bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4365: Induction of distinct p53 mutation types differentially influences the control of cellular iron metabolism
Authors: Dandekar Eshan , Srinivasan Aishwarya , Clarke Stephen , Montgomery Mckale 
Published: August 2019

Abstract
The most commonly mutated gene in all human cancers is the tumor suppressor gene p53, but in addition to loss of tumor suppressor functions, mutations in p53 can also promote cancer progression by altering cellular iron acquisition and metabolism. The primary objective of this work was to determine how p53 mutation status influences the molecular control of iron homeostasis. Though hundreds of p53 mutations have been identified, the majority occur within the DNA binding domain and can be subdivided into two broad classes: contact (e.g., R273H) or conformational (e.g., R175H). By generating cell lines with inducible versions of some of the most common conformational and contact-type p53 mutations we have established that introduction of specific p53 mutation types alone is sufficient to disrupt cellular iron metabolism. We also demonstrate these effects are mediated at least in part due to differences in the responsiveness of Iron Regulatory Proteins (IRP) to cellular iron availability. IRP are considered the master regulators of intracellular iron homeostasis because they coordinate the expression of iron storage (ferritin) and iron uptake (transferrin receptor) genes. In response to changes in iron availability cells harboring either a wild-type p53 or contact (R273H) p53 mutation display canonical IRP-mediated responses, but neither IRP1 RNA binding activity nor IRP2 protein levels are affected by changes in iron status in cells harboring the conformational type mutant (R175H). Yet, both contact and conformational mutants exhibit robust changes in ferritin and transferrin receptor protein expression in response to iron loading and iron chelation, respectively. These findings suggest a novel, IRP-independent mode of iron regulation in cells expressing conformational type p53 mutants. Preliminary proteomics data suggests that lack of IRP responsiveness in cells expressing conformational p53 mutations may result from impaired iron-sulfur cluster biogenesis. These findings are currently being explored as a means of exploiting distinct p53 mutation types to more favorably induce iron-mediated cell death via the activation of ferroptosis. As p53 is mutated in nearly half of all human cancers, and iron is necessary for cancer cell growth and proliferation, the studies have implications for a wide range of clinically important cancers.
Citation Format: Eshan Dandekar, Aishwarya Srinivasan, Stephen Clarke, Mckale Montgomery. Induction of distinct p53 mutation types differentially influences the control of cellular iron metabolism [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 4365.
Abstract 4368: Investigating the role of IDH in normal metabolic and cancer pathways
Authors: DiDuca Nicholas , Roberts Sarah H. , Sturtevant Shane , Tipping Marla 
Published: August 2019

Abstract
Isocitrate dehydrogenase (IDH) has gained much attention due its frequent mutation in acute myeloid leukemia (AML) and glioblastomas. This enzyme is responsible for converting isocitrate into α-ketoglutarate (α-KG); when this gene is mutated it further converts α-KG into another metabolite, D-2-HG, that competes with α-KG. Production of D-2-HG causes diversion to a new metabolic pathway, as well as inhibits the activity of other enzymes in the cell. We have created flies that express the IDH mutant protein to investigate the other metabolic changes. One of these changes results in an embryo lethality. Additional model systems investigating larval and adult brains have shown glial cell inhibition. We hypothesize that harboring the IDH mutation will have a negative impact on the stable development of progeny.
Note: This abstract was not presented at the meeting.
Citation Format: Nicholas DiDuca, Sarah H. Roberts, Shane Sturtevant, Marla Tipping. Investigating the role of IDH in normal metabolic and cancer pathways [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 4368.
Abstract 4381: Investigating the reversible MDH1 catalytic reaction in squamous non-small cell lung cancer
Authors: Weeks Joi L. , Wells Grace , Alexander Sati , Metallo Christian , Sohl Christal D. 
Published: August 2019

