journal

Cancer Research

journal
https://read.qxmd.com/read/32651261/nitrogen-trapping-as-a-therapeutic-strategy-in-tumors-with-mitochondrial-dysfunction
#1
Hanumantha Rao Madala, Iiro Taneli Helenius, Wen Zhou, Evanna Mills, Yiyun Zhang, Yan Liu, Ana M Metelo, Michelle L Kelley, Surendra Punganuru, Kyung Bo Kim, Benjamin Olenchock, Eugene Rhee, Andrew M Intlekofer, Othon Lliopoulos, Edward Chouchani, Jing-Ruey Joanna Yeh
Under conditions of inherent or induced mitochondrial dysfunction, cancer cells manifest overlapping metabolic phenotypes, suggesting that they may be targeted via a common approach. Here we use multiple oxidative phosphorylation (OXPHOS)-competent and -incompetent cancer cell pairs to demonstrate that treatment with alpha-ketoglutarate (aKG) esters elicits rapid death of OXPHOS-deficient cancer cells by elevating intracellular aKG concentrations, thereby sequestering nitrogen from aspartate through glutamic-oxaloacetic transaminase 1 (GOT1)...
July 10, 2020: Cancer Research
https://read.qxmd.com/read/32651260/monocyte-derived-leukemia-associated-macrophages-facilitate-extramedullary-distribution-of-t-cell-acute-lymphoblastic-leukemia-cells
#2
Feifei Yang, Wenli Feng, Hao Wang, Lina Wang, Xiaoli Liu, Rong Wang, Chong Chen, Xiao Yang, Dongyue Zhang, Qian Ren, Guoguang Zheng
Macrophages play important roles in both physiological and pathological processes and arise from successive waves of embryonic and adult hematopoiesis. Monocyte-derived macrophages (MOMF) exert distinct functions under pathological conditions, and leukemia-associated macrophages (LAM) show considerable diversities in activation and functional phenotype. However, their origin and pathological roles have not been well elucidated. Here we used wild-type (WT) and CCR2-/- mice to study the pathological roles of monocyte-derived LAM in extramedullary tissues in models of Notch1-induced T-cell acute lymphoblastic leukemia (T-ALL)...
July 10, 2020: Cancer Research
https://read.qxmd.com/read/32651259/suppression-of-abce1-mediated-mrna-translation-limits-n-myc-driven-cancer-progression
#3
Jixuan Gao, MoonSun Jung, Chelsea Mayoh, Pooja Venkat, Katherine M Hannan, Jamie I Fletcher, Alvin Kamili, Andrew J Gifford, Eric P Kusnadi, Richard B Pearson, Ross D Hannan, Michelle Haber, Murray D Norris, Klaartje Somers, Michelle J Henderson
The ability of the N-MYC transcription factor to drive cancer progression is well-demonstrated in neuroblastoma, the most common extracranial pediatric solid tumor, where MYCN-amplification heralds a poor prognosis with only 11% of patients surviving past 5 years. However, decades of attempts of direct inhibition of N-MYC or its paralogues has led to the conclusion that this protein is 'undruggable'. Therefore, targeting pathways upregulated by N-MYC signaling presents an alternative therapeutic approach. Here we show that MYCN-amplified neuroblastomas are characterized by elevated rates of protein synthesis and that high expression of ABCE1, a translation factor directly upregulated by N-MYC, is itself a strong predictor of poor clinical outcome...
July 10, 2020: Cancer Research
https://read.qxmd.com/read/32651258/mathematical-modeling-provides-evidence-for-niche-competition-in-human-aml-and-serves-as-a-tool-to-improve-risk-stratification
#4
Thomas Stiehl, Wenwen Wang, Christoph Lutz, Anna Marciniak-Czochra
Acute myeloid leukemia (AML) is a stem cell-driven malignant disease. There is evidence that leukemic stem cells (LSC) interact with stem cell niches and outcompete hematopoietic stem cells (HSC). The impact of this interaction on the clinical course of the disease remains poorly understood. We developed and validated a mathematical model of stem cell competition in the human hematopoietic stem cell niche. Model simulations predicted how processes in the stem cell niche affect the speed of disease progression...
