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Molecular Cancer Research: MCR

Priya S Dalvi, Iris F Macheleidt, So-Young Lim, Sonja Meemboor, Marion Muller, Hannah Eischeid-Scholz, Stephan C Schaefer, Reinhard Buettner, Sebastian Klein, Margarete Odenthal
Lysine-specific demethylase 1 (LSD1) is a histone modifier that is highly overexpressed in lung adenocarcinoma (LUAD), which results in aggressive tumor biology. Tumor cell proliferation and migration analysis after LSD1 inhibition in the LUAD cell line, PC9 using the LSD1 inhibitor HCI-2509 and siRNA, demonstrated that LSD1 activity was essential for proliferation and migration capacities of tumor cells. Moreover, reduced proliferation rates after LSD1 inhibition were shown to be associated with a cell cycle arrest of the tumor cells in the G2/M phase...
February 13, 2019: Molecular Cancer Research: MCR
Elizabeth C Randall, Giorgia Zadra, Paolo Chetta, Begona G C Lopez, Sudeepa Syamala, Sankha S Basu, Jeffrey N Agar, Massimo Loda, Clare M Tempany, Fiona M Fennessy, Nathalie Y R Agar
Diagnosis of prostate cancer is based on histological evaluation of tumor architecture using a system known as the 'Gleason score'. This diagnostic paradigm, while the standard of care, is time-consuming, shows intra-observer variability and provides no information about the altered metabolic pathways, which result in altered tissue architecture. Characterization of the molecular composition of prostate cancer and how it changes with respect to the Gleason score (GS) could enable a more objective and faster diagnosis...
February 11, 2019: Molecular Cancer Research: MCR
Eugenio Zoni, Letizia Astrologo, Charlotte K Y Ng, Salvatore Piscuoglio, Janine Melsen, Joel Grosjean, Irena Klima, Lanpeng Chen, Ewa B Snaar-Jagalska, Kenneth Flanagan, Gabri van der Pluijm, Peter Kloen, Marco G Cecchini, Marianna Kruithof-de-Julio, George N Thalmann
Prostate Cancer (PCa) is the most common cancer and the second leading cause of cancer-related death in males. When PCa acquires castration resistance, incurable metastases, primarily in the bone, occur. The aim of this study is to test the applicability of targeting MCAM (CD146) with a monoclonal antibody for the treatment of lytic PCa bone metastasis. We evaluated the effect of targeting MCAM using in vivo preclinical bone metastasis models and an in vitro bone niche co-culture system. We utilized FACS, cell proliferation assays, and gene expression profiling to study the phenotype and function of MCAM knockdown in vitro and in vivo...
February 11, 2019: Molecular Cancer Research: MCR
Rebecca E Schweppe, Nikita Pozdeyev, Laura A Pike, Christopher Korch, Qiong Zhou, Sharon B Sams, Vibha Sharma, Umarani Pugazhenthi, Christopher Raeburn, Maria B Albuja-Cruz, Philip Reigan, Daniel LaBarbera, Inigo Landa-Lopez, Jeffrey A Knauf, James A Fagin, Bryan R Haugen
Cancer cell lines are critical models to study tumor progression and response to therapy. In 2008, we showed that ~50% of thyroid cancer cell lines were redundant or not of thyroid cancer origin. We therefore generated new authenticated thyroid cancer cell lines and patient derived xenograft (PDX) models using in vitro and feeder cell approaches, and characterized these models in vitro and in vivo. We developed four thyroid cancer cell lines, two derived from two different patients with papillary thyroid cancer (PTC) pleural effusions, CUTC5 and CUTC48; one derived from a patient with anaplastic thyroid cancer (ATC), CUTC60; and one derived from a follicular thyroid cancer patient (FTC), CUTC61...
February 7, 2019: Molecular Cancer Research: MCR
Brock A Humphries, Johanna M Buschhaus, Yu-Chih Chen, Henry R Haley, Tonela Qyli, Benjamin Chiang, Nathan Shen, Shrila Rajendran, Alyssa Cutter, Yu-Heng Cheng, Yu-Ting Chen, Jason Cong, Phillip C Spinosa, Euisik Yoon, Kathryn E Luker, Gary D Luker
Migration and invasion of cancer cells constitute fundamental processes in tumor progression and metastasis. Migratory cancer cells commonly upregulate expression of plasminogen activator inhibitor 1 (PAI1), and PAI1 correlates with poor prognosis in breast cancer. However, mechanisms by which PAI1 promotes migration of cancer cells remain incompletely defined. Here we show that increased PAI1 drives rearrangement of the actin cytoskeleton, mitochondrial fragmentation, and glycolytic metabolism in triple negative breast cancer (TNBC) cells...
