bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4593: Inhibition of invasion of HER2-positive breast cancer cells by lysosome targeting drugs
Authors: Hansen Malene B. , Postol Maria , Egan Davig A. , Jäättelä Marja , Kallunki Tuula 
Published: August 2019

Abstract
Up to 20% of all breast cancers are over-expressing HER2/ErbB2, leading to malignant and invasive cancers with a poor patient outcome. Though good ErbB2-targeting treatments have been developed, metastasis formation and drug resistance are still major challenges for the long-term cure. This project aims to find out if some of the numerous pre-existing compounds and clinically approved drugs can be repurposed to treat or improve the treatment of HER2/ErbB2-positive breast cancer. We have therefore set up a high-throughput and high-content screen of the Prestwick Chemical Library to identify drugs that can reverse the ErbB2-induced, invasion-promoting, peripheral distribution of lysosomes. Using a breast cancer cell model expressing N-terminally truncated version of ErbB2, we mimic breast cancer that is resistant to the currently used antibodies, trastuzumab and pertuzumab. This cell line shows a highly invasive phenotype with increased activation of the lysosomal proteases, cysteine cathepsin B and L, as well as anterograde movement of lysosomes. This repositioning of the lysosomes enables them to fuse with the plasma membrane and empty their acidic and hydrolyzing content to the extracellular matrix, promoting invasion. Treatment with the clinically used drug lapatinib will reverse this phenotype. The cells ability to reverse the phenotype, through increasing the number of perinuclear lysosomes while removing lysosomes form cellular protrusions, was evaluated for each screened drug, using the ImageXpress Micro Confocal High-Content Imaging System. We have hereby identified eight drugs that can redirect lysosomes from the invadosome-like cellular protrusions to their non-invasive perinuclear position in ErbB2 expressing breast cancer cells. We are currently analyzing the impact of these drugs on breast cancer cell invasion though migration assays and three-dimensional invasion assays. We are also addressing their effect on lysosomal membrane permeabilization, lysosomal pH and investigating their effect on proteins that are known to be involved in lysosomal distribution.
Clinically, our findings may facilitate repurposing or new development of drugs to treat HER2/ErbB2-positive and invasive breast cancers that are resistant to current treatments.
Citation Format: Malene B. Hansen, Maria Postol, Davig A. Egan, Marja Jäättelä, Tuula Kallunki. Inhibition of invasion of HER2-positive breast cancer cells by lysosome targeting 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 4593.
Abstract 4601: Phospholipid and enzyme antibodies for the evaluation of novel cancer biomarkers
Authors: Day Cameron , Neilsen Paul 
Published: August 2019

Abstract
Sphingosine 1-phosphate (S1P) and lysophosphatidic acid (LPA) are well characterized bioactive phospholipids with migratory and proliferative effects in cancer progression. Recent studies show that the enzyme responsible for production of S1P, sphingosine kinase (SK), is upregulated in a variety of cancers, S1P is a tumorigenic growth factor, and there is an association between S1P levels in cancer patients and their resulting clinical outcomes. Similarly, LPA has been shown to drive angiogenesis and tumor invasion. LPA receptors and the LPA synthesizing enzyme autotaxin (ATX) have also been shown to be abnormally expressed in at least ovarian and breast tumors. S1P, SK, LPA, and ATX therefore represent potential biomarkers for the detection and staging of cancer. We have now characterized anti-S1P and anti-LPA antibodies for basic immunochemical methods in cells and ovary tissue. These antibodies were previously developed as anti-cancer immunotherapeutic agents. Here we highlight the potential for these reagents as bonafide cancer biomarkers for S1P and LPA.
Citation Format: Cameron Day, Paul Neilsen. Phospholipid and enzyme antibodies for the evaluation of novel cancer biomarkers [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 4601.
Abstract 4625: Mouse strains for cancer research at The Jackson Laboratory Repository
Authors: Boswell Deborah , Rockwood Stephen , Lutz Cathleen ,   The JAX Repository Team
Published: August 2019

