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Cancer Research

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https://read.qxmd.com/read/31519689/muc1-c-activates-the-nurd-complex-to-drive-dedifferentiation-of-triple-negative-breast-cancer-cells
#1
Tsuyoshi Hata, Hasan Rajabi, Hidekazu Takahashi, Yota Yasumizu, Wei Li, Caining Jin, Mark D Long, Qiang Hu, Song Liu, Atsushi Fushimi, Nami Yamashita, Ling Kui, Deli Hong, Masaaki Yamamoto, Masaaki Miyo, Masayuki Hiraki, Takahiro Maeda, Yozo Suzuki, Mehmet K Samur, Donald Kufe
The NuRD chromatin remodeling and deacetylation complex, which includes MTA1, MBD3, CHD4 and HDAC1 among other components, is of importance for development and cancer progression. The oncogenic MUC1-C protein activates EZH2 and BMI1 in the epigenetic reprogramming of triple-negative breast cancer (TNBC). However, there is no known link between MUC1-C and chromatin remodeling complexes. Here we showed that MUC1-C binds directly to the MYC HLH-LZ domain and identified a previously unrecognized MUC1-C->MYC pathway that regulates the NuRD complex...
September 13, 2019: Cancer Research
https://read.qxmd.com/read/31519688/neutrophil-extracellular-traps-drive-mitochondrial-homeostasis-in-tumors-to-augment-growth
#2
Hamza O Yazdani, Eva Roy, Alexander J Comerci, Dirk J van der Windt, Hongji Zhang, Hai Huang, Patricia Loughran, Sruti Shiva, David A Geller, David L Bartlett, Allan Tsung, Tai Sheng, Richard L Simmons, Samer Tohme
Neutrophil infiltration and neutrophil extracellular traps (NETs) in solid cancers are associated with poorer prognosis but the mechanisms are incompletely understood. We hypothesized that NETs enhance mitochondrial function in tumor cells providing extra energy for accelerated growth. Metastatic colorectal cancer tissue showed increased intratumoral NETs and supranormal preoperative serum MPO-DNA, a NET marker. Higher MPO-DNA correlated with shorter survival. In mice, subcutaneous tumor implants and hepatic metastases grew slowly in PAD4-KO mice, genetically incapable of NETosis...
September 13, 2019: Cancer Research
https://read.qxmd.com/read/31519687/diminished-ahr-signaling-drives-human-acute-myeloid-leukemia-stem-cell-maintenance
#3
Michelle Ly, Stefan Rentas, Ana Vujovic, Nicholas Wong, Steven Moreira, Joshua Xu, Nicholas Holzapfel, Sonam Bhatia, Damian Tran, Mark D Minden, Jonathan S Draper, Kristin J Hope
Eliminating leukemic stem cells (LSCs) is a sought after therapeutic paradigm for the treatment of acute myeloid leukemia (AML). While repression of aryl hydrocarbon receptor (AHR) signaling has been shown to promote short term maintenance of primitive AML cells in culture, no work to date has examined whether altered AHR signaling plays a pathological role in human AML or whether it contributes at all to endogenous LSC function. Here we show AHR signaling is repressed in human AML blasts and preferentially downregulated in LSC-enriched populations within leukemias...
September 13, 2019: Cancer Research
https://read.qxmd.com/read/31515237/drug-sensitivity-prediction-models-reveal-a-link-between-dna-repair-defects-and-poor-prognosis-in-hnscc
#4
Paul B M Essers, Martijn van der Heijden, Caroline V M Verhagen, Emily M Ploeg, Reinout H de Roest, C René Leemans, Ruud H Brakenhoff, Michiel W M van den Brekel, Harry Bartelink, Marcel Verheij, Conchita Vens
Head and neck squamous cell carcinoma (HNSCC) is characterized by the frequent manifestation of DNA crosslink repair defects. We established novel expression-based DNA repair defect markers to determine the clinical impact of such repair defects. Using hypersensitivity to the DNA crosslinking agents mitomycin C and olaparib as proxies for functional DNA repair defects in a panel of 25 HNSCC cell lines, we applied machine learning to define gene expression models that predict repair defects. The expression profiles established predicted hypersensitivity to DNA damaging agents and were associated with mutations in crosslink repair genes, as well as downregulation of DNA damage response and repair genes, in two independent datasets...