Abstract
Non-small-cell lung cancer (NSCLC) is a leading cause of death in men and women worldwide. NSCLC relies on glycolysis to support cell proliferation and to synthesize proteins, nucleic acids and lipids. Malate dehydrogenase (MDH) is an enzyme critical for replenishing intermediates in the tricarboxylic acid (TCA) cycle and for helping to drive glycolysis through its reversible coenzyme system NAD+/NADH by interconverting oxaloacetate and malate. The cytosolic form of MDH (MDH1) has been reported to be amplified in squamous cell NSCLC, which has high glycolytic activity. Elucidation of the role of MDH1 in altering cellular metabolism to drive tumorigenic progression has yet to be determined. Thus, our interest lies in identifying the chemical and cellular characteristics required to drive the reversible MDH1 catalytic reaction in squamous cell NSCLC. Previously, we have shown that metabolic dehydrogenases are regulated by microenvironmental changes in pH and oxidation levels, and we are currently extending this work to MDH1. We are also evaluating various cell lines to gain a better understanding of how the MDH1 reaction can be altered to decrease the tumorigenic capacity of squamous cell NSCLC. Experimental knowledge obtained has the potential to increase our understanding of the MDH1 reaction and educate the design of future anti-tumor therapeutics.
Citation Format: Joi L. Weeks, Grace Wells, Sati Alexander, Christian Metallo, Christal D. Sohl. Investigating the reversible MDH1 catalytic reaction in squamous non-small cell lung 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 4381.
Abstract 4387: hnRNP Q1 promotes cell proliferation and tumorigenesis by translationally up-regulating cell cycle-related genes through the EGF pathway
Authors: Hung Liang-Yi 
Published: August 2019

Abstract
Heterogeneous nuclear ribonucleoprotein (hnRNP) Q1, an RNA-binding protein, has been reported as overexpressing in cancer cells. However, the role of hnRNP Q1 in tumorigenesis remains unclear. By using RNA-immunoprecipitation (IP) assay following next-generation sequencing, a group of cell cycle-related genes targeted by hnRNP Q1 were identified, including Aurora-A kinase. Overexpressed hnNRP Q1 can up-regulate Aurora-A and many spindle assembly checkpoint (SAC) proteins, but not alter their mRNA levels, through enhancing translational efficiency by interacting with the mRNA 5’-UTR. Ribosomal S6-IP and ribosomal profiling assay further confirmed the translational regulation of these mRNAs by hnRNP Q1. Stimulation with epidermal growth factor (EGF) enhances both binding between hnRNP Q1 and these mRNAs as well as the efficacy of the hnRNP Q1-induced translation of these mRNAs. EGF/hnRNP Q1-induced translation is mediated by the mTOR and ERK pathways. In addition, hnRNP Q1 overexpression is positively correlated with the levels of Aurora-A and these SAC genes in human colorectal cancer tissues. Taken together, our data suggest that hnRNP Q1 plays an important role in translationally regulating the expression of Aurora-A and a group of cell cycle-related genes, which increases cell proliferation and contributes to tumorigenesis in colorectal cancer. It may thereby contribute to tumorigenesis by translationally up-regulating these genes in colorectal cancer.
Citation Format: Liang-Yi Hung. hnRNP Q1 promotes cell proliferation and tumorigenesis by translationally up-regulating cell cycle-related genes through the EGF pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4387.
Abstract 4389: Post-translational modifications of histone demethylase JMJD1A in prostate cancer cells
Authors: Xu Songhui , Fan Lingling , Cui Xiaolu , Zhang Fengbo , Hussain Arif , Fazli Ladan , Gleave Martin , Qi Jianfei 
Published: August 2019