February 4, 2019: Molecular Cancer Research: MCR
Yangsook Song Green, Timothy Sargis, Ethan Conrad Reichert, Eleanor Rudasi, Daniel Fuja, Eric Jonasch, Mei Yee Koh
Low oxygen or hypoxia is a feature of all solid tumors, and has been associated with aggressive disease. Here, we describe a novel mechanism for the hypoxia-dependent degradation of the Ras-GTPase activating protein neurofibromin, by hypoxia-associated factor (HAF). We have previously characterized HAF as an oxygen-independent ubiquitin ligase for HIF-1α. Here, we show that HAF promotes neurofibromin ubiquitination and degradation independently of oxygen and pVHL, resulting in Ras-ERK pathway activation. Hypoxia enhanced HAF:neurofibromin binding independently of HAF-SUMOylation, whereas HAF knockdown increased neurofibromin levels primarily in hypoxia, supporting the role of HAF as a hypoxia-specific neurofibromin regulator...
January 31, 2019: Molecular Cancer Research: MCR
Jonathan T Fleming, Emily Brignola, Lei Chen, Yan Guo, Shilin Zhao, Quan Wang, Bingshan Li, Hernan Correa, Alexandre N Ermilov, Andrzej A Dlugosz, Chin Chiang
Aberrant activation of the Hedgehog (Hh) signaling pathway has been linked to the formation of numerous cancer types, including the myogenic soft tissue sarcoma, embryonal rhabdomyosarcoma (eRMS). Here, we report PCG2, a novel mouse model in which human GLI2A, a constitutive activator of Hh signaling, induced undifferentiated sarcomas that were phenotypically divergent from eRMS. Rather, sarcomas arising in PCG2 mice featured some characteristics that were reminiscent of Ewing sarcoma (ES). Even though it is widely understood that ES formation is driven by EWS-ETS gene fusions, a genetically-defined mouse model is not well-established...
January 25, 2019: Molecular Cancer Research: MCR
Ahmed Diab, Micheal Kao, Keffy Kehrli, Hee Yeon Kim, Julia Sidorova, Eduardo Méndez
The p53 gene is the most commonly mutated gene in solid tumors but leveraging p53 status in therapy remains a challenge. Previously, we determined that p53 deficiency sensitizes head and neck cancer cells to AZD1775, a WEE1 kinase inhibitor, and translated our findings into a Phase I clinical trial. Here we investigate how p53 affects cellular responses to AZD1775 at the molecular level. We found that p53 modulates both replication stress and mitotic deregulation triggered by WEE1 inhibition. Without p53, slowing of replication forks due to replication stress is exacerbated...
January 24, 2019: Molecular Cancer Research: MCR
Vesselin R Penchev, Yu-Tai Chang, Asma Begum, Theodore Ewachiw, Christian Gocke, Joey Li, Ross H McMillan, Qiuju Wang, Robert Anders, Luigi Marchionni, Anirban Maitra, Aykut Uren, Zeshaan Rasheed, William Matsui
Self-renewal maintains the long-term clonogenic growth that is required for cancer relapse and progression, but the cellular processes regulating this property are not fully understood. In many diseases self-renewal is enhanced in cancer stem cells (CSCs), and in pancreatic ductal adenocarcinoma (PDAC) CSCs are characterized by the surface expression of CD44. In addition to cell adhesion, CD44 impacts cell shape and morphology by modulating the actin cytoskeleton via Ezrin, a member of the Ezrin/Radixin/Moesin (ERM) family of linker proteins...
