bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2100: Resistance of gastric carcinoma cells towards c-met inhibition is mediated by compensatory HER3 upregulation involving SATB1 and PKC
Authors: Jenke Robert , Büch Thomas , Rein Miriam , Müller Stefanie , Lordick Florian , Aigner Achim M. 
Published: August 2019

Abstract
Introduction: In patients with gastric cancer expressing high levels of c-met, inhibitors of the receptor tyrosine kinase (RTK) c-met are explored as targeted therapeutics. Unfortunately, clinical trials have failed to improve survival so far. This might be due to compensatory stimulation of other oncogenic RTKs. Here, we highlight the role of HER3 upregulation and its specific stimulation as resistance mechanism. On the mechanistic side, we demonstrate the genome regulator special AT-rich sequence-binding protein-1 (SATB1) as a critical mediator of this HER3 upregulation, with further manipulation being executed by contrary roles of Protein kinase C (PKC) and Phosphatidylinositol 3-kinase (PI3K).
Methods: We used gastric cancer cell lines with a c-met amplification and evaluated the impact of pharmacological or siRNA-mediated c-met inhibition on cellular proliferation and survival. Moreover, we analyzed the expression of HER family receptors after inhibitor treatment. Furthermore, we used transient knockdown of SATB1 as well as inhibitors of PKC and PI3K to gain insight into signaling mechanisms.
Results: The use of c-met kinase inhibitors or RNAi-induced downregulation of c-met led to a complete disruption of cellular proliferation. Without addition of c-met inhibitors, the investigated gastric cancer cells expressed HER1, HER2, and HER3 receptors, but no HER3 ligands. After pretreatment with c-met inhibitors, HER3 expression was markedly upregulated. Treatment of gastric cancer cells with the HER3 ligand beta-heregulin, usually secreted by cancer associated fibroblasts, partially reversed the anti-proliferative effects of c-met inhibitors. The induction of HER3 was reduced after pretreating cells with SATB1 siRNA. SATB1 is a known regulator of HER receptor expression in other tumor entities. The regulatory functions of SATB1 can be further modulated by phosphorylation via PKC or PI3K. Therefore, we investigated the effect of PKC and PI3K inhibition on HER3 induction. Of note, PKC inhibition markedly reduced HER3 upregulation, whereas PI3K inhibitors even increased HER3 levels.
Conclusions: PKC and SATB1 are involved in the compensatory upregulation of HER3 upon c-met inhibition. Since this represents a critical resistance factor, interference with PKC and SATB1 signaling is a potential avenue to prevent resistance towards c-met inhibitors in gastric cancer.
Citation Format: Robert Jenke, Thomas Büch, Miriam Rein, Stefanie Müller, Florian Lordick, Achim M. Aigner. Resistance of gastric carcinoma cells towards c-met inhibition is mediated by compensatory HER3 upregulation involving SATB1 and PKC [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 2100.
Abstract 2103: NETs promote tumor resistance to anthracyclines
Authors: Lin Cindy , Herlihy Sarah E. , Li Marina , Deng Hui , Bernabei Luca , Gabrilovich Dmitry I. , Vogl Dan T. , Nefedova Yulia 
Published: August 2019