July 10, 2020: Cancer Research
https://read.qxmd.com/read/32651257/exploiting-the-microhomology-mediated-end-joining-pathway-in-cancer-therapy
#5
Jeffrey Patterson-Fortin, Alan D D'Andrea
Repair of DNA double strand breaks (DSB) is performed by two major pathways: homology-dependent repair and classical non-homologous end joining. Recent studies have identified a third pathway: microhomology-mediated end-joining (MMEJ). MMEJ has similarities to homology-dependent repair in that repair is initiated with end resection, leading to single-stranded 3' ends which require microhomology upstream and downstream of the DSB. Importantly, the MMEJ pathway is commonly upregulated in cancers, especially in homologous recombination-deficient cancers which display a distinctive mutational signature...
July 10, 2020: Cancer Research
https://read.qxmd.com/read/32651256/circadian-rhythm-is-disrupted-by-znf704-in-breast-carcinogenesis
#6
Chao Yang, Jiajing Wu, Xinhua Liu, Yue Wang, Beibei Liu, Xing Chen, Xiaodi Wu, Dong Yan, Lulu Han, Shumeng Liu, Lin Shan, Yongfeng Shang
Copy number gain in chromosome 8q21 is frequently detected in breast cancer, yet the oncogenic potential underlying this amplicon in breast carcinogenesis remains to be delineated. We report here that ZNF704, a gene mapped to 8q21, is recurrently amplified in various malignancies including breast cancer. ZNF704 acted as a transcriptional repressor and interacted with the transcriptional corepressor SIN3A complex. Genome-wide interrogation of transcriptional targets revealed that the ZNF704/SIN3A complex represses a panel of genes including PER2 that are critically involved in the function of circadian clock...
July 10, 2020: Cancer Research
https://read.qxmd.com/read/32651255/bromodomain-selective-bet-inhibitors-are-potent-antitumor-agents-against-myc-driven-pediatric-cancer
#7
P Jake Slavish, Liying Chi, Mi-Kyung Yun, Lyudmila Tsurkan, Nancy E Martinez, Barbara Jonchere, Sergio C Chai, Michele Connelly, M Brett Waddell, Sourav Das, Geoffrey Neale, Zhenmei Li, William R Shadrick, Rachelle R Olsen, Kevin W Freeman, Jonathan A Low, Jeanine E Price, Brandon M Young, Nagakumar Bharatham, Vincent A Boyd, Jun Yang, Richard E Lee, Marie Morfouace, Martine F Roussel, Taosheng Chen, Daniel Savic, R Kiplin Guy, Stephen W White, Anang A Shelat, Philip M Potter
Inhibition of members of the bromodomain and extra terminal (BET) family of proteins has proven a valid strategy for cancer chemotherapy. All BET identified to date contain two bromodomains (BD; BD1 and BD2) that are necessary for recognition of acetylated lysine residues in the N-terminal regions of histones. Chemical matter that targets BET (BETi) also interact via these domains. Molecular and cellular data indicate that BD1 and BD2 have different biological roles depending upon their cellular context, with BD2 particularly associated with cancer...
July 10, 2020: Cancer Research
https://read.qxmd.com/read/32646968/epigenetic-crispr-screens-identify-npm1-as-a-therapeutic-vulnerability-in-non-small-cell-lung-cancer
#8
Fei Li, Wai-Lung Ng, Troy A Luster, Hai Hu, Vladislav O Sviderskiy, Catríona M Dowling, Kate E R Hollinshead, Paula Zouitine, Hua Zhang, Qingyuan Huang, Michela Ranieri, Wei Wang, Zhaoyuan Fang, Ting Chen, Jiehui Deng, Kai Zhao, Hon-Cheong So, Alireza Khodadadi-Jamayran, Mousheng Xu, Angeliki Karatza, Val Pyon, Shuai Li, Yuanwang Pan, Kristen Labbe, Christina Almonte, John T Poirier, George Miller, Richard Possemato, Jun Qi, Kwok-Kin Wong
Despite advancements in treatment options, the overall cure and survival rates for non-small cell lung cancers (NSCLC) remain low. While small-molecule inhibitors of epigenetic regulators have recently emerged as promising cancer therapeutics, their application in patients with NSCLC is limited. To exploit epigenetic regulators as novel therapeutic targets in NSCLC, we performed pooled epigenome-wide CRISPR knockout screens in vitro and in vivo and identified the histone chaperone nucleophosmin 1 (NPM1) as a potential therapeutic target...
