bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2403: Pyruvate dehydrogenase mediates chemo-resistance in pancreatic cancer
Authors: Zayou Fouzia , Chheda Chintan , Lim Adrian , Elmadbouh Omer H. , Pandol Stephen J. , Edderkaoui Mouad 
Published: July 2021

Abstract
Background: Resistance of pancreatic ductal adenocarcinoma (PDAC) to current treatment regimens contributes to the dismal prognosis for patients diagnosed with the disease. Accumulated evidence indicates that metabolic alterations may play a role in chemo-resistance. In this project, we investigated the role of pyruvate dehydrogenase Alpha1 (PDHA1) in chemo-resistance.
Methods: Wild type and Gemcitabine-resistant pancreatic cancer cell lines MIA PaCa-2, HPAF-II, and UN-KPC-961 were used. Mitochondrial respiration, ATP production and glycolytic activities were measured by seahorse. PDHA1 was overexpressed or its activity inhibited by over-expressing PDHA1 kinase in these cells and cancer cell survival was measured by MTT and cancer stemness measured by Western and RT-PCR. PDHA1 level was measured in human and mouse PDAC tissues.
Results: Seahorse analysis showed a significantly lower mitochondrial activity, ATP production, and increased glycolytic activity and lactate production in gemcitabine-resistant compared to non- resistant pancreatic cancer cells. PDHA1 mRNA and protein levels were less in gemcitabine-resistant cancer cells compared to non-resistant cells. PDHA1 levels were less in human PDAC tissues from patients and mice who developed resistance to chemotherapy. PDHA1 over-expression in gemcitabine-resistant cancer cells reversed resistance to chemotherapy, decreased cancer cell survival and decreased expression of cancer stemness markers. Whereas, PDHA1 inhibition by over-expressing PDHA1 kinase, in non-resistant cancer cells, induced resistance to chemotherapy, increased cancer cell survival and increased expression of cancer stemness markers. We found that inhibition of histone deacetylase (HDAC) (class 1 and 2) increased transcription level of PDHA1 and reversed chemo-resistance.
Conclusion: We show that PDHA1 is a regulator of chemo-resistance in pancreatic cancer cells. PDHA1is a novel target for treating chemo-resistant PDAC.
Citation Format: Fouzia Zayou, Chintan Chheda, Adrian Lim, Omer H. Elmadbouh, Stephen J. Pandol, Mouad Edderkaoui. Pyruvate dehydrogenase mediates chemo-resistance in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2403.
Abstract 2406: The essential role of ATP binding to the mitochondrial protein ATAD3A in driving oncogenesis of head and neck squamous cell carcinoma
Authors: Lang Liwei , Lam Tiffany , Chen Alex , Shay Chole , Teng Yong 
Published: July 2021

Abstract
Head and neck squamous cell carcinoma (HNSCC) represents only 4% of all cancers in the US, but the adverse impact of this disease on health quality is dramatic. There has been little improvement in HNSCC treatment outcomes in decades, and a better understanding of the molecular biology of HNSCC is urgently needed to facilitate the design of anti-HNSCC therapies. The mitochondrial ATPase family AAA-domain containing protein 3A (ATAD3A) has been demonstrated as an oncogene in breast and lung cancer. However, nothing has been reported regarding its role in HNSCC. We report here that loss of ATAD3A expression inhibits HNSCC cell growth as evidenced by reduced cell proliferation and decreased the ability of colony formation and anchorage-independent growth in soft agar, whereas gain of ATAD3A expression counteracts the observed effects. Overexpression of a Walker A dead mutant of ATAD3A (ATAD3AK358) leads to a suppression in HNSCC cell growth and lipids synthesis, suggesting a potent dominant-negative effect of defective ATP-binding of ATAD3A. In line with the in vitro data, overexpression of ATAD3A facilities tumor growth in an orthotopic mouse model of HNSCC. In contrast, inhibition of ATAD3A function by knockout of ATAD3A or expression of ATAD3AK358 induces significant repression of tumor growth. These findings indicate that the mitochondrial protein ATAD3A plays an oncogenic role in HNSCC, and abrogating its ATP-binding ability may represent a promising regimen for better treatment of patients with HNSCC.
Citation Format: Liwei Lang, Tiffany Lam, Alex Chen, Chole Shay, Yong Teng. The essential role of ATP binding to the mitochondrial protein ATAD3A in driving oncogenesis of head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2406.
Abstract 2426: Effects of MEN2 mutations on RET receptor localization and function
Authors: Reyes-Alvarez Eduardo , Hyndman Brandy D. , Mulligan Lois M. 
Published: July 2021

