bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2334: Sialylation of the TNFR1 death receptor promotes cancer cell survival
Authors: Holdbrooks Andrew T. , Schultz Matthew J. , Liu Zhongyu , Bullard Daniel C. , Bellis Susan L. 
Published: August 2018

Abstract
Studies have well-established that activation of TNFR1, a ubiquitously expressed cell surface receptor, by TNF can induce either cell survival or cell death signaling cascades, however, the mechanisms regulating TNFR1 to initiate these disparate outcomes are poorly understood. TNF-induced apoptosis is initiated by clustering of activated TNFR1 at the cell surface, followed by internalization of the receptor complexes and subsequent caspase activation. Conversely, surface retention of activated TNFR1 promotes cell survival signaling mediated by NFκB and MAPKs pathways. Our group has identified a glycosylation-dependent mechanism that controls this TNFR1 signaling switch (i.e. apoptosis vs. survival). Specifically, we have found that TNFR1 activity is modified by the addition of a distinct sugar, an α2-6 linked sialic acid, by the Golgi sialyltransferase, ST6Gal-I. Importantly, ST6Gal-I is highly upregulated in numerous cancer types, and through its sialylation of a select cohort of cell surface receptors, various studies have indicated ST6Gal-I as a potent tumor cell survival factor. The effect of sialylation on TNFR1 was examined in multiple cancer cell models, including leukemia and epithelial cancer cell lines with forced overexpression or knockdown of ST6Gal-I. These models show that TNFR1 sialylation blocks TNF-induced apoptosis (indicated by the inhibition of caspase activation), and data from our group suggests that the underlying mechanism of this inhibition of apoptosis involves the sialylation-driven interference of TNFR1 oligomerization and internalization. Considering sialylated TNFR1 is retained on the cell surface following activation, we hypothesize that cells with abundant ST6Gal-I not only block TNFR1-mediated apoptosis but also divert signaling towards survival, indicated by increased activity and expression of many pro-survival factors (NFkB, AKT, etc.). Based on these collective findings, we conclude that the ST6Gal-I-mediated sialylation of TNFR1 controls the cellular response to TNF by blocking TNFR1 internalization, resulting in apoptosis inhibition and the promotion of survival signaling. Considering the tumor microenvironment is rich in immune cell-derived TNF, we posit that ST6Gal-I protects tumor cells within this inflammatory milieu by providing a mechanism by which tumor cells can evade immune cell killing.
Citation Format: Andrew T. Holdbrooks, Matthew J. Schultz, Zhongyu Liu, Daniel C. Bullard, Susan L. Bellis. Sialylation of the TNFR1 death receptor promotes cancer cell survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2334.
Abstract 2339: Targeting ICMT in pancreatic cancer
Authors: Manu Kanjoormana A. , Chai Tin F. , Teh Jing T. , Zhu Wan , Casey Patrick J. , Wang Mei 
Published: August 2018

Abstract
Introduction: Pancreatic Cancer remains one of the most difficult to treat human cancers with the 5-year survival as low as 5%. No targeted therapy yet developed against Pancreatic cancer. Here we want to target Isoprenylcysteine carboxylmethyltransferase (ICMT), an enzyme that post translationally modifies a group of proteins including several small GTPases against Pancreatic Cancer. Method: ICMT inhibition was achieved using lentivirus expressing ICMT shRNA and a pharmacological inhibitor named Cysmethynil. We evaluated a panel of human pancreatic cancer cell lines and identified those that are sensitive to ICMT inhibition by cell viability assay. This responsiveness to ICMT inhibition was confirmed in in vivo xenograft tumor mouse models using both Cysmethynil and shRNA-targeting ICMT. Flow cytometry analysis after DAPI or PI staining is used to detect cell cycle arrest and apoptosis. We used western blot analysis to study autophagy, apoptosis and cell cycle markers. ShRNA for P21 is used for p21 knock down studies. SiRNA for p53 is used to study whether p21 induction is p53 dependent. BNIP3, ULK1 and ATG5 knock down was done using specific shRNAs to study their role in ICMT inhibition induced autophagy and apoptosis. BCL-xL is over expressed in the cells using retroviral vectors to study the role of apoptosis in ICMT inhibition induced cell death. Cell and mitochondrial respiration was determined by oxygen consumption rate analysis using Seahorse XF24 analyzer. Summary: In sensitive pancreatic cancer cells, ICMT inhibition induces mitochondrial respiratory deficiency and cellular energy depletion, leading to significant upregulation of p21 and p21 dependent induction of BNIP3 leading to autophagy and apoptosis. But unlike in prostate and liver cancer, ICMT inhibition induced apoptosis not the autophagy responsible for inhibition of cell viability in pancreatic cancer. Conclusion: These findings suggest ICMT is a potential therapeutic target against pancreatic cancers and atleast in pancreatic cancer, ICMT inhibition induced apoptosis but not autophagy responsible for its therapeutic efficacy.