Abstract
Multiple Myeloma (MM) is an incurable blood cancer characterized by the clonal proliferation of plasma cells that accumulate in the bone marrow (BM). Resistance to chemotherapy represents one of the main challenges in the treatment of this disease. We have previously shown that neutrophils, one of the major cellular populations in the BM, protect MM cells from chemotherapies including anthracyclines; however, the mechanisms of this effect remain unknown. Thus, we set out to investigate the mechanisms by which neutrophils reduce sensitivity of tumor cells to anthracyclines. Neutrophil extracellular traps (NETs) are structures composed of chromatin and protein formed by neutrophils that are a part of an innate immune mechanism of binding and killing pathogens. Recently, NETs have been shown to form in cancer patients as well as tumor-bearing animals and have been implicated in solid tumor progression; however, their role in hematological malignancies remain poorly understood. Utilizing an in vitro culture system, we demonstrated that MM cells were able to induce NET formation by BM neutrophils. Interestingly, neutrophils isolated from the BM of patients with MM have a significantly higher ability to produce NETs in response to tumor cells as compared to BM neutrophils from donors. NET formation was accompanied by an increase in the level of extracellular DNA. Using imaging flow cytometry and confocal microscopy we demonstrated that extracellular DNA is internalized by tumor cells and localizes to the cytoplasm. This internalized DNA was able to bind to doxorubicin and other anthracyclines thereby reducing their cytotoxic effects. Significantly increased cell-free DNA levels were detected in BM aspirates from MM patients as well as in tumor-bearing mice. Targeting the extracellular DNA in vivo using the clinically available DNase, Pulmozyme, restored the sensitivity of tumor cells to doxorubicin resulting in prolonged survival of tumor-bearing animals. Here, we have identified a novel mechanism of resistance to anthracyclines that is mediated by neutrophils in the tumor microenvironment and provided evidence to support the premise that targeting this mechanism would be of significant benefit in the treatment of MM.
Citation Format: Cindy Lin, Sarah E. Herlihy, Marina Li, Hui Deng, Luca Bernabei, Dmitry I. Gabrilovich, Dan T. Vogl, Yulia Nefedova. NETs promote tumor resistance to anthracyclines [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 2103.
Abstract 2106: Role of organic cation transporter-1 (OCT-1) in drug resistance condition of ph+ chronic myeloid leukemia (CML)
Authors: Patel Saumya , Shah Krupa , Rawal Rakesh 
Published: August 2019

Abstract
A solute carrier (SLC) superfamily member, a major influx protein Organic Cation Transporter-1 (OCT-1), reported to be involved in influx of the Imatinib and other drugs in target cells. Despite the excellent responses to Imatinib and other tyrosine kinase inhibitors (TKIs) in CML, around a quarter of patients demonstrate primary resistance or suboptimal response within one year of therapy. Hence, present study mainly emphases the possible translocation mechanism of Imatinib, major TKIs and other chemotherapeutic agents that is mediated by OCT-1 transporter and OCT-1 gene expression level in progressive phases of CML. Homology based comparative modeling of OCT-1 protein, and its in-depth systemic interaction binding pattern analysis with Imatinib and other TKIs were conducted using computational modeling and molecular dynamics studies, respectively. Quantitative expression analysis of OCT-1 has also been evaluated in patients receiving Imatinib alone, hydroxyurea alone or both drug in different CML phases such as chronic, accelerated and blastic crisis phases for both in bone marrow and PBMNC samples (n=120). The interaction profile of Imatinib with OCT-1 revealed major conformational between ligand and protein interaction sites. However, generated protein-ligand complexes proceeded for molecular dynamics studies (100ns) that have confirmed the selectivity of Imatinib and other drugs towards the OCT-1 and possible translocation path of ligands in the OCT-1 cavities. In quantitative gene expression analysis, downregulation of OCT-1 expression as evident by decreased fold change values in patients with blastic crisis compared to chronic phase responsible for lower uptake of Imatinib into the cells. Hence, cells can not achieve optimum Imatinib inhibitory concentration which may be responsible for disease progression and ultimately leads to drug resistance. Thus, proposed combined computational and experimental approaches suggests OCT-1 mediated activation of bcr-abl independent mechanism, which may be potential confounder of developing Imatinib resistance in CML patients.
Citation Format: Saumya Patel, Krupa Shah, Rakesh Rawal. Role of organic cation transporter-1 (OCT-1) in drug resistance condition of ph+ chronic myeloid leukemia (CML) [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 2106.
Abstract 2109: A novel role for ESRP1 in regulating proliferation in therapy-resistant ER-positive breast cancer
Authors: Gökmen-Polar Yesim , Gu Yuan , Gu Xiaoping , Badve Sunil S. 
Published: August 2019