Abstract
Multiple Endocrine Neoplasia type 2 (MEN2) is a cancer syndrome characterized by medullary thyroid carcinoma (MTC) and adrenal tumors. MEN2 is caused by activating point mutations of the REarranged during Transfection (RET) receptor tyrosine kinase, a protein essential for normal cell proliferation, migration, and differentiation in multiple tissues. MEN2 RET mutations can result in constitutive receptor dimerization (MEN2A) or in loss of receptor autoinhibition (MEN2B), which are associated with distinct disease courses and oncogenic potential. However, the specific cellular mechanisms contributing to these differences have not been well characterized. We have previously shown that RET maturation, cell surface localization and trafficking through the endolysosomal system modulate RET signaling and contribute to regulation of normal RET functions. Here, we have explored the contributions of these processes to MEN2A and MEN2B RET mutant activity. In preliminary studies using immunofluorescence (IF) microscopy and MTC cell lines endogenously expressing MEN2A (2ARET) or MEN2B (2BRET) RET mutant forms, we showed that RET mutants do not accumulate in pre-membrane compartments (ER, Golgi) at significant levels. Both 2ARET and 2BRET mutant receptors matured and reached the cell membrane efficiently. Using IF and cell surface protein labeling methods, we demonstrated that wildtype RET, 2ARET and 2BRET forms had differential patterns of plasma membrane distribution in the absence of ligand stimulation. Further, constitutive stimulation of wildtype RET receptors could not recapitulate the pattern observed for MEN2 RET mutants. We showed that, in the absence of ligand, 2ARET and 2BRET, but not wildtype RET, were constitutively phosphorylated, activated downstream signaling pathways and could localize to multiple endosomal compartments. We also showed different extents of protein turnover in 2ARET and 2BRET, which is important for sustained signals and suggests distinct endosomal sorting mechanisms for these receptors. Together, our data indicate that constitutive activation of MEN2 RET mutant receptors is not the only mechanism contributing to aberrant RET function in MEN2. Our results suggest that receptor localization at the membrane and trafficking through endosomal compartments is mutation-specific and may modulate RET signals that contribute to its roles in MEN2 oncogenicity.
Citation Format: Eduardo Reyes-Alvarez, Brandy D. Hyndman, Lois M. Mulligan. Effects of MEN2 mutations on RET receptor localization and function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2426.
Abstract 2446: IL4 receptor-induced proliferation is mediated via Glut1 activity in metastatic breast cancer
Authors: Hargrove-Wiley Ebony , Valent Daniel , Williams Demond , Bindeman Wendy , Fingleton Barbara 
Published: July 2021

Abstract
Breast cancer is the leading cause of cancer mortality in women. The breast cancer microenvironment supplies immune signals that influence tumor growth and metastatic behavior. The cytokine, Interleukin-4 (IL4), promotes increased survival, proliferation and invasion upon stimulation of the type II IL4 receptor alpha (IL4Rα) which is aberrantly expressed on epithelial cancer cells. Previously, we have shown that metastatic mouse mammary cancer cells have a strong dependence on IL4 signaling for colonization of metastatic sites in the lung and liver. Additionally, these cells uptake more glucose when treated with IL4 in vitro. Here, we assessed the importance of glucose consumption on pro-tumorigenic phenotypes induced by IL4/IL4Rα. In 4T1 cells, IL4/IL4Rα signaling increased protein expression of the glucose transporter, Glut1. IL4/IL4Rα activation also increased global glycosylation of Glut1. In human metastatic breast cancer cells (MDA-MB-231 and BT549), Crispr-mediated knockout (KO) of Glut1 significantly reduced glucose consumption when assayed by 2-NBDG uptake, a fluorescently labelled glucose analog. Additionally, Glut1 KO reversed the proliferative effects of IL4/IL4Rα stimulation on human cancer cells in vitro. Our data suggest that IL4-induced Glut1 expression supports the increased metabolic activity necessary for cancer cell proliferation. Targeting the IL4/IL4Rα signaling axis could potentially be a therapeutic strategy to impede tumor-associated metabolism and reduce tumor burden at primary and metastatic sites.
Citation Format: Ebony Hargrove-Wiley, Daniel Valent, Demond Williams, Wendy Bindeman, Barbara Fingleton. IL4 receptor-induced proliferation is mediated via Glut1 activity in metastatic breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2446.
Abstract 2465: The opposing regulation of ALDOA and FBP1 in Glucose metabolism contribute to cancer progression
Authors: Li Chien Hsiu , Chang Yu-Chan , Hsiao Michael 
Published: July 2021