July 9, 2020: Cancer Research
https://read.qxmd.com/read/32646967/physical-activity-does-not-lower-the-risk-of-lung-cancer
#9
Sebastian-Edgar Baumeister, Michael F Leitzmann, Martin Bahls, Christa Meisinger, Christopher I Amos, Rayjean J Hung, International Lung Cancer Consortium, Lung Cancer Cohort Consortium, Alexander Teumer, Hansjörg Baurecht
Observational studies have suggested that physical activity might lower the risk of lung can-cer in former and current smokers but not in never smokers. Using genetic instruments for self-reported and accelerometer-measured physical activity traits implemented through two-sample Mendelian randomization (MR), we sought to strengthen the evidence for causality. We used 18 genome-wide significant (P < 5x10-8) single nucleotide polymorphisms (SNP) for self-reported moderate-to-vigorous physical activity and seven SNP for accelerometer-measured ('average acceleration') physical activity from up to 377,234 UK Biobank partici-pants and evaluated these in relation to risk using 29,266 lung cancer cases (including 11,273 adenocarcinomas, 7,426 squamous cell carcinoma and 2,664 small cell carcinoma cases) and 56,450 controls...
July 9, 2020: Cancer Research
https://read.qxmd.com/read/32641416/brain-metastasis-cell-lines-panel-a-public-resource-of-organotropic-cell-lines
#10
Manuel Valiente, Amanda E D Van Swearingen, Carey K Anders, Amos Bairoch, Adrienne Boire, Paula D Bos, Diana M Cittelly, Neta Erez, Gino B Ferraro, Dai Fukumura, Brunilde Gril, Meenhard Herlyn, Sheri L Holmen, Rakesh K Jain, Johanna A Joyce, Mihaela Lorger, Joan Massague, Josh Neman, Nicola R Sibson, Patricia S Steeg, Frits Thorsen, Leonie S Young, Damir Varešlija, Adina Vultur, Frances Weis-Garcia, Frank Winkler
Spread of cancer to the brain remains an unmet clinical need in spite of the increasing number of cases among patients with lung, breast cancer and melanoma most notably. Although research on brain metastasis was considered a minor aspect in the past due to its untreatable nature and invariable lethality, nowadays limited but encouraging examples have questioned this statement making it more attractive for basic and clinical researchers. Evidences of its own biological identity (i.e. specific microenvironment) and particular therapeutic requirements (i...
July 8, 2020: Cancer Research
https://read.qxmd.com/read/32641415/plasma-gelsolin-inhibits-cd8-t-cell-function-and-regulates-glutathione-production-to-confer-chemoresistance-in-ovarian-cancer
#11
Meshach Asare-Werehene, Laudine Communal, Euridice Carmona, Youngjin Han, Yong Sang Song, Dylan Burger, Anne-Marie Mes-Masson, Benjamin K Tsang
Although initial treatment of ovarian cancer (OVCA) is successful, tumors typically relapse and become resistant to treatment. Due to poor infiltration of effector T cells, patients are mostly unresponsive to immunotherapy. Plasma gelsolin (pGSN) is transported by exosomes (sEV) and plays a key role in OVCA chemoresistance, yet little is known about its role in immunosurveillance. Here we report the immunomodulatory roles of sEV-pGSN in OVCA chemoresistance. In chemosensitive conditions, secretion of sEV-pGSN was low, allowing for optimal CD8+ T cell function...