September 12, 2019: Cancer Research
https://read.qxmd.com/read/31506334/oncogenic-kras-sensitizes-lung-adenocarcinoma-to-gsk-j4-induced-metabolic-and-oxidative-stress
#5
Beom-Jin Hong, Woo-Yong Park, Hwa-Ryeon Kim, Jin Woo Moon, Ho Yeon Lee, Jun Hyung Park, Seon-Kyu Kim, Youngbin Oh, Jae-Seok Roe, Mi-Young Kim
Genetic and epigenetic changes (e.g., histone methylation) contribute to cancer development and progression, but our understanding of whether and how specific mutations affect a cancer's sensitivity to histone demethylase (KDM) inhibitors is limited. Here, we evaluated the effects of a panel of KDM inhibitors on lung adenocarcinomas (LuAC) with various mutations. Notably, LuAC lines harboring KRAS mutations showed hypersensitivity to the histone H3K27 demethylase inhibitor GSK-J4. Specifically, GSK-J4 treatment of KRAS mutant-containing LuAC downregulated cell cycle progression genes with increased H3K27me3...
September 10, 2019: Cancer Research
https://read.qxmd.com/read/31506333/dynamics-of-genomic-epigenomic-and-transcriptomic-aberrations-during-stepwise-hepatocarcinogenesis
#6
Byul A Jee, Ji-Hye Choi, Hyungjin Rhee, Sarah Yoon, So Mee Kwon, Ji Hae Nahm, Jeong Eun Yoo, Youngsic Jeon, Gi Hong Choi, Hyun Goo Woo, Young Nyun Park
Hepatocellular carcinoma (HCC) undergoes a stepwise progression from liver cirrhosis (LC) to low-grade dysplastic nodule (LGDN), high-grade dysplastic nodule (HGDN), early HCC (eHCC), and progressed HCC (pHCC). Here, we profiled multi-layered genomic, epigenomic, and transcriptomic aberrations in the stepwise hepatocarcinogenesis. Initial DNA methylation was observed in eHCC (e.g., DKK3, SALL3, and SOX1) while more extensive methylation was observed in pHCC. In addition, eHCCs showed an initial loss of DNA copy numbers of tumor suppressor genes in the 4q and 13q regions, thereby conferring survival benefits to cancer cells...
September 10, 2019: Cancer Research
https://read.qxmd.com/read/31506332/kras-adam17-dependent-jag1-icd-reverse-signalling-sustains-colorectal-cancer-progression-and-chemoresistance
#7
Maria Pelullo, Francesca Nardozza, Sabrina Zema, Roberta Quaranta, Carmine Nicoletti, Zein Mersini Besharat, Maria Pia Felli, Bruna Cerbelli, Giulia d'Amati, Rocco Palermo, Carlo Capalbo, Claudio Talora, Lucia Di Marcotullio, Giuseppe Giannini, Saula Checquolo, Isabella Screpanti, Diana Bellavia
Colorectal cancer (CRC) is characterized by well-known genetic defects and approximately 50% of cases harbour oncogenic RAS mutations. Increased expression of Notch ligand Jagged1 occurs in several human malignancies, including CRC, and correlates with cancer progression, poor prognosis and recurrence. Herein, we demonstrated that Jagged1 was constitutively processed in CRC tumours with mutant Kras, which ultimately triggered intrinsic reverse signalling via its nuclear-targeted intracellular domain Jag1-ICD...
September 10, 2019: Cancer Research
https://read.qxmd.com/read/31501192/drugging-mycn-oncogenic-signalling-through-the-mycn-pa2g4-binding-interface
#8
Jessica Koach, Jessica K Holien, Hassina Massudi, Daniel R Carter, Olivia C Ciampa, Mika Herath, Taylor Lim, Janith A Seneviratne, Giorgio Milazzo, Jayne E Murray, Joshua A McCarroll, Bing Liu, Chelsea Mayoh, Bryce Keenan, Brendan W Stevenson, Michael A Gorman, Jessica L Bell, Larissa Doughty, Stefan Hüttelmaier, Andre Oberthuer, Matthias Fischer, Andrew J Gifford, Tao Liu, Xiaoling Zhang, Shizhen Zhu, W Clay Gustafson, Michelle Haber, Murray D Norris, Jamie I Fletcher, Giovanni Perini, Michael W Parker, Belamy B Cheung, Glenn M Marshall
MYCN is a major driver for the childhood cancer, neuroblastoma, however, there are no inhibitors of this target. Enhanced MYCN protein stability is a key component of MYCN oncogenesis and is maintained by multiple feedforward expression loops involving MYCN transactivation target genes. Here, we reveal the oncogenic role of a novel MYCN target and binding protein, proliferation-associated 2AG4 (PA2G4). ChIP studies demonstrated that MYCN occupies the PA2G4 gene promoter, stimulating transcription. Direct binding of PA2G4 to MYCN protein blocked proteolysis of MYCN, and enhanced colony formation in a MYCN-dependent manner...