Abstract
Genetically defined mice have been the cornerstone of cancer research and resources at The Jackson Laboratory since the founding of the laboratory nearly nine decades ago. The Jackson Laboratory distributes more than 10,500 strains to the scientific community, many with applications in cancer research, including mouse models for specific cancers, xenograft models, immunodeficient platforms for PDX studies, multi-purpose “tool strains” (such as CRISPR cas9-expressing lines), recombinase expressing strains, as well as conditional and inducible expression lines (such as Cre-lox). New to the JAX Repository collection is a KrasLSL-A146T strain with inducible mutant Kras A146T for use in research of gastrointestinal tract and hematological cancers. The tamoxifen-inducible model for pancreatic ductal adenocarcinoma (PDAC), KPCX, and the related conditional activatable Kras allele/floxed Trp53 double mutant line, KP, have recently been developed. Inducible expression of mutant human speckle-type POZ protein (SPOP) in one newly acquired line allows study of prostate tumorigenesis. The portfolio of strains useful for engraftment studies has expanded, complementing the versatile humanized NOD scid gamma (NSG) platform lines. For custom generation of mutant strains, the Repository distributes a variety of research tool strains such as cas9-expressing lines, both constitutive expressing and Cre-inducible models, on different defined genetic backgrounds. Other recently added mutants allow research of the role of inflammation in cancer and screening immunomodulatory cancer therapies.
In addition to safeguarding each strain by cryopreservation, the Repository‘s comprehensive quality control program confirms mutation identity and genetic background, and screens for unwanted alleles (such as stray GFP, cre, lacZ, etc.). Investigators can search for specific strains on the JAX Mice website, or peruse the Oncology Therapeutic Area webpage for cancer research related strains and resources. Researchers can submit their strains to be considered for inclusion in the Repository on The Jackson Laboratory website:
www.jax.org/donate-a-mouse
The Jackson Laboratory Repository is supported by the NIH, The Howard Hughes Medical Institute, and other private charitable foundations.
Citation Format: Deborah Boswell, Stephen Rockwood, Cathleen Lutz, The JAX Repository Team. Mouse strains for cancer research at The Jackson Laboratory Repository [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 4625.
Abstract 4635: Newly established mouse oral carcinoma cell lines and their syngeneic tumorigenesis models
Authors: Chen Yi-Fen , Liu Chung-Ji , Kao Shou-Yen , Lin Shu-Chun , Chang Kuo-Wei 
Published: August 2019

Abstract
Oral squamous cell carcinoma (OSCC) is one of the most prevalent malignancies worldwide. Despite the advances in diagnosis and treatment, the survival of OSCC remains to be improved. miR-211 is an oncogenic microRNA frequently disrupted in human OSCC and its high expression is a determinant of patient’s poor survival. Herein, we established four murine OSCC cell lines, designated MOC-L1 - MOC-L4 from the tongue tumor tissues induced by 4-nitroquinoline 1-oxide in K14-EGFP-miR-211 transgenic mice. All cell lines appear green fluorescence and express epithelial markers. The gene expression profiles among cell lines are complex and diverse, while MOC-L1 - MOC-L3 cells carry missense mutations in p53 gene. MOC-L1 exhibits tremendous epithelial-mesenchymal transition and the associated aggressive characteristics. On the contrary, MOC-L4 displays the least invasiveness. Both MOC-L1 and MOC-L2 are clonogenic in vitro and tumorigenic when implemented into dermis or tongue in syngeneic recipients. But, only MOC-L1 exhibits high potential for local regional and distal metastasis. Since the expression of miR-196b in MOC-L1 xenografts drastically decreased upon cisplatin treatment, targeting of miR-196b might facilitate tumor abrogation. As these cell lines originate from the C57BL/6 mouse, which is the strain most suitable for transgenic engineering, to approach the interplay of these OSCC cells with other type of genetically modified cells in immune-competent mice would bestow profound insight on OSCC pathogenesis.
Note: This abstract was not presented at the meeting.
Citation Format: Yi-Fen Chen, Chung-Ji Liu, Shou-Yen Kao, Shu-Chun Lin, Kuo-Wei Chang. Newly established mouse oral carcinoma cell lines and their syngeneic tumorigenesis models [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 4635.
Abstract 4650: TOPK is a prognostic marker and therapeutic target in skin carcinogenesis
Authors: Roh Eunmiri 
Published: August 2019