Abstract
Castration-resistant prostate cancer (CRPC) is the major cause of death for prostate cancer (PCa) patients. Re-activation of androgen receptor (AR) activity during androgen-deprivation therapy is believed to underlie CRPC development. We have found that histone demethylase JMJD1A primarily regulates AR and c-Myc activity and thus plays a key role in promoting PCa cell proliferation or survival. Unfortunately, specific JMJD1A inhibitors are not yet available. Here, we identified several post-translational modifications of JMJD1A by performing the JMJD1A immunoprecipitation and mass spectrometry analysis. These modifications include the canonical ubiquitination that targets JMJD1A for proteasome-dependent degradation, non-canonical ubiquitination that enhances the recruitment of co-activators, as well as those that can regulate these ubiquitination events. We also found that these modifications could be manipulated by commercially available inhibitors, to reduce the JMJD1A protein level and prostate cancer cell growth. Thus, targeting the JMJD1A modifications may serve as an alternative means to inhibit JMJD1A activity for the anti-PCa therapy.
Note: This abstract was not presented at the meeting.
Citation Format: Songhui Xu, Lingling Fan, Xiaolu Cui, Fengbo Zhang, Arif Hussain, Ladan Fazli, Martin Gleave, Jianfei Qi. Post-translational modifications of histone demethylase JMJD1A in prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4389.
Abstract 4396: Gli, not Androgen Receptor, is the primary driver of prostate cell growth
Authors: Foo Jane , Li Na , Massah Shabnam , Nouri Mannan , Wang Mike , Buttyan Ralph 
Published: August 2019

Abstract
Introduction Hedgehog (Hh) signaling regulates the activity of Gli transcription factors. Gli controls genes needed for development, cell growth and cell motility. Canonical Hh signaling through Smoothened [Smo] suppresses the proteolysis of Gli2 and Gli3, maintaining them in high molecular weight active forms. Previously, we showed that active androgen receptors ([AR] liganded AR full length and AR-V7) recognize and binds Gli3 its Protein Processing Domain. This binding overrides the need for Smo action and provides a means for stabilization and activation of Gli3 in prostate cancer (PCa) cells without Hh. Studies on the effects of AR binding to Gli2 are more challenging because it is expressed at much lower levels than Gli3. Here, we report that AR also affects Gli2 protein stability and show that Gli2, like Gli3, is a driver of PCa cell growth that is overexpressed in castration resistant disease. Method Immunohistochemistry (IHC) using Gli2- and Gli3-specific antibodies was used to assess expression of Gli2 and Gli3 in human PCa tumor microarrays. Western blot were used to identify and quantify levels of active Gli2 and Gli3 in androgen-treated PCa cells (LNCaP, LNCaP-AI, LAPC4). Proximity ligation assays (PLA) was used to visualize in situ and quantify AR-Gli2 complexes in PCa cells. Gli2- and Gli3-specific siRNAs were used to knock down Gli expression in AR+ (LNCaP-AI, LAPC4, 22Rv1) and AR- (PC3) PCa, cells followed by the Gli reporter assay and the cell growth assay. Results IHC outcomes showed that nuclear Gli2 and Gli3 protein expression was significantly higher in castration resistant tumors compared to primary disease. Androgens increased expression of active Gli2 and Gli3 protein expression in PCa cells and stimulated Gli reporter activity. PLA showed the presence of intranuclear complexes of Gli2/Gli3-AR-Full-length in androgen-treated LNCaP and Gli2-AR-V7 complexes in CWR22rv1 cells. Knockdown of Gli2 or Gli3 present significant reduction in Gli transcriptional activity as well as inhibition on growth of both AR+ and AR- PCa cells that were tested. Conclusion AR activity affects Gli2 processing, as it does for Gli3. We can visualize and quantify AR-Gli2/Gli3 complexes in situ in PCa cells. Gli2 suppression, as well as Gli3 suppression, has a profound effect on PCa cell growth but combined suppression has the strongest effects in certain PCa cells. Finally, Gli2 and Gli3 protein expression is elevated in castration resistant disease.
Citation Format: Jane Foo, Na Li, Shabnam Massah, Mannan Nouri, Mike Wang, Ralph Buttyan. Gli, not Androgen Receptor, is the primary driver of prostate cell growth [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 4396.
Abstract 4398: KDM3A and DCLK1 interactions promote stemness and tumorigenesis in PDAC
Authors: Ghosh Chandrayee , Palaniyandi Kankaraj , Paul Santanu , Dandawate Prasad , Rawal Sonia , Subramaniam Dharmalingam , Padhye Subhash , Gunewardena Sumedha , Thomas Sufi , O'Neil Maura , Jensen Roy , Welch Danny , Milisky Sally , Weir Scott , Iwakuma Tomoo , Anant Shrikant , Dhar Animesh 
Published: August 2019