September 9, 2019: Cancer Research
https://read.qxmd.com/read/31501191/genetic-variants-implicate-dual-oxidase-2-duox2-in-familial-and-sporadic-non-medullary-thyroid-cancer
#9
Darrin V Bann, Qunyan Jin, Kathryn E Sheldon, Kenneth R Houser, Lan Nguyen, Joshua I Warrick, Maria J Baker, James Broach, Glenn S Gerhard, David Goldenberg
Highly penetrant hereditary thyroid cancer manifests as familial nonmedullary thyroid cancer (FNMTC), while low-penetrance hereditary thyroid cancer manifests as sporadic disease and is associated with common polymorphisms, including rs965513. Whole-exome sequencing of an FNMTC kindred identified a novel Y1203H germline Dual Oxidase-2 (DUOX2) mutation. DUOX2Y1203H is enzymatically active and increased production of reactive oxygen species. Furthermore, sporadic thyroid cancer patients homozygous for rs965513 demonstrated higher DUOX2 expression than heterozygous or homozygous negative patients...
September 9, 2019: Cancer Research
https://read.qxmd.com/read/31492820/predictive-signatures-inform-the-effective-repurposing-of-decitabine-to-treat-k-ras-dependent-pancreatic-ductal-adenocarcinoma
#10
Carla Mottini, Hideo Tomihara, Diego Carrella, Alessia Lamolinara, Manuela Iezzi, Justin K Huang, Carla A Amoreo, Simonetta Buglioni, Isabella Manni, Frederick S Robinson, Rosalba Minelli, Ya'an Kang, Jason B Fleming, Michael P Kim, Christopher A Bristow, Daniela Trisciuoglio, Antonella Iuliano, Donatella Del Bufalo, Diego di Bernardo, Davide Melisi, Giulio F Draetta, Gennaro Ciliberto, Alessandro Carugo, Luca Cardone
Mutated K-RAS protein is a pivotal tumor driver in pancreatic cancer. However, despite comprehensive efforts, effective therapeutics that can target oncogenic K-RAS are still under investigation or awaiting clinical approval. Using a specific K-RAS-dependent gene signature, we implemented a computer-assisted inspection of a drug-gene network to in silico repurpose drugs that work like inhibitors of oncogenic K-RAS. We identified and validated decitabine-a U.S. Food and Drug Administration-approved drug-as a potent inhibitor of growth in pancreatic cancer cells and patient-derived xenograft models that showed K-RAS dependency...
September 5, 2019: Cancer Research
https://read.qxmd.com/read/31488423/mitochondrial-nix-promotes-tumor-survival-in-the-hypoxic-niche-of-glioblastoma
#11
Jinkyu Jung, Ying Zhang, Orieta Celiku, Wei Zhang, Hua Song, Brian J Williams, Amber J Giles, Jeremy N Rich, Roger Abounader, Mark R Gilbert, Deric M Park
Cancer cells rely on mitochondrial functions to regulate key survival and death signals. How cancer cells regulate mitochondrial autophagy (mitophagy) in the tumor microenvironment as well as utilize mitophagy as a survival signal is still not well understood. Here we elucidate a key survival mechanism of mitochondrial NIX-mediated mitophagy within the hypoxic region of glioblastoma, the most malignant brain tumor. NIX was overexpressed in the pseudopalisading cells that envelop the hypoxic-necrotic regions, and mitochondrial NIX expression was robust in patient-derived glioblastoma tumor tissues and glioblastoma stem cells (GSC)...