January 17, 2019: Molecular Cancer Research: MCR
Henry J Pegg, Hannah Harrison, Connor Rogerson, Paul Shore
CBFβ, the essential co-regulator of RUNX transcription factors, is one of the most frequently mutated genes in ER positive (ER+) breast cancer. Many of these mutations are nonsense mutations and are predicted to result in loss of function, suggesting a tumour suppressor role for CBFβ. However, the impact of missense mutations and the loss of CBFβ in ER+ breast cancer cells has not been determined. Here we demonstrate that missense mutations in CBFβ accumulate near the Runt domain binding region. These mutations inhibit the ability of CBFβ to form CBFβ-Runx-DNA complexes...
January 17, 2019: Molecular Cancer Research: MCR
Taylor E Escher, Asona J Lui, Eric S Geanes, Katherine R Walter, Ossama Tawfik, Christy R Hagan, Joan Lewis-Wambi
The human oncoprotein, mucin 1 (MUC1), drives tumorigenesis in breast carcinomas by promoting epithelial-mesenchymal transition (EMT), epigenetic reprogramming, and evasion of immune response. MUC1 interacts with STAT1, through JAK/STAT signaling, and stimulates transcription of interferon-stimulated genes, specifically interferon-induced transmembrane protein 1 (IFITM1). Our lab has previously shown that IFITM1 overexpression in aromatase inhibitor (AI)-resistant breast cancer cells promotes aggressiveness...
January 17, 2019: Molecular Cancer Research: MCR
Surojeet Sengupta, Catherine M Sevigny, Poulomi Bhattacharya, V Craig Jordan, Robert Clarke
Approximately thirty percent of aromatase-inhibitor resistant, estrogen receptor positive breast cancer patients benefit from treatment with estrogen. This enigmatic estrogen action is not well understood and how it occurs remains elusive. Studies indicate that the unfolded protein response and apoptosis pathways play important roles in mediating estrogen-triggered apoptosis. Using MCF7:5C cells, which mimic aromatase inhibitor resistance, and are hypersensitive to estrogen as evident by induction of apoptosis, we define increased global protein translational load as the trigger for estrogen-induced apoptosis...
January 17, 2019: Molecular Cancer Research: MCR
Peter C Hart, Tatsuyuki Chiyoda, Xiaojing Liu, Melanie Weigert, Marion Curtis, Chun-Yi Chiang, Rachel Loth, Ricardo Lastra, Stephanie M McGregor, Jason W Locasale, Ernst Lengyel, Iris L Romero
The role of phospholipid signaling in ovarian cancer (OvCa) is poorly understood. Sphingosine-1-phosphate (S1P) is a bioactive metabolite of sphingosine that has been associated with tumor progression through enhanced cell proliferation and motility. Similarly, sphingosine kinases (SPHK), which catalyze the formation of S1P and thus regulate the sphingolipid rheostat, have been reported to promote tumor growth in a variety of cancers. The findings reported here show that exogenous S1P or overexpression of SPHK1 increased proliferation, migration, invasion and stem-like phenotypes in OvCa cell lines...
January 17, 2019: Molecular Cancer Research: MCR
Alejandra Valenzuela-Iglesias, Hope E Burks, Christopher Rashad Arnette, Amulya Yalamanchili, Oxana Nekrasova, Lisa M Godsel, Kathleen J Green
Loss of the desmosomal cell-cell adhesion molecule, Desmoglein 1 (Dsg1), has been reported as an indicator of poor prognosis in head and neck squamous cell carcinomas (HNSCC) overexpressing Epidermal Growth Factor Receptor (EGFR). It has been well established that EGFR signaling promotes the formation of invadopodia, actin-based protrusions formed by cancer cells to facilitate invasion and metastasis, by activating pathways leading to actin polymerization and ultimately matrix degradation. We previously showed that Dsg1 downregulates EGFR/Erk signaling by interacting with the ErbB2 binding protein Erbin (ErbB2 Interacting Protein) to promote keratinocyte differentiation...
January 17, 2019: Molecular Cancer Research: MCR
Sarah P Short, Joshua J Thompson, Anthony J Bilotta, Xi Chen, Frank L Revetta, M Kay Washington, Christopher S Williams
Serine Threonine Kinase 17A (STK17A) is a ubiquitously expressed kinase originally identified as a regulator of apoptosis; however, whether it functionally contributes to colorectal cancer (CRC) has not been established. Here, we have analyzed STK17A in CRC and demonstrate decreased expression of STK17A in primary tumors which is further reduced in metastatic lesions, indicating a potential role in regulating the metastatic cascade. Interestingly, changes in STK17A expression did not modify proliferation, apoptosis, or sensitivity of CRC cell lines to treatment with the chemotherapeutic 5-fluorouracil...