Abstract
Epithelial Splicing Regulatory Protein 1 (ESRP1) is a key splicing factor that plays an important role in cancer. We have previously demonstrated that ESRP1 is associated with poor prognosis and tamoxifen resistance in human ER-positive (ER+) breast tumors. Knockdown of ESRP1 decreased the tumor growth in ER+ breast cancer models resistant to endocrine therapy. In this study, we explored the upstream/downstream regulatory mechanisms of ESRP1 in tamoxifen-resistant breast cancer using ESRP1 knockdown model. Probe based-Human Transcriptome Array 2.0 (HTA; Applied Biosystems/Thermo Fisher) was performed using RNAs from control and ESRP1 knockdown cells [tamoxifen-resistant LCC2 cells (2-control) versus LCC2 cells with ESRP1 knockdown (2C3)] in ER+ breast cancer. Transcriptome profiling of ESRP1 in 2C3 knockdown model revealed that CEBP gamma, a transcription factor belonging to the CCAAT/enhancer-binding protein (C/EBP) family, was significantly decreased in ESRP1 knockdown cells (p value=2.33E-06). The expression of other related proteins C/EBP family including C/EBP alpha, C/EBP beta, and C/EBP delta that form homodimers and heterodimers with each other was also assessed. In knockdown cells, C/EBP alpha was increased (p value=0.0022), while two different C/EBP beta transcripts were decreased (p values=0.0010 and 0.03, respectively). C/EBP delta expression was not significantly altered. Using a competitive promoter-binding transcription-factor assay, we measured the transcription activity of C/EBP gamma in the absence and presence of ESRP1 promoter DNA fragment. We identified strong binding of C/EBP gamma to ESRP1 promoter region indicating that it is upstream regulator of ESRP1. CEBP transcription factor family members are important regulators of proliferation via cyclin-dependent kinases (CDKs). We further demonstrated that CDK4/CDK6 inhibitor abemaciclib decreases the expression of ESRP1 and C/EBPG levels significantly (p values= 0.0009 and 0.0019, respectively). In conclusion, for the first time, we identify that C/EBP gamma upregulates ESRP1 expression, which further regulates proliferation through control of expression of CDKs.
Citation Format: Yesim Gökmen-Polar, Yuan Gu, Xiaoping Gu, Sunil S. Badve. A novel role for ESRP1 in regulating proliferation in therapy-resistant ER-positive breast 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 2109.
Abstract 2118: Collateral resistance trajectories following failure to antimitotic drugs
Authors: Aldonza Mark Borris D. 
Published: August 2019

Abstract
Secondary drug resistance stems from dynamic clonal evolution during the development of a prior primary resistance. This collateral type of resistance is often a characteristic of cancer recurrence. Yet, mechanisms that drive this collateral resistance and their drug-specific trajectories are still poorly understood. Using resistance selection in concert with small-scale pharmacological screens and data mining in a large pharmacogenomics database, we identified and validated unique collateral resistance trajectories that occur between chemically-different classes of drugs. One convincing case is the co-resistance between microtubule-targeting drugs and EGFR-tyrosine kinase inhibitors (EGFR-TKIs). With paclitaxel resistance as a proxy first-line drug failure model and EGFR-TKI resistance as a collateral, we find that a prior resistance can follow distinct trajectories towards collateral resistance, leading to formation of more stable resistant cell populations. These trajectories can be directed by mechanisms regulating the entry to a drug-tolerant persistent state during exposure to therapy. Collectively, our work unravels the alterations in cellular states defining collateral resistance trajectories to EGFR-TKIs following prior resistance to antimitotic drugs.
Note: This abstract was not presented at the meeting.
Citation Format: Mark Borris D. Aldonza. Collateral resistance trajectories following failure to antimitotic drugs [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 2118.
Abstract 2137: Aberrant nuclear-expressed SLC29A2 as a therapeutic target in hepatocellular carcinoma
Authors: Shen Roger , Jou Yuh-Shan 
Published: August 2019