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the major leading cause of cancer related human death in USA. There is no possible treatment or target available in PDAC. It was proposed that the cancer stem cells (CSCs) can regulates malignancy in PDAC. DCLK1 is one of the quiescent cancer stem cell marker in PDAC that can regulate tumor progression. Identification of the key factors that influence stemness will help to target PDAC. Histone lysine demethylase KDM3A is an enzyme/protein which can regulate stem cell renewability and tumor progression, thereby KDM3A can interact with DCLK1 for tumor progression. KDM3A influences tumor growth and regulates stemness. Therefore, our goal is to find out the the role of KDM3A in tumor progression in PDAC through interactions with DCLK1. We observed expression of KDM3A in both PDAC patients’ samples and cells. Knockdown and overexpression of KDM3A were executed by using lentiviral vector. Tumor progression were also observed in orthotopic mice model. ChIP and RNA seq were performed to validate the data. KDM3A was overexpressed in human PDAC patient tissues and human pancreatic cancer cells with concomitant increase of CSC marker, DCLK1. Moreover, DCLK1 and KDM3A was found to be co-localized in patient tissue samples and identified binding sites of KDM3A with DCLK1 using ChIP-seq. Knockdown of KDM3A abrogates oncogenic potential whereas, overexpressed KDM3A in transformed HPNE cells showed malignant properties with enhanced invasive property, pancosphere formation, foci formation and tumor formation in mouse. Moreover, ChIP-seq and RNA seq suggested that KDM3A regulated DCLK1 expression in tumor progression. In conclusion, co-expression of DCLK1 with KDM3A influenced stemness and enhance tumor progression in PDAC.
Citation Format: Chandrayee Ghosh, Kankaraj Palaniyandi, Santanu Paul, Prasad Dandawate, Sonia Rawal, Dharmalingam Subramaniam, Subhash Padhye, Sumedha Gunewardena, Sufi Thomas, Maura O'Neil, Roy Jensen, Danny Welch, Sally Milisky, Scott Weir, Tomoo Iwakuma, Shrikant Anant, Animesh Dhar. KDM3A and DCLK1 interactions promote stemness and tumorigenesis in PDAC [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 4398.
Abstract 44: Assessment of pancreatic cancer 3D organotypic cultures as models for functional preclinical analysis
Authors: Nelson Shannon R. , Roche Sandra , O'Neill Fiona , Larkin AnneMarie , Crown John , Walsh Naomi 
Published: August 2019