July 8, 2020: Cancer Research
https://read.qxmd.com/read/32641414/the-pathognomonic-foxl2-c134w-mutation-alters-dna-binding-specificity
#12
Annaïck Carles, Genny Trigo-Gonzalez, Rachelle Cao, S-W Grace Cheng, Michelle Moksa, Misha Bilenky, David G Huntsman, Gregg B Morin, Martin Hirst
The somatic missense point mutation c.402C>G (p.C134W) in the FOXL2 transcription factor is pathognomonic for adult-type granulosa cell tumors (AGCT) and a diagnostic marker for this tumor type. However, the molecular consequences of this mutation and its contribution to the mechanisms of AGCT pathogenesis remain unclear. To explore these mechanisms, we engineered V5-FOXL2WT- and V5-FOXL2C134W-inducible isogenic cell lines and performed ChIP-seq and transcriptome profiling. FOXL2C134W associated with the majority of the FOXL2 WT DNA elements as well as a large collection of unique elements genome-wide...
July 8, 2020: Cancer Research
https://read.qxmd.com/read/32641413/accumulation-of-molecular-aberrations-distinctive-to-hepatocellular-carcinoma-progression
#13
Yutaka Midorikawa, Shogo Yamamoto, Kenji Tatsuno, Claire Renard-Guillet, Shingo Tsuji, Akimasa Hayashi, Hiroki Ueda, Shiro Fukuda, Takanori Fujita, Hiroto Katoh, Shumpei Ishikawa, Kyle R Covington, Chad J Creighton, Masahiko Sugitani, David A Wheeler, Tatsuhiro Shibata, Genta Nagae, Tadatoshi Takayama, Hiroyuki Aburatani
Cancer develops through the accumulation of genetic and epigenetic aberrations. To identify sequential molecular alterations that occur during the development of hepatocellular carcinoma (HCC), we compared 52 early and 108 overt HCC samples by genome sequencing. Gene mutations in the p53/RB1 pathway, WNT pathway, MLL protein family, SWI/SNF complexes, and AKT/PI3K pathway were common in HCC. In the early phase of all entities, TERT was the most frequently upregulated gene owing to diverse mechanisms. Despite frequent somatic mutations in driver genes, including CTNNB1 and TP53, early HCC was a separate molecular entity from overt HCC as each had a distinct expression profile...
July 8, 2020: Cancer Research
https://read.qxmd.com/read/32641412/genome-wide-association-study-data-reveal-genetic-susceptibility-to-chronic-inflammatory-intestinal-diseases-and-pancreatic-ductal-adenocarcinoma-risk
#14
Fangcheng Yuan, Rayjean J Hung, Naomi Walsh, Han Zhang, Elizabeth A Platz, William Wheeler, Lei Song, Alan A Arslan, Laura E Beane Freeman, Paige Bracci, Federico Canzian, Mengmeng Du, Steven Gallinger, Graham G Giles, Phyllis J Goodman, Charles Kooperberg, Loic Le Marchand, Rachel E Neale, Jonas Rosendahl, Ghislaine Scelo, Xiao-Ou Shu, Kala Visvanathan, Emily White, Wei Zheng, Demetrius Albanes, Pilar Amiano, Gabriella Andreotti, Ana Babic, William R Bamlet, Sonja I Berndt, Paul Brennan, Bas Bueno-de-Mesquita, Julie E Buring, Peter T Campbell, Stephen J Chanock, Charles S Fuchs, J Michael Gaziano, Michael G Goggins, Thilo Hackert, Patricia Hartge, Manal M Hassan, Elizabeth A Holly, Robert N Hoover, Verena Katzke, Holger Kirsten, Robert C Kurtz, I-Min Lee, Nuria Malats, Roger Milne, Neil Murphy, Kimmie Ng, Ann L Oberg, Miquel Porta, Kari G Rabe, Francisco X Real, Nathaniel Rothman, Howard D Sesso, Debra T Silverman, Ian M Thompson, Jean Wactawski-Wende, Xiaoliang Wang, Nicolas Wentzensen, Lynne R Wilkens, Herbert Yu, Anne Zeleniuch-Jacquotte, Jianxin Shi, Eric J Duell, Laufey T Amundadottir, Donghui Li, Gloria M Petersen, Brian M Wolpin, Harvey A Risch, Kai Yu, Alison P Klein, Rachael Stolzenberg-Solomon
Registry-based epidemiologic studies suggest associations between chronic inflammatory intestinal diseases and pancreatic ductal adenocarcinoma (PDAC). As genetic susceptibility contributes to a large proportion of chronic inflammatory intestinal diseases, we hypothesize that the genomic regions surrounding established genome-wide associated variants for these chronic inflammatory diseases are associated with PDAC. We examined the association between PDAC and genomic regions (+/- 500 kb) surrounding established common susceptibility variants for ulcerative colitis, Crohn's disease, inflammatory bowel disease, celiac disease, chronic pancreatitis, and primary sclerosing cholangitis...