Citation Format: Kanjoormana A. Manu, Tin F. Chai, Jing T. Teh, Wan Zhu, Patrick J. Casey, Mei Wang. Targeting ICMT in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2339.
Abstract 2351: Transcriptome-wide association study reveals candidate causal genes for lung cancer
Authors: Clemenceau Alisson , Lamontagne Maxime , Torres Robert Carreras , Obeidat Ma'en , Timens Wim , Joubert Philippe , Amos Christopher I. , McKay James D. , Bossé Yohan 
Published: August 2018

Abstract
Genome-wide association studies have identified robust susceptibility loci associated with lung cancer. As part of the OncoArray-TRICL consortium, we have recently completed the largest GWAS on lung cancer including 29,266 cases and 56,450 controls of European descent. The goal of this study is to integrate the complete GWAS results with a large-scale expression quantitative trait loci (eQTL) mapping study in human lung tissues (n=1,038) to identify candidate causal genes for lung cancer. Transcriptome-wide association study (TWAS) was used to integrate GWAS and lung eQTL signals and identify genes whose levels of expression in lung tissue are causally related to lung cancer. TWAS was performed on six histologic and smoking subgroups, namely overall lung cancer, adenocarcinoma, squamous cell carcinoma, small cell carcinoma, never-smokers, and ever-smokers. As expected, the main TWAS signal for all histologic subtypes and ever-smokers was on chromosome 15q25. The genes most strongly associated with lung cancer at this locus were IREB2 (PTWAS=4.97E-104), and to a lower extent, CHRNA5 (PTWAS=5.26E20) and HYKK (PTWAS=2.04E-17). TWAS identified causal genes were different from those reported in GWAS, including JAML on 11q23.3 in overall lung cancer (PTWAS=1.39E-6) and adenocarcinoma (PTWAS=2.09E-8), NOTCH4 on 6p21.32 in squamous cell carcinoma (PTWAS=1.24E-12), ZNRD1 on 6p22.1 in overall lung cancer (PTWAS=3.41E-14) and ever-smokers (PTWAS=1.29E-9), HIST1H2BD on 6p22.2 for small cell carcinoma (PTWAS=1.54E-6), and NEXN on 1p31.1 in never-smokers (PTWAS=2.64E-5). In addition, a new small cell carcinoma susceptibility locus was identified on 4q32.2 and associated with the expression levels of TMA16 (PTWAS=4.2E-6). In conclusion, lung tissue TWAS on lung cancer, histologic subtypes and smoking subgroups revealed novel causal genes in GWAS-nominated loci. A new locus for small cell carcinoma (4q32.2-TMA16) was also identified and will require further validation.
Citation Format: Alisson Clemenceau, Maxime Lamontagne, Robert Carreras Torres, Ma'en Obeidat, Wim Timens, Philippe Joubert, Christopher I. Amos, James D. McKay, Yohan Bossé. Transcriptome-wide association study reveals candidate causal genes for lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2351.
Abstract 2363: Novel CDH1 mutations in breast invasive lobular carcinoma
Authors: Frampton Garrett M. , Hartmaier Ryan , Sokol Ethan , Gupta Anika , Greenbowe Joel , Roels Steven , Gay Laurie , Stephens Philip J. 
Published: August 2018

Abstract
Breast invasive lobular carcinoma (ILC) is the second most common type of breast cancer, making up approximately 10% of all invasive breast cancers. Breast ILC is characterized by loss of e-cadherin protein expression (CDH1), which is usually caused by loss of function mutations in the CDH1 gene. A subset of breast ILC cases have no identifiable CDH1 mutation, but presumably inactivate CDH1 through currently unknown mechanisms.
