmation with gain and loss of function of individual genes. We found Sema4F affects infiltration of tumors as well as overall survival. Currently we wish to study the abrogation of this infiltration with Sema4F knockout in the context of DREADD stimulation. Completion of this study will provide new insights into neuronal interactions driving tumor progression in GBM.
Citation Format: Emmet J. Huang-Hobbs, Yi-Ting Cheng, Yeungjun Ko, Junsung Woo, Akdes Harmanci, Ganesh Rao, Benjamin Deneen. Neural control of glioma infiltration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2534.