Abstract
Solar ultraviolet (sUV) is linked to development of cutaneous squamous cell carcinoma (cSCC) as a non-melanoma skin cancer (NMSC). Actinic keratosis (AK), induced by sUV irradiation, acts as precursor to cutaneous squamous cell carcinoma (cSCC) and is a pre-malignant skin lesion characterized with an abnormal proliferation of atypical keratinocytes confined to the epidermis of the skin. Therefore, to identify the major signaling molecules in the prevention, development and metastasis of cSCC is a critically important task. Here, we suggested a promising protein target, T-LAK cell-originated protein kinase (TOPK) as an active form of MEK1 continuously phosphorylating downstream targets, which appears to be critical in mediating skin carcinogenesis. We detected high levels of total and phosphorylated TOPK protein expression in SCC, and phosphorylated TOPK levels were also markedly higher in AKs and SCCs from patients compared to matched normal skin. Inflammation is known to contribute to tumor development and thus we examined the effect of a 2-minimal erythema dose (MED) of solar stimulated light (SSL) exposure in clinical human skin samples. Our results indicated that acute SSL irradiation increased epidermal thickness as a feature of inflammation and also enhanced total protein and phosphorylation levels of TOPK in human skin in a time-dependent manner. TOPK phosphorylation in human precancerous HaCaT keratinocytes was also increased by SSL irradiation in a dose- and time-dependent manner. Interestingly, TOPK knockout (TOPK-/-) SKH1 (Crl: SKH1-Hrhr) hairless mice showed no tumors on SSL-exposed skin tissues. In contrast, wild-type (TOPK+/+) control SKH1 hairless mice treated with SSL showed increased tumor volume and number. Furthermore, TOPK-/- mice showed base levels of epidermal thickness similar to the SSL-unexposed control group and the Ki-67 proliferation marker was decreased in SSL-exposed TOPK-/- mouse skin compared to SKH1 TOPK+/+ mice. Notably, levels of the anti-apoptotic protein Bcl-2 were decreased in TOPK-/- mice, compared to SSL-treated TOPK+/+ mice. Moreover, our results indicated that phosphorylated and total TOPK protein levels in SCC metastasized to skin or lymph nodes were significantly higher compared to human SCC primary tumors. These results indicated that phosphorylated and total TOPK proteins are associated with both SCC development and metastasis. Thus, molecular targeting of TOPK could be an effective approach in the clinic to treat or prevent cSCC.
Citation Format: Eunmiri Roh. TOPK is a prognostic marker and therapeutic target in skin carcinogenesis [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 4650.
Abstract 4658: Cigarette smoke extract and benzo(a)pyrene induce osteopontin expression in lung cancer and promote mesenchymal stem cell recruitment
Authors: Jiang Ya-Jing , Chang An-Chen , Chen Po-Chun , Tang Chih-Hsin 
Published: August 2019