September 5, 2019: Cancer Research
https://read.qxmd.com/read/31488422/posttraumatic-stress-disorder-ptsd-is-associated-with-increased-risk-of-ovarian-cancer-a-prospective-and-retrospective-longitudinal-cohort-study
#12
Andrea L Roberts, Tianyi Huang, Karestan C Koenen, Yongjoo Kim, Laura D Kubzansky, Shelley S Tworoger
Ovarian cancer is the deadliest gynecologic cancer. Chronic stress accelerates tumor growth in animal models of ovarian cancer. We therefore postulated that posttraumatic stress disorder (PTSD) may be associated with increased risk of ovarian cancer. We used data from the Nurses' Health Study II, a longitudinal cohort study with 26 years of follow up, conducted from 1989-2015 with 54,710 subjects. Lifetime PTSD symptoms were measured in 2008. Self-reported ovarian cancer was validated with medical records. Risk of ovarian cancer was estimated with Cox proportional hazards models and further adjusted for known ovarian cancer risk factors (e...
September 5, 2019: Cancer Research
https://read.qxmd.com/read/31484670/deoxycytidine-release-from-pancreatic-stellate-cells-promotes-gemcitabine-resistance
#13
Simona Dalin, Mark R Sullivan, Allison N Lau, Beatrice Grauman-Boss, Helen S Mueller, Emanuel Kreidl, Silvia Fenoglio, Alba Luengo, Jacqueline A Lees, Matthew G Vander Heiden, Douglas A Lauffenburger, Michael T Hemann
Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer deaths in the United States. The deoxynucleoside analog gemcitabine is among the most effective therapies to treat PDAC; however, nearly all patients treated with gemcitabine either fail to respond or rapidly develop resistance. One hallmark of PDAC is a striking accumulation of stromal tissue surrounding the tumor, and this accumulation of stroma can contribute to therapy resistance. To better understand how stroma limits response to therapy, we investigated cell-extrinsic mechanisms of resistance to gemcitabine...
September 4, 2019: Cancer Research
https://read.qxmd.com/read/31484669/clonal-mutations-activate-the-nf-%C3%AE%C2%BAb-pathway-to-promote-recurrence-of-nasopharyngeal-carcinoma
#14
Rui You, You-Ping Liu, De-Chen Lin, Qing Li, Tao Yu, Xiong Zou, Mei Lin, Xiao-Long Zhang, Gui-Ping He, Qi Yang, Yi-Nuan Zhang, Yu-Long Xie, Rou Jiang, Chen-Yan Wu, Chao Zhang, Cheng Cui, Jing-Qi Wang, Yue Wang, Ai-Hua Zhuang, Gui-Fang Guo, Yi-Jun Hua, Rui Sun, Jing-Ping Yun, Zhi-Xiang Zuo, Ze-Xian Liu, Xiao-Feng Zhu, Tie-Bang Kang, Chao-Nan Qian, Hai-Qiang Mai, Ying Sun, Mu-Sheng Zeng, Lin Feng, Yi-Xin Zeng, Ming-Yuan Chen
The genetic events occuring in recurrent nasopharyngeal carcinoma (rNPC) are poorly understood. Here, we performed whole-genome and whole-exome sequencing in 55 rNPC and 44 primarily diagnosed NPC (pNPC) patients; with 7 patients having paired rNPC and pNPC samples. Previously published pNPC exome data were integrated for analysis. rNPC and pNPC tissues had similar mutational burdens, however, the number of clonal mutations was increased in rNPC samples. TP53 and three NF-κB pathway components (TRAF3, CYLD and NFKBIA) were significantly mutated in both pNPC and rNPC...
September 4, 2019: Cancer Research
https://read.qxmd.com/read/31484668/mitohormesis-uprmt-and-the-complexity-of-mitochondrial-dna-landscapes-in-cancer
#15
Timothy C Kenny, Maria Gomez, Doris Germain
The discovery of the Warburg effect - the preference of cancer cells to generate ATP via glycolysis rather than oxidative phosphorylation has fostered the misconception that cancer cells become independent of the electron transport chain (ETC) for survival. This is inconsistent with the need of ETC function for the generation of pyrimidines. Along with this misconception, a large body of literature has reported numerous mutations in mitochondrial DNA (mtDNA) further fueling the notion of non-functional ETC in cancer cells...