Tumors from more than 150,000 unique patients including more than 15,000 breast cancers were examined by comprehensive genomic profiling to detect base substitutions, indels, copy number alterations, and genomic rearrangements in the full coding regions of up to 465 genes. Statistical significance of the disease distributions was calculated using Fisher's exact test with false discovery rate multiple hypothesis testing correction.
Of 760 breast ILC cases, 583 (76.7%) had a known loss-of-function mutation in the CDH1 gene. To identify previously unknown mutations that result in or substitute for CDH1 loss-of-function we performed statistical analysis on all mutations, in any gene, occurring more than once in the 177 ILC cases without an identifiable CDH1 mutation. The most statistically significant mutation was very near to a splice site of CDH1 (chr16:68863554 c.2296-3A&gt;G), occurring in 7 CDH1 negative ILC cases as well as 9 other cases in cancer types that frequently harbor CDH1 mutations (7 breast, 2 gastroesophageal junction) and 1 colorectal cancer. Based on tumor-only test based zygosity modeling, this mutation is only observed as somatic and usually homozygous in the tumor. Four other positions near to splice sites of CDH1 (chr16:68844247 c.832+3A&gt;G, chr16:68849667 c.1565+5G&gt;A, chr16:68856133 c.1936+5G&gt;A, chr16:68857532 c.2164+3A&gt;C), mutated in 13 CDH1 negative ILC cases, were also statically significant, somatic, and usually homozygous. No statistically significant mutations were found in genes other than CDH1.
Previously unappreciated somatic, non-canonical splice site mutations in CDH1 occur in ~10% (20/177) of breast ILC cases with no known CDH1 mutation. These mutations occur almost exclusively in tumor types known to harbor frequent CDH1 mutations and are usually homozygous in the tumor, strongly indicating that they are CDH1 loss-of-function mutations.
Citation Format: Garrett M. Frampton, Ryan Hartmaier, Ethan Sokol, Anika Gupta, Joel Greenbowe, Steven Roels, Laurie Gay, Philip J. Stephens. Novel CDH1 mutations in breast invasive lobular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2363.
Abstract 2364: The phosphatase PRL-3 is a pro-survival oncogene in acute lymphoblastic leukemia
Authors: Wei Min , O'Leary Kristin , Liu Jinpeng , Wang Chi , Blackburn Jessica 
Published: August 2018

Abstract
PRL-3, phosphatase of regenerating liver 3, is one member of a subfamily of protein tyrosine phosphatases that belongs to the dual-specificity phosphatases (DSPs). Accumulating evidence shows that PRL-3 is a biomarker of tumor progression and metastasis and high PRL-3 expression is associated with reduced overall and disease-free survival in a variety of solid tumors, suggesting it's importance in tumor recurrence. However, the role for PRL-3 in leukemia relapse has not yet been described.
We have found that PRL-3 contributes to Acute Lymphoblastic Leukemia (ALL) malignancy by acting as a pro-survival gene, both in vitro and in vivo. Expression of PRL-3 in a MYC-induced zebrafish T-cell ALL model showed that PRL-3 expressing ALL had shorter latency and higher penetrance, compared with the fish injected with rag2:Myc; rag2:GFP alone. Growth after transplantation at low cell number was also significantly faster in the PRL3 expressing T-ALL, suggesting that PRL-3 plays an important role in ALL development and progression.
We found PRL-3 to be highly expressed in a majority of human ALL compared to normal peripheral blood mononuclear cells (PBMNC), which suggests clinical relevance. Analysis of gene expression microarray data of 119 patient samples reveals that PRL-3 was highly expressed in 58% of the patients. In addition, PRL-3 had the highest expression in the most aggressive and treatment resistant subgroups of T-ALL, the TAL/LMO and Immature subtypes. PRL-3 is also expressed by human T-ALL cell lines using quantitative RT- PCR and immunoblotting. PRL-3 knockdown leads to significant apoptosis in T-ALL cells. The treatment of T-ALL cells using small molecule drugs including 2-cyano-2-ene-ester compound (Analog 3) and thieno [3,2-b] pyridine 1-oxide (thienopyridone) , also resulted in significant growth inhibition of T-ALL cells in part through &gt;4-fold increase in apoptosis, measured by annexin V staining.