January 17, 2019: Molecular Cancer Research: MCR
Joan Repullés, Teresa Anglada, David Soler, Juan Carlos Ramírez, Anna Genescà, Mariona Terradas
Radiation is used in multiple procedures as a therapeutic and diagnostic tool. However, ionising radiation can induce mutations in the DNA of irradiated cells, which can promote tumorigenesis. As malignant transformation is a process that takes many years, there are intermediate stages of cells that have initiated the process but have not yet evolved into cancer. The study here aimed to investigate the effect of ionising radiation on normal and partially-transformed human mammary epithelial cells. Breast Primary Epithelial Cells were derived from normal breast tissue from two different donors and modified by transduction with the SV40 small and Large T antigen and hTERT genes to obtain partially-transformed cells and also with HRAS to completely and experimentally transform them...
January 16, 2019: Molecular Cancer Research: MCR
Julie E McGrath, Louis Panzica, Ryan Ransom, Henry G Withers, Irwin H Gelman
Cancer tumor cell dormancy is a significant clinical problem in breast cancer (BrCa). We used a 3D in vitro model of the endosteal bone niche (EN), consisting of endothelial, bone marrow stromal cells and fetal osteoblasts in a 3D collagen matrix (GELFOAMTM), to identify genes required for dormancy. Human triple-negative MDA-MB-231 BrCa cells, but not the bone-tropic metastatic variant, BoM1833, established dormancy in 3D-EN cultures in a p38-MAPK-dependent manner, whereas both cell types proliferated on 2D plastic or in 3D collagen alone...
January 16, 2019: Molecular Cancer Research: MCR
Ajay Chatrath, Manjari Kiran, Pankaj Kumar, Aakrosh Ratan, Anindya Dutta
Lower grade gliomas are invasive brain tumors that are difficult to completely resect neurosurgically. They often recur following resection and progress, resulting in death. Although previous studies have shown that specific germline variants increase the risk of tumor formation, no previous study has screened many germline variants to identify variants predictive of survival in glioma patients. In this study, we present an approach to identify the small fraction of prognostic germline variants from the pool of over four million variants that we variant called in The Cancer Genome Atlas whole exome sequencing and RNA sequencing datasets...
January 16, 2019: Molecular Cancer Research: MCR
Samuel W Brady, Xiaotu Ma, Armita Bahrami, Gryte Satas, Gang Wu, Scott Newman, Michael Rusch, Daniel K Putnam, Heather L Mulder, Donald Yergeau, Michael N Edmonson, John Easton, Ludmil B Alexandrov, Xiang Chen, Elaine R Mardis, Richard K Wilson, James R Downing, Alberto S Pappo, Benjamin J Raphael, Michael A Dyer, Jinghui Zhang
To investigate the genomic evolution of metastatic pediatric osteosarcoma, we performed whole-genome and targeted deep sequencing on 14 osteosarcoma metastases and two primary tumors from four patients (2-8 samples per patient). All four patients harbored ancestral (truncal) somatic variants resulting in TP53 inactivation and cell cycle aberrations, followed by divergence into relapse-specific lineages exhibiting a cisplatin-induced mutation signature. In three of the four patients, the cisplatin signature accounted for >40% of mutations detected in the metastatic samples...
January 16, 2019: Molecular Cancer Research: MCR
Timothy F Day, Bhaskar V S Kallakury, Jeffrey S Ross, Olga Voronel, Shantashri Vaidya, Christine Sheehan, Usha N Kasid
Aberrant regulation of EGFR is common in non-small cell lung carcinomas (NSCLC), and tumor resistance to targeted therapies has been attributed to emergence of other co-occurring oncogenic events, parallel bypass receptor tyrosine kinase pathways including IGF1R, and TNF-α-driven adaptive response via NF--κB. TNFAIP8, TNF-α-inducible protein 8, is an NF-αB-activated pro-survival and oncogenic molecule. TNFAIP8 expression protects NF-κB null cells from TNF-α-induced cell death by inhibiting caspase-8 activity...
January 15, 2019: Molecular Cancer Research: MCR
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