Abstract
Hepatocellular carcinoma (HCC) is the second most prevalent causes of death in cancer worldwide, and there is lack of promising therapeutic target for patients. Here, we demonstrate that SLC29A2 (Solute Ligand Carrier Family 29 Member 2), an equilibrative nucleoside transporter, is commonly amplified and upregulated in varieties of cancers including hepatocellular carcinoma (HCC). SLC29A2 expression is increased and accumulated in nucleus during HCC progression, accompanied by interacting with phospho-STAT3, and further regulated STAT3-downstream genes to promote tumorigenic and metastatic features in HCC cell lines and preclinical orthotopic mouse model. Oncogenic properties of nuclear SLC29A2 could be suppressed by disrupting the nuclear translocation with nuclear importing mutant RanQ69L, SLC29A2 membrane anchoring mutant, and treating the inhibitor of SLC29A2. Treating inhibitor reduces nuclear SLC29A2-driven oncogenic features by reducing STAT3 phosphorylation, interrupting SLC29A2/STAT3 interaction, and nuclear translocation of SLC29A2 while SLC29A2 is amplified or upregulated in HCC cells. Combined treatment of FDA-approved late stage HCC medicine sorafenib with SLC29A2 inhibitor further suppresses tumor progression and metastasis to prolong mice survival in preclinical orthotopic model. Together, our results suggest that SLC29A2 is a theranostic target, and provide molecular insights for targeting nuclear SLC29A2.
Citation Format: Roger Shen, Yuh-Shan Jou. Aberrant nuclear-expressed SLC29A2 as a therapeutic target 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 2137.
Abstract 2138: Complex copy number profiles in oligodendroglioma associate with anaplastic morphology and recurrence
Authors: Lowe Steve , Lindhorst Scott , Cachia David , Olar Adriana 
Published: August 2019

Abstract
Oligodendroglioma (O) comprises approximately 6% of all diffuse gliomas (DG) and is associated with favorable outcome. It is characterized by the presence of 1p/19q full arm co-deletion and concurrent IDH mutations. Despite a general favorable outcome selected patients with Os experience repeated radiological and histological progression. Copy number aberrations in Os may highlight profiles that correlate with patient's outcome.
Thirty-three Os from the files of our institution were profiled by immunohistochemistry, sequencing, and SNP-microarray. Pertinent clinical, pathological, and radiological data was collected. Descriptive statistics and survival analyses were performed.
Median age at initial diagnosis was 39 (range:19-80 years). Male to female ratio=1.2. All tumors were supratentorial with most common location the frontal lobe (21/33, 64%). Six tumors were anaplastic (WHO grade III). Nine patients experienced tumor recurrence, of which 5 experienced multiple recurrences. Only one patient died after 9.8 years from initial diagnosis. The median follow-up time = 2.5 years (range:0.01-23.6). 21/33(63%), 9/33(27%), and 3/33(0.09%) underwent subtotal, gross total resection, or biopsy respectively. 48%(16/33) patients received chemotherapy and/or radiation therapy at initial diagnosis. Most tumors (28; 85%) had additional copy number aberrations most commonly involving chromosomes 11q, 12q, 9p, 4q, 3p, 11p. Chromosomal deletions/full-arm losses were more common than gains. Diploidy/tetraploidy was detected in 2 cases and chromothripsis in 1. Anaplastic and recurrent tumors had more complex copy numbers aberrations, including numerous loci of loss of heterozygosity. Statistical significance however was not reached. Additional copy number aberrations characterize Os. Complex copy number profiles associate with aggressive morphology and recurrence.
Citation Format: Steve Lowe, Scott Lindhorst, David Cachia, Adriana Olar. Complex copy number profiles in oligodendroglioma associate with anaplastic morphology and recurrence [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 2138.
Abstract 2147: Galectin-1: A marker for claudin-low breast cancer
Authors: Balestrieri Kassondra , McDaniel Moses , Shoopman Christiana , Vohra Nasreen , Verbanac Kathryn 
Published: August 2019