Abstract
Metabolism reprogramming and increased glycolysis of cancer are associated with rapid cell growth, motility, and resistance to drug treatment. Fructose-1, 6-bisphosphate (F-1,6-BP), an important product involvement in glucose metabolism, especially in cancer development. It is known that the essential enzymes of gluconeogenesis and glycolysis, fructose-1,6-bisphosphonates 1 (FBP1) and glycolytic enzyme aldolase A (ALDOA) expression are involved in the F-1,6-BP conversion process. Especially, increased expression of ALDOA has been identified to contribute to multiple human cancer development. However, the underlying molecular mechanism involvement of ALDOA and FBP1 on the switching of F-1,6-BP is still being uncovered. This study shows that the expression levels of ALDOA and FBP1 with an inversed correlation during the cancer progression, especially in lung adenocarcinoma and hepatocellular carcinoma. Immunoprecipitation and proteomics analyses revealed the candidates, including the anterior gradient 2 (AGR2), ubiquitin ligase gene cullin 4B (CUL4B), and telomeric repeat binding factor 1 (TERF1) are significantly correlated with ALDOA and FBP1 expression. We designed a specific peptide to interfere the interaction of candidates on both ALDOA and FBP1. Moreover, we evaluate the relative glucose metabolism events. Further, we raised the hypothesis that these candidates may serve as a modulator to regulate the conversion of F-1,6-BP and contribute to cancer progression, which can be used as a therapeutic target for further research.
Citation Format: Chien Hsiu Li, Yu-Chan Chang, Michael Hsiao. The opposing regulation of ALDOA and FBP1 in Glucose metabolism contribute to cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2465.
Abstract 2480: RE1-silencing transcription factor (REST) controls neuroendocrine gene programs in pancreatic ductal adenocarcinoma
Authors: MacPherson Kevin Alexander , Joly Meghan M. , Allen-Petersen Brittany , Pelz Carl , Thoma Mary C. , Torkenczy Kristof , Adey Andrew , Liefwalker Daniel , Worth Patrick J. , Sears Rosalie C. 
Published: July 2021

Abstract
Neuroendocrine (NE) differentiation features contribute to intratumoral heterogeneity and aggressive biology in a subset of pancreatic ductal adenocarcinoma (PDAC) tumors associated with poor disease outcome. We recently showed that treating pancreatic cancer cells with gemcitabine, a standard-of-care chemotherapy for PDAC, increases expression of NE markers, suggesting that ductal to neuroendocrine lineage plasticity could play a role in drug resistance. NE features in prostate cancer have been previously associated with loss of the neuronal gene repressor RE1-Silencing Transcription Factor (REST); in the present study, we explore a potential role of REST in regulating NE differentiation in PDAC. Our experiments show that loss of REST in PDAC cells increases NE gene expression, gemcitabine resistance, and colony formation. RNA sequencing data from gemcitabine-treated PDAC cells were enriched for REST target genes, suggesting gemcitabine relieves REST-mediated repression. Chromatin immunoprecipitation experiments corroborated this by demonstrating that gemcitabine reduces REST binding to the NE genes SYP and SNAP25. In addition, single cell ATAC sequencing also uncovered a heterogeneous response to gemcitabine treatment, revealing two gemcitabine-driven cell states with differing REST motif accessibility. Our study indicates that REST controls NE gene programs in PDAC and that loss of REST promotes gemcitabine resistance and oncogenic growth. Mirroring the heterogeneity of PDAC tumors, a subset of PDAC cells treated with gemcitabine have reduced REST motif accessibility, which may reflect a therapy resistant NE-like subpopulation.
Citation Format: Kevin Alexander MacPherson, Meghan M. Joly, Brittany Allen-Petersen, Carl Pelz, Mary C. Thoma, Kristof Torkenczy, Andrew Adey, Daniel Liefwalker, Patrick J. Worth, Rosalie C. Sears. RE1-silencing transcription factor (REST) controls neuroendocrine gene programs in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2480.
Abstract 2485: Metabolic implications of TIGAR in glioblastoma multiforme
Authors: Sahagun Joseph 
Published: July 2021