In summary, our study provides evidence for a role of PRL-3 in T- ALL malignancy, and suggests that PRL3 may be a useful drug target in the treatment of this disease. Our future studies are focused on identifying the mechanisms by which PRL3 promotes T-ALL progression and survival.
Citation Format: Min Wei, Kristin O'Leary, Jinpeng Liu, Chi Wang, Jessica Blackburn. The phosphatase PRL-3 is a pro-survival oncogene in acute lymphoblastic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2364.
Abstract 2366: The tyrosine phosphatase, SHP-2, participates in regulating PD-L1 expression in non-small cell lung cancer
Authors: Toral Keller , Harris Brent , Creameans Jarrod , Black Penni 
Published: August 2018

Abstract
Immune checkpoint inhibitors, specifically those which target T cell surface receptor Programmed Cell Death-1 (PD-1) and its ligand, Programmed cell death ligand-1 (PD-L1), have demonstrated clinical benefit in patients with non-small cell lung cancer (NSCLC). Currently, tumor expression of PD-L1 serves as the FDA-approved companion diagnostic for response to anti-PD-1/PD-L1 therapy. However, a fraction of patients who express PD-L1 exhibit a response to treatment, and in some cases, patient tumors that do not express PD-L1 demonstrate response to therapy, making this a poor predictive biomarker. Further, the mechanism by which PD-L1 expression is controlled remains under-studied.
In this study, we seek to determine the impact of the protein tyrosine phosphatase, SHP-2, on PD-L1 expression through Jak/STAT- mediated signaling in NSCLC cell lines. SHP-2 can harbor activating mutations which prevent auto-inhibition of the catalytic phosphatase domain, and that may be pro-tumorigenic in some tumors. To understand the impact of SHP-2 activity on PD-L1 expression, we first assessed activation of STAT3 in NSCLC tumor cells after treatment with IFNγ and other mitogens. We then transfected NSCLC cells with wildtype and hyperactive SHP-2 mutants or ablated SHP-2 with siRNA specific for SHP-2 and measured both STAT3 and PD-L1 expression. Cell lines A549 and H661 exhibit low endogenous expression of both SHP-2 and PD-L1, and thus were chosen for transfection with hyperactive SHP-2 mutants (E76K and G503V), which also altered PD-L1 expression by western blot analysis. Quantitative real-time PCR (qPCR) and western blot analysis revealed that siRNA ablation of SHP-2 led to increased PD-L1 expression in the H460 cell line. Cells transfected with the SHP-2 activating mutants will also be assessed alteration of cell proliferation. Finally, using data obtained from The Cancer Genome Atlas project, STAT3 and PD-L1 expression levels are being evaluated in NSCLC tumor samples in which SHP-2 is mutated (E76K or G503V). With these data, we expect to gain a more complete understanding of the role of SHP-2 within the tumor microenvironment and the extent to which it controls PD-L1 expression, leading to new drug targets or combinations of drugs and better predictive biomarkers of response to PD-1 and PD-L1 inhibitors.
Citation Format: Keller Toral, Brent Harris, Jarrod Creameans, Penni Black. The tyrosine phosphatase, SHP-2, participates in regulating PD-L1 expression in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2366.