July 8, 2020: Cancer Research
https://read.qxmd.com/read/32641411/mutant-foxl2c134w-highjacks-smad4-and-smad2-3-to-drive-adult-granulosa-cell-tumors
#15
Stine Emilie Weis-Banke, Mads Lerdrup, Daniela Kleine-Kohlbrecher, Faizaan Mohammad, Simone Sidoli, Ole N Jensen, Toshihiko Yanase, Tomoko Nakamura, Akira Iwase, Anthe Stylianou, Nadeem R Abu-Rustum, Carol Aghajanian, Robert Soslow, Arnaud Da Cruz Paula, Richard P Koche, Britta Weigelt, Jesper Christensen, Kristian Helin, Paul A C Cloos
The mutant protein FOXL2C134W is expressed in at least 95% of adult-type ovarian granulosa cell tumors (AGCT) and is considered to be a driver of oncogenesis in this disease. However, the molecular mechanism by which FOXL2C134W contributes to tumorigenesis is not known. Here we show that mutant FOXL2C134W acquires the ability to bind SMAD4, forming a FOXL2C134W/SMAD4/SMAD2/3 complex that binds a novel hybrid DNA motif AGHCAHAA, unique to the FOXL2C134W mutant. This binding induced an enhancer-like chromatin state, leading to transcription of nearby genes, many of which are characteristic of epithelial-to-mesenchymal transition...
July 8, 2020: Cancer Research
https://read.qxmd.com/read/32641410/leveraging-systematic-functional-analysis-to-benchmark-an-in-silico-framework-distinguishes-driver-from-passenger-mek-mutants-in-cancer
#16
Aphrothiti J Hanrahan, Brooke E Sylvester, Matthew T Chang, Arijh Elzein, JianJiong Gao, Weiwei Han, Ye Liu, Dong Xu, Sizhi P Gao, Alexander N Gorelick, Alexis M Jones, Amber J Kiliti, Moriah H Nissan, Clare A Nimura, Abigail N Poteshman, Zhan Yao, Yijun Gao, Wenhuo Hu, Hannah C Wise, Elena I Gavrila, Alexander N Shoushtari, Shakuntala Tiwari, Agnes Viale, Omar Abdel-Wahab, Taha Merghoub, Michael F Berger, Neal Rosen, Barry S Taylor, David B Solit
Despite significant advances in cancer precision medicine, a significant hurdle to its broader adoption remains the multitude of variants of unknown significance identified by clinical tumor sequencing and the lack of biologically validated methods to distinguish between functional and benign variants. Here we used functional data on MAP2K1 and MAP2K2 mutations generated in real-time within a co-clinical trial framework to benchmark the predictive value of a three-part in silico methodology. Our computational approach to variant classification incorporated hotspot analysis, three-dimensional molecular dynamics simulation, and sequence paralogy...
July 8, 2020: Cancer Research
https://read.qxmd.com/read/32641409/cellular-senescence-promotes-skin-carcinogenesis-through-p38mapk-and-p44-p42mapk-signaling
#17
Fatouma Alimirah, Tanya Pulido, Alexis Valdovinos, Sena Alptekin, Emily Chang, Elijah Jones, Diego A Diaz, Jose Flores, Michael C Velarde, Marco Demaria, Albert R Davalos, Christopher D Wiley, Chandani Limbad, Pierre-Yves Desprez, Judith Campisi
Cellular senescence entails an irreversible growth arrest that evolved in part to prevent cancer. Paradoxically, senescent cells secrete pro-inflammatory and growth-stimulatory molecules, termed the senescence-associated secretory phenotype (SASP), which is correlated with cancer cell proliferation in culture and xenograft models. However, at what tumor stage and how senescence and SASP act on endogenous tumor growth in vivo is unknown. To understand the role of senescence in cancer etiology, we subjected p16-3MR transgenic mice, which permit the identification and selective elimination of senescent cells in vivo, to the well-established two-step protocol of squamous cell skin carcinoma (SCC), in which tumorigenesis is initiated by a carcinogen 7,12-dimethylbenz[α]anthracene (DMBA) and then promoted by 12-O-tetradecanoyl-phorbol-13-acetate (TPA)...