September 4, 2019: Cancer Research
https://read.qxmd.com/read/31481502/quantification-and-localization-of-protein-rna-interactions-in-patient-derived-archival-tumor-tissue
#16
Emmeline L Blanchard, Danae Argyropoulou, Chiara Zurla, Sushma M Bhosle, Daryll Vanover, Philip J Santangelo
Abnormal post-transcriptional regulation induced by alterations of mRNA-protein interactions is critical during tumorigenesis and cancer progression and is a hallmark of cancer cells. A more thorough understanding is needed to develop treatments and foresee outcomes. Cellular and mouse tumor models are insufficient for vigorous investigation as they lack consistency and translatability to humans. Moreover, to date, studies in human tumor tissue are predominately limited to expression analysis of proteins and mRNA, which do not necessarily provide information about the frequency of mRNA-protein interactions...
September 3, 2019: Cancer Research
https://read.qxmd.com/read/31481501/heparanase-accelerates-obesity-associated-breast-cancer-progression
#17
Esther Hermano, Rachel Goldberg, Ariel M Rubinstein, Amir Sonnenblick, Bella Maly, Daniela Nahmias, Jin-Ping Li, Marinka A H Bakker, Johan van der Vlag, Israel Vlodavsky, Tamar Peretz, Michael Elkin
Obese women have higher risk of bearing breast tumors which are highly aggressive and resistant to therapies. Tumor-promoting effects of obesity occur locally via adipose inflammation and related alterations to the extracellular matrix (ECM) as well as systemically via circulating metabolic mediators (e.g. free fatty acids, FFA) associated with excess adiposity and implicated in toll-like receptor-mediated activation of macrophages - key cellular players in obesity-related cancer progression. While the contribution of macrophages to pro-neoplastic effects of obesity is well-documented, the role of ECM components and their enzymatic degradation is less appreciated...
September 3, 2019: Cancer Research
https://read.qxmd.com/read/31481500/a-biophysical-model-uncovers-the-size-distribution-of-migrating-cell-clusters-across-cancer-types
#18
Federico Bocci, Mohit Kumar Jolly, Jose' N Onuchic
Migration from the primary tumor is a crucial step in the metastatic cascade. Cells with various degrees of adhesion and motility migrate and are launched into the bloodstream as single circulating tumor cells (CTCs) or multi-cellular CTC clusters. The frequency and size distributions of these clusters has been recently measured, but the underlying mechanisms enabling these different modes of migration remain poorly understood. We present a biophysical model that couples the phenotypic plasticity enabled by the epithelial-mesenchymal transition (EMT) and cell migration to explain the modes of individual and collective cancer cell migration...
September 3, 2019: Cancer Research
https://read.qxmd.com/read/31481499/integrated-pan-cancer-map-of-ebv-associated-neoplasms-reveals-functional-host-virus-interactions
#19
Srishti Chakravorty, Bingyu Yan, Chong Wang, Luopin Wang, Joseph Taylor Quaid, Chin Fang Lin, Scott D Briggs, Joydeb Majumder, D Alejandro Canaria, Daniel Chauss, Gaurav Chopra, Matthew R Olson, Bo Zhao, Behdad Afzali, Majid Kazemian
Epstein-Barr virus (EBV) is a complex oncogenic symbiont. The molecular mechanisms governing EBV carcinogenesis remain elusive and the functional interactions between virus and host cells are incompletely defined. Here we present a comprehensive map of the host cell-pathogen interactome in EBV-associated cancers. We systematically analyzed RNA-sequencing from >1000 patients with 15 different cancer types, comparing virus and host factors of EBV+ to EBV- tissues. EBV preferentially integrated at highly accessible regions of the cancer genome with significant enrichment in super-enhancer architecture...
September 3, 2019: Cancer Research
https://read.qxmd.com/read/31481498/atmin-is-a-tumor-suppressor-gene-in-lung-adenocarcinoma
#20
Hanna Foster, E Josue Ruiz, Christopher Moore, Gordon W H Stamp, Emma L Nye, Ningning Li, Yihang Pan, Yulong He, Julian Downward, Axel Behrens
Tumor cells proliferate rapidly, and thus are frequently subjected to replication stress and the risk of incomplete duplication of the genome. Fragile sites are replicated late, making them more vulnerable to damage when DNA replication fails to complete. Therefore, genomic alterations at fragile sites are commonly observed in tumors. FRA16D is one of the most common fragile sites in lung cancer, however, the nature of the tumor suppressor genes affected by FRA16D alterations has been controversial. Here, we show that the ATMIN gene, which encodes a cofactor required for activation of ATM kinase by replication stress, is located close to FRA16D and is commonly lost in lung adenocarcinoma (LUAD)...
September 3, 2019: Cancer Research
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