Abstract 2378: Histone H4 tyr88-phosphorylation mediated by ACK1 promotes castration-resistant prostate cancer by epigenetic reprogramming of androgen receptor
Authors: Mahajan Nupam P. , Mahajan Kiran , Lawrence Nicholas , Lawrence Harshani 
Published: August 2018

Abstract
Androgen receptor (AR) plays a paramount role in the onset and progression of prostate cancer (PC). This very facet underlies androgen deprivation therapy (ADT), a preferred treatment to negate AR transcriptional activity. While ADT provides immediate palliative benefits, it is ineffective long term, as the recalcitrant disease recurs within 2-3 years and progresses to a lethal stage, referred to as the metastatic castration-resistant prostate cancer (mCRPC). The AR gene (AR) is amplified or mutated in &gt;50% of mCRPCs, suggesting that PC cells may have reinvigorated AR transcription as a response to the loss of existing AR activity by ADT. Consequently, resistance to ADT has become one of the most vexing problems in PC therapy. AR antagonists are often ineffective due to their inability to repress the expression of AR or its splice variant, AR-V7. Here, we report that the tyrosine kinase ACK1 (TNK2) phosphorylates histone H4 at tyrosine 88 upstream of the AR transcription start site. The WDR5/MLL2 complex reads the H4-Y88-phosphorylation marks and deposits the transcriptionally activating H3K4-trimethyl marks promoting AR transcription. We developed a new class of ACK1 kinase-specific small molecule inhibitor (R)-9bMS that suppresses ACK1 kinase activity at IC50= 48 nM. Reversal of the pY88-H4 epigenetic marks by the ACK1 inhibitor (R)-9bMS-sensitized naive and enzalutamide-resistant prostate cancer cells and reduced AR and AR-V7 levels to mitigate CRPC tumor growth. Thus, a feedforward ACK1/pY88-H4/WDR5/MLL2/AR epigenetic circuit drives CRPC and is necessary for maintenance of the malignant state.
Citation Format: Nupam P. Mahajan, Kiran Mahajan, Nicholas Lawrence, Harshani Lawrence. Histone H4 tyr88-phosphorylation mediated by ACK1 promotes castration-resistant prostate cancer by epigenetic reprogramming of androgen receptor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2378.
Abstract 2383: EGFR expression increases following decline in activity of N-acetylgalactosamine 4-sulfatase (ARSB) and SHP2 (PTPN11) and increases in chondroitin 4-sulfate and JNK in prostate
Authors: Bhattacharyya Sumit , Feferman Leo , Tobacman Joanne K. 
Published: August 2018

Abstract
The enzyme arylsulfatase B (ARSB; N-acetylgalactosamine 4-sulfatase) removes 4-sulfate groups from the non-reducing end of dermatan sulfate and chondroitin 4-sulfate (C4S) and is required for degradation of these sulfated glycosaminoglycans. Decline in ARSB and the resultant increase in C4S was previously reported to inhibit the activity of the enzyme SHP2 (PTPN11), a ubiquitous, non-receptor tyrosine phosphatase, and to lead to transcriptional events mediated by the sustained phosphorylation of phospho-ERK1,2 and phospho-p38. Previous experiments had shown that decline in ARSB was associated with increased expression of the epidermal growth factor receptor (EGFR; Her1/ErbB1) in human prostate malignant tissue and in human prostate cells, but the mechanism for this increase was unknown. The current experiments were performed to determine how decline in ARSB leads to increased expression of EGFR. Experiments were performed in human prostate stem and epithelial cells and normal and malignant human prostate tissues. Measurements included: EGFR promoter activity, chromatin immunoprecipitation assay, and binding studies of chondroitin sulfates with SHP2. Materials used included: SR11302, an inhibitor of c-fos binding with nuclear DNA; c-Jun peptide that acts as a c-Jun mimetic and inhibits c-Jun phosphorylation by JNK; JNK-selective inhibitor peptide that inhibits JNK phosphorylation; SHP2 dominant negative and constitutively active DNA constructs; PHPS1, an inhibitor of SHP2; ARSB siRNA, and galectin-3 siRNA. Increased EGFR promoter activation and EGFR expression followed decline in ARSB, decline in activity of SHP2 (PTPN11), enhanced activity of c-Jun N-terminal kinase (JNK), increased nuclear DNA binding of c-Jun and c-Fos, and EGFR promoter activation. These effects demonstrate an impact of ARSB and chondroitin 4-sulfation on the activation of a critical dual phosphorylation threonine-tyrosine kinase and on the mRNA expression of an important tyrosine kinase receptor in prostate cells. Restoration of ARSB activity may provide a new therapeutic approach to malignancies in which there is activation of EGFR-mediated tyrosine kinase signaling pathways.
Citation Format: Sumit Bhattacharyya, Leo Feferman, Joanne K. Tobacman. EGFR expression increases following decline in activity of N-acetylgalactosamine 4-sulfatase (ARSB) and SHP2 (PTPN11) and increases in chondroitin 4-sulfate and JNK in prostate [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2383.