July 8, 2020: Cancer Research
https://read.qxmd.com/read/32641408/exosomal-noncoding-rnas-and-tumor-drug-resistance
#18
Chengyao Guo, Jinbo Liu, Quanbo Zhou, Junmin Song, Zhiyong Zhang, Zhen Li, Guixian Wang, Zhenqiang Sun, Weitang Yuan
Tumor drug resistance is a major challenge in the treatment of cancer. Non-coding RNAs (ncRNA) play a role in the progression of drug resistance. Recent studies have indicated that exosomes, with their in vitro and in vivo compatibility, are the best natural carrier of ncRNA, and their transport of ncRNA into cells could regulate drug resistance. Exosomal ncRNA impact drug resistance through participation in drug efflux, regulation of signaling pathways, and modification of the tumor microenvironment. In this review, we evaluate the mechanism of exosomal ncRNA related to tumor drug resistance, their role in different tumors, and potential clinical applications...
July 8, 2020: Cancer Research
https://read.qxmd.com/read/32641407/calibration-of-pathogenicity-due-to-variant-induced-leaky-splicing-defects-by-using-brca2-exon-3-as-a-model-system
#19
Hélène Tubeuf, Sandrine M Caputo, Teresa Sullivan, Julie Rondeaux, Sophie Krieger, Virginie Caux-Moncoutier, Julie Hauchard, Gaia Castelain, Alice Fiévet, Laëtitia Meulemans, Françoise Révillion, Mélanie Léone, Nadia Boutry-Kryza, Capucine Delnatte, Marine Guillaud-Bataille, Linda Cleveland, Susan Reid, Eileen Southon, Omar Soukarieh, Aurélie Drouet, Daniela Di Giacomo, Myriam Vezain, Françoise Bonnet-Dorion, Violaine Bourdon, Hélène Larbre, Danièle Muller, Pascal Pujol, Fátima Vaz, Séverine Audebert-Bellanger, Chrystelle Colas, Laurence Venat-Bouvet, Angela R Solano, Dominique Stoppa-Lyonnet, Claude Houdayer, Thierry Frebourg, Pascaline Gaildrat, Shyam K Sharan, Alexandra Martins
BRCA2 is a clinically actionable gene implicated in breast and ovarian cancer predisposition that has become a high priority target for improving the classification of variants of unknown significance (VUS). Amongst all BRCA2 VUS, those causing partial/leaky splicing defects are the most challenging to classify because the minimal level of full-length transcripts (FL) required for normal function remains to be established. Here, we explored BRCA2 exon 3 (BRCA2e3) as a model for calibrating variant-induced spliceogenicity and estimating thresholds for BRCA2 haploinsufficiency...
July 8, 2020: Cancer Research
https://read.qxmd.com/read/32636316/microenvironmental-activation-of-nrf2-restricts-the-progression-of-nrf2-activated-malignant-tumors
#20
Makiko Hayashi, Ayumi Kuga, Mikiko Suzuki, Harit Panda, Hiroshi Kitamura, Hozumi Motohashi, Masayuki Yamamoto
The transcription factor Nrf2 activates transcription of cytoprotective genes during oxidative and electrophilic insults. Nrf2 activity is regulated by Keap1 in a stress-dependent manner in normal cells, and somatic loss-of-function mutations of Keap1 are known to induce constitutive Nrf2 activation, especially in lung adenocarcinomas, conferring survival and proliferative benefits to tumors. Therefore, several therapeutic strategies that aim to inhibit Nrf2 in tumors have been developed for the treatment of Nrf2-activated cancers...
July 7, 2020: Cancer Research
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