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the deadliest of all cancers, with a five-year survival rate of 8%. Decades of research has done little to improve patient outcomes. To identify key therapeutic strategies, appropriate research preclinical models are critical for testing the efficacy of drugs or downstream functional genomic analysis. Current methods of growing PDAC established cell lines in a 2D monolayer do not fully represent how the tumor cells grow in vivo as they fail to recapitulate the physiology of tumors in vivo due to different architecture, adherence structures and biochemical gradients. Patient-derived xenografts can retain the histological and genetic characteristics of their donor tumor and can remain stable across passages. Three-dimensional (3D) organoids grown ex vivo are tractable also retain the architecture, genotype and phenotype of a patients’ tumor.
However, a detailed comparative assessment of the utility of organoids, matched 2D cell lines and 3D cell organotypic models to assess the complex biology, interactions, response to therapeutic regimens has not been performed.
Using our unique protocol, we have established PDAC organoids and isogenetically matched 2D cell lines derived from PDAC PDX tumors. To establish if these matched 2D cell lines grown in 3D can recapitulate the organoid model, we cultured the matched cell lines in 3D organoid media in non-adherent, Matrigel containing cultures. The expression of PDAC histological markers between the original tumor, the PDX tumor, organoid and matched cell line in 3D and 2D has identified differential expression of tumor initiating cell (TIC) markers. RNA-seq transcriptomics of the 2D cell line models, matched recapitulated 3D organotypic models, organoids, PDX-tumor and patient tumor will reveal the application of these models for ex vivo downstream functional analysis.
Citation Format: Shannon R. Nelson, Sandra Roche, Fiona O'Neill, AnneMarie Larkin, John Crown, Naomi Walsh. Assessment of pancreatic cancer 3D organotypic cultures as models for functional preclinical analysis [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 44.
Abstract 4413: CDK6 overexpression promotes resistance to CDK4/6 inhibitors in breast cancer
Authors: Li Qing , Razavi Pedram , Li Zhiqiang , Paula Arnaud F. Da Cruz , Brogi Edi , Scaltriti Maurizio , Reis-Filho Jorge S. , Chandarlapaty Sarat 
Published: August 2019

Abstract
CDK4/6 inhibitors (CDK4/6i) are highly active therapies in estrogen receptor-positive (ER+) breast cancer. Unfortunately, tumor relapse on these agents is frequently encountered in clinical practice with limited data on the biologic mechanisms that can mediate resistance. We utilized cell line models, patient derived xenografts and patient samples to interrogate mechanisms of resistance to CDK4/6 inhibitors. A survey of genomic alterations associated with limited benefit of CDK4/6iidentified several alterations involving the Hippo pathway which could potentially impact CDK6 kinase expression. Immunohistochemistry from these patients revealed increased YAP nuclear translocation and high levels of CDK6 protein specifically in the group of patients with short progression-free survival (PFS) on CDK4/6i. A PDX model of acquired resistance to CDK4/6i also showed that prolonged treatment with CDK4/6i led to a subset of tumors that developed resistance, all of which showed Hippo pathway suppression and CDK6 upregulation. Finally, cell lines models exposed to CDK4/6i showed multiple clones that featured upregulation of CDK6 through suppression of the Hippo pathway or amplification of the CDK6 gene. Identifying CDK6 overexpression as a recurrent feature of CDK4/6i resistant tumors, we next investigated the function(s) of CDK6 in our models. We performed knockdown of CDK6 by shRNA and found its overexpression to be necessary for drug resistance in these models while reinforced CDK6 could restore resistance or confer resistance when overexpressed in naïve cells. Given the close homology of CDK4 and CDK6, we asked whether any differences might exist between CDK4 and CDK6 complexes, performing immunoprecipitation and mass spectrometry (IP-MS) and found CDK6 to bind a distinct partition of proteins from CDK4 including INK4 proteins. In vitro kinase assays revealed that INK4 proteins impaired the ability of CDK4/6i to block CDK6 activity. INK4 proteins were found to cooperate with CDK6 in mediating drug resistance as their knockdown restored drug sensitivity to resistant cells, while INK4 overexpression promoted resistance in CDK6-high cells. Taken together, the data revealed that high levels of a CDK6-INK4 complex to be a recurrent mechanism of resistance to CDK4/6i and suggest novel CDK6 inhibitors as a strategy to overcome resistance.
Citation Format: Qing Li, Pedram Razavi, Zhiqiang Li, Arnaud F. Da Cruz Paula, Edi Brogi, Maurizio Scaltriti, Jorge S. Reis-Filho, Sarat Chandarlapaty. CDK6 overexpression promotes resistance to CDK4/6 inhibitors in 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 4413.