Abstract
The incidence of glioblastoma multiforme (GBM) has been rising throughout the last decade, yet interventional medical advances have not been able to keep up. With current literature focusing on hypoxia-inducible factor 1 and angiogenic properties of GBM, our study focuses on Tp53 glycolysis and apoptosis regulator (TIGAR) enzyme in order to supplement the limited amount of published literature. Recent literature implicates Tp53 glycolysis and apoptosis regulator (TIGAR) in tumor survival and proliferation by shunting glycolytic intermediates to generate NADPH and activation of AKT, respectively. In this study, we aimed at establishing TIGAR's dependence on p53 and whether pifithrin-α blocks transcription of TIGAR within the proneuronal subtype of glioblastoma. This cell line is of interest due to its frequent mutations and loss of heterogeneity within p53 and association with chemotherapy resistance in GBM. In this cell line, both p53 and TIGAR protein expression were confirmed using western blot. An MTT assay determined the minimal concentration of pifithrin-α required to inhibit p53 expression in the proneuronal cell line. A known p53 null line, SAOS-2, was used to monitor TIGAR expression using real-time PCR to determine the dependence of p53 expression. Through this study, we determined that TIGAR behaves independently of p53 expression, and a knockdown of p53 with pifithrin-α has no influence on the transcription of TIGAR. We hypothesize that p53 is required to act as a barrier against TIGAR overexpression in GBM.
Citation Format: Joseph Sahagun. Metabolic implications of TIGAR in glioblastoma multiforme [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2485.
Abstract 2503: Crispr/cas-9-mediated genome editing reveals that RBPMS acts as a tumor suppressor in ovarian cancer
Authors: Sharma Rohit K. , Santiago-Sánchez Ginette S. , Rabelo-Fernández Robert J. , Quiñones-Díaz Blanca I. , Valiyeva Fatima , Vivas-Mejia Pablo E. 
Published: July 2021

Abstract
RNA-Binding Protein with Multiple Splicing (RBPMS) is a member of a family of proteins that bind to the nascent RNA transcripts and regulate their processing, which includes pre-mRNA splicing and transport/localization/stability of the RNA molecule. Evidence indicates that RBPMS also binds to members of the AP-1 (c-Jun and c-Fos) transcription factor repressing his activity. Until now, little is known about the biological function of RBPMS in ovarian cancer. To understand the role of RBPMS in ovarian cancer we generated CRISPR (clustered regularly interspaced short palindromic repeats)-mediated RBPMS knock-out vectors that were stably transfected in the ovarian cancer cells OVCAR3. The Guide-it Genotype confirmation Kit was used to determine the type of mutations (monoallelic, biallelic, or unchanged) present in the developed clones. Additionally, resulting CRISPR-cleavage products were analyzed to establish the cleavage efficiency of the Cas9/sgRNA complex by densitometry analysis. We found that CRISPR clone cells grow faster and increase their invasiveness ability compared with control CRISPR cells. Furthermore, immunohistochemical (IHC) analysis in a tissue array showed that RBPMS staining was significantly lower in high-grade serous ovarian cancer (HGSOC) tissues as compared to normal ovarian tissues. RBPMS was also decreased in platinum-resistant ovarian cancer cells as compared to platinum-sensitive cancer cells. Senescence-associated β-galactosidase (β-Gal) levels were higher in CRISPR-clones as compared with empty vector and ovarian cancer cells, which suggest RBPMS knockdown induces senescence. These studies along with the data of proteomics and RNAseq suggest that RBPMS acts as a tumor suppressor gene and lower levels of RBPMS are associated with the cisplatin resistance of ovarian cancer cells.
Citation Format: Rohit K. Sharma, Ginette S. Santiago-Sánchez, Robert J. Rabelo-Fernández, Blanca I. Quiñones-Díaz, Fatima Valiyeva, Pablo E. Vivas-Mejia. Crispr/cas-9-mediated genome editing reveals that RBPMS acts as a tumor suppressor in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2503.
Abstract 2506: Smarca4 inactivation promotes lineage-specific transformation and early metastatic features in the lung
Authors: Concepcion Carla P. , Ma Sai , LaFave Lindsay M. , Bhutkar Arjun , Liu Manyuan , DeAngelo Lydia P. , Kim Jonathan Y. , Priore Isabella Del , Schoenfeld Adam J. , Kartha Vinay K. , Westcott Peter M. , Sánchez-Rivera Francisco J. , Meli Kevin , Gupta Manav , Riely Gregory J. , Rekhtman Natasha , Rudin Charles M. , Kim Carla F. , Regev Aviv , Buenrostro Jason D. , Jacks Tyler 
Published: July 2021