Abstract
Cigarette smoking produces many organic compounds, including the carcinogenic polycyclic aromatic hydrocarbon benzo(a)pyrene, (BAP), which is linked to lung cancer. Tumor tissue recruits mesenchymal stem cells (MSCs; undifferentiated multipotent adult stem cells) to increase cancer cell proliferation, invasion and metastasis. We sought to determine the effects of cigarette smoke extract (CSE) and BAP stimulation on lung cancer cells and MSCs. We found that CSE and BAP increased mRNA and protein expression of osteopontin (OPN), a member of the small integrin-binding ligand N-linked glycoproteins (SIBLINGs) family, but had no such effects on any other SIBLINGs proteins. A National Center for Biotechnology Information (NCBI) analysis of data from the Gene Expression Omnibus (GEO) database (GSE31210) identified much higher OPN expression in current and ex-cigarette smokers with lung cancer than in lung cancer patients who were nonsmokers. Our analysis found that stimulating lung cancer cells with CSE and BAP led to the recruitment of MSCs, which adhered to lung cancer cells via OPN production. Next, we used a gene set from the BioCarta database to investigate signaling pathways associated with lung cancer. We found that the MAPK, JAK/STAT and RAS signaling pathways had the highest repeatability in lung cancer patients who were cigarette smokers. We discovered that CSE and BAP only activated the JAK2/STAT3 pathway and that transfection of lung cancer cells with JAK2 and STAT3 small interfering RNAs interrupted CSE- and BAP-induced OPN expression, inhibiting MSC recruitment and adhesion. We are now investigating whether MSCs link back to lung cancer cells and further induce migration and invasion. In summary, our data indicate that CSE and BAP increase OPN expression in lung cancer cells through the JAK2/STAT3 signaling pathway and thereby recruit MSCs and their adhesion to cancer cells.
Citation Format: Ya-Jing Jiang, An-Chen Chang, Po-Chun Chen, Chih-Hsin Tang. Cigarette smoke extract and benzo(a)pyrene induce osteopontin expression in lung cancer and promote mesenchymal stem cell recruitment [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 4658.
Abstract 4859: MFP-FePt-GO nanocomposite promotes radiosensitivity of non-small cell lung cancer via activating caspase system and impairing DNA damage repair
Authors: Peng Shan , Sun Yingming , Luo Yuan , Ma Shijing , Gong Yan , Xie Conghua 
Published: August 2019

Abstract
Recent advances in nanomedicine provide promising alternatives for cancer treatment that may improve the survival and life quality of patients with cancer. A novel nanocomposite (MFP-FePt-GO) based on a lamellar-structure magnetic graphene oxide (GO) and polyethylene glycol drug delivery system was designed, synthesized and functionalized for co-delivery of metronidazole and 5-fluorouracil. The chemical synthesis efficiency was measured by Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy and energy dispersive X-ray spectroscope. The morphology, dispersion and sizes of this nanocomposite were also measured with transmission electron microscope. This new nanocomposite exhibited good solubility, stability and biocompatibility. While no severe allergies, liver and kidney damage or drug-related deaths were observed, MFP-FePt-GO promoted radiosensitivity of non-small cell lung cancer (NSCLC) cells both in vivo and in vitro. MFP-FePt-GO imrpvoed the effects of radiation through activation of the caspase system and impairment of DNA damage repair. This novel nanocomposite also induced a reactive oxygen species burst, which suppressed the antioxidant protein expression and induced cell apoptosis. Furthermore, MFP-FePt-GO prevented the migration and invasion of NSCLC cells. Taken together, MFP-FePt-GO showed a synergistic anti-tumor effect with radiation in eliminating the tumors. With good safety and efficacy, this novel nanocomposite might be a potential radiosensitive agent for NSCLC patients.
Citation Format: Shan Peng, Yingming Sun, Yuan Luo, Shijing Ma, Yan Gong, Conghua Xie. MFP-FePt-GO nanocomposite promotes radiosensitivity of non-small cell lung cancer via activating caspase system and impairing DNA damage repair [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 4859.
Abstract 487: A high percentage of LCNEC shows DLL3 expression in association with molecular subtypes and neuroendocrine markers
Authors: Speel Ernst-Jan M. , Hermans Bregtje C. , Derks Jules L. , Thunnissen Erik , Suylen Robert Jan van , Bakker Michael A. den , Groen Harry J. , Smit Egbert F. , Damhuis Ronald A. , Broek Esther C. van den , Stallinga Cecile M. , Roemen Guido M. , Dingemans Anne-Marie C. 
Published: August 2019