Abstract
Metastasis and mortality among patients with triple negative breast cancer (TNBC) of the claudin-low subtype remain high because these tumors are clinically aggressive, chemoresistant, and lack targeted therapies. We have previously used proteomic approaches to analyze orthotopic and metastatic tumors from the syngeneic murine T11 tumor model, which displays gene expression profiles that mirror human claudin-low TNBC. These studies identified Galectin-1 (Gal-1), an N-acetyllactosamine-binding protein, as an overexpressed protein in cultured T11 cells, primary tumors, and lung metastases compared to normal lung and mammary fat pad tissue from healthy control mice. These results were confirmed by Western immunoblot and immunohistochemistry and were further supported by analysis of murine tumor microarray data sets, which revealed Gal-1 overexpression in the claudin-low subtype compared to other breast cancer subtypes. Here we extend our murine studies to investigate Gal-1 expression in breast cancer patients, with specific inclusion of claudin-low tumors. To compare differential Gal-1 expression across breast cancer subtypes, we initially analyzed published human microarray data sets from normal breast and primary breast tumors (total n=423, of which 51 are the claudin-low subtype): the highest Gal-1 expression was observed in claudin-low breast cancer. In order to validate these findings, we are examining breast cancer specimens from a unique cohort of ethnically diverse patients from rural Eastern North Carolina with a median follow-up of over 8 years. RNASeq data from a subset of this cohort (n=121) was used to assign subtypes (using PAM50 and the claudin-low classifier). Further studies are in progress to compare Gal-1 expression between subtypes and correlate with clinicopathologic factors and outcome. Immunohistochemical Gal-1 staining of primary tumor tissue blocks is underway to confirm expression in each subtype at the protein level. Immunohistochemistry will also define Gal-1 expression in the cell types comprising the heterogeneous tumor microenvironment (tumor, stromal, immune cells) and its subcellular localization (nuclear, cytoplasmic, membrane-associated). Through this ongoing work evaluating Gal-1 across breast cancer subtypes, we will help corroborate initial findings from the T11 claudin-low mouse model and yield further insights into the role of Gal-1 in breast cancer progression.
Citation Format: Kassondra Balestrieri, Moses McDaniel, Christiana Shoopman, Nasreen Vohra, Kathryn Verbanac. Galectin-1: A marker for claudin-low breast 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 2147.
Abstract 2154: A novel dual-function polymeric scaffold for cancer drug screening
Authors: Wu Tianfu , Lin Zuan-Tao 
Published: August 2019

Abstract
Cell-based assay has been used as a conventional strategy for discovery of new anti-cancer drugs in pharmaceutical industries. Traditionally, two-dimensional (2D) cell culture based cytotoxicity assays are the most common approaches, despite the fact that they have significant limitations in simulating tissue or organ microenvironment. In comparison, 3-dimensional (3D) cell culture provides a more promising tool for new drug discovery, however, next-generation cell growth monitoring device for 3D cell culture is still challenging. Recent studies have shown the potential of metallic nanoparticle-polymeric composites in biosensing systems. We hypothesize that in a polymer-based 3D-cell culture system, cancer cell growth and the subsequent spheroid formation can cause structural change of the polymer network. With the incorporation of metallic nanoparticles into the polymeric network, electrical conductance change of the 3D-scafold may be monitored to reflect cell growth and spheroid formation. Here, we developed a dual-function polymer scaffold (DPS) by integrating thermosensitive polymers, silver flake-decorated polymers, and gNP-decorated polymers as a biosensor to monitor cancer cell growth. We found that the Triple negative breast cancer stem cell line MDA-MB-231 formed spheroid in DPS. It is notable that the increase of cancer cell numbers during the formation of spheroid was proportional to the change of electrical conductance of the 3D-scafold. Importantly, the results from DPS cell growth monitoring method correlate well with conventional cell counting during 3D cell culture of breast cancer cells. SEM imaging and AFM imaging have confirmed the integration of silver flakes and gold nanoparticles in the DPS. Finally, we demonstrated that the DPS 3D-scafold exhibited robust responses to MDA-MB-436 cells when exposed to 3 nM of paclitaxel (PTX) and docetaxel (DTX), respectively. This dual-function 3D-scaffold, for both cell growth and growth monitoring may have a good potential in drug screening in the future.
Note: This abstract was not presented at the meeting.
Citation Format: Tianfu Wu, Zuan-Tao Lin. A novel dual-function polymeric scaffold for cancer drug screening [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 2154.