Abstract
SMARCA4 (BRG1) encodes for one of two mutually-exclusive ATPases present in SWI/SNF chromatin remodeling complexes, and is among the most frequently mutated genes in human lung adenocarcinoma. Despite its prevalence, the functional consequences of SMARCA4 alterations on lung cancer initiation and progression remain poorly understood. Using genetically engineered mouse models, patient-derived xenografts, and single-cell epigenomic profiling, we demonstrate that loss of Smarca4 sensitizes CCSP+ cells within the lung to malignant transformation and tumor progression, resulting in highly advanced dedifferentiated tumors and increased metastatic incidence. Consistent with these phenotypes, Smarca4-deficient tumors lack lung lineage transcription factor activities and instead show activation of embryonic stem cell-like programs, resembling a metastatic cell state. Thus, the SWI/SNF complex - via Smarca4 - acts as a gatekeeper for lineage-specific cellular transformation and metastasis during lung cancer evolution.
Citation Format: Carla P. Concepcion, Sai Ma, Lindsay M. LaFave, Arjun Bhutkar, Manyuan Liu, Lydia P. DeAngelo, Jonathan Y. Kim, Isabella Del Priore, Adam J. Schoenfeld, Vinay K. Kartha, Peter M. Westcott, Francisco J. Sánchez-Rivera, Kevin Meli, Manav Gupta, Gregory J. Riely, Natasha Rekhtman, Charles M. Rudin, Carla F. Kim, Aviv Regev, Jason D. Buenrostro, Tyler Jacks. Smarca4 inactivation promotes lineage-specific transformation and early metastatic features in the lung [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2506.
Abstract 2520: Detection of transcriptional active HPV 16/18 in patients with oropharyngeal squamous cell carcinoma by dual immunohistochemistry p16INK4 and in situ hybridization E6/E7 mRNA in archival material older than 25 years
Authors: Tornaas Stian , Fromreid Siren , Aarstad Hans Jørgen , Vintermyr Olav Karsten , Costea Daniela Elena , Dongre Harsh Nitin 
Published: July 2021

Abstract
Introduction: Determination of Human Papillomavirus (HPV) status in oropharyngeal squamous cell carcinomas (OPSCC) is important because it influences the therapeutic decision. A dual protocol combining immunohistochemistry (IHC) for detection of p16INK4 overexpression with in situ hybridization (ISH) for mRNA E6/E7 detection may improve the accuracy of determining the HPV status in OPSCC patients. The aim of this study was to optimize a multiplex method for simultaneous detection of p16 and mRNA E6/E7 on the same formalin-fixed paraffin-embedded (FFPE) tissue samples.
Methods: IHC for the detection of p16INK4 and chromogenic ISH for mRNA E6/E7 were combined in different sequences and with different intermediate steps for fixation on OPSCC tissue samples from primary tumors and lymph node metastases. Archival tissue samples stored at Department of Pathology at Haukeland University Hospital since 1990 has been used for tests.
Results: A combined method for simultaneous detection of p16INK4 and mRNA E6/E7 transcripts on the same tissue slides were successfully developed. Active HPV status was detected in OPSCC tissue samples from both primary and metastatic lymph nodes for all cases tested, including tissue samples stored for 30 years. The result was correlated to DNA HPV status.
Conclusion: This study confirms that a more precise detection of active HPV infection is possible on FFPE tissue slides. This method could be easily implemented in clinical settings for more specific stratification of OPSCC patients. At the same time, the method is also robust and sensitive on retrospective archival material, and this could be used for answering important research questions on HPV-related OPSCC.
Citation Format: Stian Tornaas, Siren Fromreid, Hans Jørgen Aarstad, Olav Karsten Vintermyr, Daniela Elena Costea, Harsh Nitin Dongre. Detection of transcriptional active HPV 16/18 in patients with oropharyngeal squamous cell carcinoma by dual immunohistochemistry p16INK4 and in situ hybridization E6/E7 mRNA in archival material older than 25 years [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2520.