Abstract
Background Pulmonary large cell neuroendocrine carcinoma (LCNEC) can be subdivided in two types: the co-mutated TP53 and RB1 subtype, and the TP53 and STK11/KEAP1 mutated subtype (Derks et al. Clin Cancer Res 2018; J Thorac Oncol 2018). DLL3 is a member of the Notch ligand family and a possible treatment target for neuroendocrine carcinoma. We investigated DLL3 and NE marker expression in mutational subtypes of metastatic LCNEC.
Methods Immunohistochemical (IHC) analysis for DLL3 (clone SC16.65) was performed on 94 pathological reviewed pretreatment stage IV LCNEC. Samples were scored positive if ≥1% tumor cells showed cytoplasmic or dotlike DLL3 immunostaining. Also an H-score was calculated by multiplying intensity by percentage of positive cells. Targeted next generation sequencing (TP53, RB1, STK11, KEAP1) could be performed in 66 patients.
Results DLL3 was expressed in 70/94 (75%) LCNEC, 56 of which showed cytoplasmic immunostaining. 37/70 (53%) samples had an H-score&gt;100. DLL3 staining was more often seen in STK11 and/or KEAP1 mutated LCNEC (13/14;93%) than in tumors with wildtype STK11/KEAP1 (36/52;69%) (trend;p=0.093). In addition, DLL3 positivity was associated with expression of ≥2 NE-markers (64/79 LCNEC (81%) vs 3/8 (37%) tumors with &lt;2 NE-markers; p=0.014).
Conclusions A high percentage (75%) of stage IV LCNEC shows cytoplasmatic DLL3 epression in association with NE markers, half of which with H-scores&gt;100. Interestingly, DLL3 positivity was observed in almost all STK11/KEAP1 mutated LCNEC, which is in agreement with recent data (George et al. Nat Commun 2018). It thus might be worthwhile to investigate the efficacy of DLL3 targeted therapy in LCNEC.
Citation Format: Ernst-Jan M. Speel, Bregtje C. Hermans, Jules L. Derks, Erik Thunnissen, Robert Jan van Suylen, Michael A. den Bakker, Harry J. Groen, Egbert F. Smit, Ronald A. Damhuis, Esther C. van den Broek, Cecile M. Stallinga, Guido M. Roemen, Anne-Marie C. Dingemans. A high percentage of LCNEC shows DLL3 expression in association with molecular subtypes and neuroendocrine markers [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 487.
Abstract 4870: Dedicator of cytokinesis-x promotes chemo and radioresistance of gastric cancer by modulating WNT signaling and cancer stem cell traits
Authors: Chi Hsiang-Cheng , Lin Kwang-Huei 
Published: August 2019

Abstract
Prognosis of gastric cancer (GC) remains poor and the key players in its molecular pathogenesis are unknown at present. There is therefore a critical need to identify novel prognostic factors of GC. Dedicator of cytokinesis represents a protein family belonging to atypical Rho guanine nucleotide exchange factors (GEF) for Rac and/or Cdc42 GTPases. Dedicator of cytokinesis-x, a member of the Dock-C subfamily, exchanges GDP for GTP for Rac1 and Cdc42, both in vitro and in vivo. Here, we identified Dedicator of cytokinesis-x as an independent biomarker for GC prognosis. Elevated Dedicator of cytokinesis-x expression was associated with significantly shorter cumulative survival in both univariate and multivariate analyses. Moreover, higher dedicator of cytokinesis-x expression is positively correlated with tumor size, depth of invasion, lymph node metastasis, vascular invasion and pathological stage. To establish the downstream effectors of dedicator of cytokinesis-x, we analyzed the genes in relation to dedicator of cytokinesis-x expression using three independent clinical GC cohorts. Genes displaying a positive correlation with dedicator of cytokinesis-x were subsequently subject to gene ontology analysis and shown to be significantly involved in the WNT/β-catenin signaling pathway. Depletion of dedicator of cytokinesis-x suppressed cell proliferation, chemo- and radio-resistance, metastasis, oncosphere formation ability and tumorigenicity as well as expression of gastric cancer stem cell (CSC) markers. Dedicator of cytokinesis-x depletion was accompanied by a concomitant decrease in CD44, CD133 and nuclear β-catenin expressions. Moreover, interactions between dedicator of cytokinesis-x and β-catenin were observed in the nucleus of GC cells. This finding suggested that dedicator of cytokinesis-x may act as a tumor promoter through WNT/β-catenin activation.
Citation Format: Hsiang-Cheng Chi, Kwang-Huei Lin. Dedicator of cytokinesis-x promotes chemo and radioresistance of gastric cancer by modulating WNT signaling and cancer stem cell traits [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 4870.