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Cancer Research

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https://www.readbyqxmd.com/read/29463581/a-novel-mechanism-for-activation-of-gli1-by-nuclear-smo-that-escapes-anti-smo-inhibitors
#1
Muhammad M Rahman, Allon Hazan, Joanne L Selway, Dimalee S Herath, Catherine A Harwood, Muhammad S Pirzado, Ravinder Atkar, David P Kelsell, Kenneth J Linton, Mike P Philpott, Graham W Neill
Small molecule inhibitors of the Hedgehog (HH) pathway receptor Smoothened (SMO) have been effective in treating some patients with basal cell carcinoma (BCC), where the HH pathway is often activated, but many patients are poorly responsive. In this study, we report the results of investigations on PTCH1 signalling in the HH pathway that suggest why most BCC patients respond poorly to SMO inhibitors. In immortalised human keratinocytes, PTCH1 silencing led to the generation of a compact, holoclone-like morphology with increased expression of SMO and the downstream HH pathway transcription factor GLI1...
February 20, 2018: Cancer Research
https://www.readbyqxmd.com/read/29463580/truncated-glioma-associated-oncogene-homolog-1-tgli1-mediates-mesenchymal-glioblastoma-via-transcriptional-activation-of-cd44
#2
Tadas K Rimkus, Richard L Carpenter, Sherona R Sirkisoon, Dongqin Zhu, Boris Pasche, Michael D Chan, Glenn J Lesser, Stephen B Tatter, Kounosuke Watabe, Waldemar Debinski, Hui-Wen Lo
The molecular pathways driving mesenchymal glioblastoma (GBM) are still not well understood. We report here that truncated glioma-associated oncogene homolog 1 (tGLI1) is a tumor-specific transcription factor that facilitates GBM growth, is enriched in the mesenchymal subtype of GBM and glioma stem cells (GSC), and promotes mesenchymal GSC by upregulating transcription of CD44. In an orthotopic GBM xenograft mouse model, tGLI1-overexpressing tumors grew more aggressively with increased proliferation and angiogenesis compared to control and GLI1-overexpressing xenografts...
February 20, 2018: Cancer Research
https://www.readbyqxmd.com/read/29459407/crosstalknet-a-visualization-tool-for-differential-co-expression-networks-and-communities
#3
Venkata Sk Manem, George A Adam, Tina Gruosso, Mathieu Gigoux, Nicholas R Bertos, Morag Park, Benjamin Haibe-Kains
Variations in physiological conditions can rewire molecular interactions between biological compartments, which can yield novel insights into gain or loss of interactions specific to perturbations of interest. Networks are a promising tool to elucidate intercellular interactions, yet exploration of these large-scale networks remains a challenge due to their high dimensionality. To retrieve and mine interactions, we developed CrosstalkNet, a user friendly, web-based network visualization tool that provides a statistical framework to infer condition-specific interactions coupled with a community detection algorithm for bipartite graphs to identify significantly dense subnetworks...
February 19, 2018: Cancer Research
https://www.readbyqxmd.com/read/29449267/single-cell-transcriptome-analyses-reveal-endothelial-cell-heterogeneity-in-tumors-and-changes-following-anti-angiogenic-treatment
#4
Qi Zhao, Alexandra Eichten, Asma A Parveen, Christina Adler, Ying Huang, Wei Wang, Yueming Ding, Alexander Adler, Thomas Nevins, Min Ni, Yi Wei, Gavin Thurston
Angiogenesis involves dynamic interactions between specialized endothelial tip and stalk cells that are believed to be regulated in part by VEGF and Dll4-Notch signaling. However, our understanding of this process is hampered by limited knowledge of the heterogeneity of endothelial cells and the role of different signaling pathways in specifying endothelial phenotypes. Here we characterized by single cell transcriptomics the heterogeneity of mouse endothelial cells and other stromal cells during active angiogenesis in xenograft tumors as well as from adult normal heart, following pharmacologic inhibition of VEGF and Dll4-Notch signaling...
February 15, 2018: Cancer Research
https://www.readbyqxmd.com/read/29440147/the-balance-players-of-the-adaptive-immune-system
#5
Mads Hald Andersen
Equilibrium between immune activation and suppression may be necessary to maintain immune homeostasis, because proinflammatory effector T cells (defined as antiregulatory T cells) counteract the functions of regulatory immune cells. These self-reactive T cells recognize human leukocyte antigen (HLA)-restricted epitopes derived from proteins expressed by regulatory immune cells such as IDO, PD-L1, PD-L2, or arginase. The activation of such proinflammatory effector T cells offers a novel way to directly target the tumor microenvironment, potentially giving them considerable clinical value, especially in patients with cancer...
February 13, 2018: Cancer Research
https://www.readbyqxmd.com/read/29440146/a-ddx31-mutant-p53-egfr-axis-promotes-multistep-progression-of-muscle-invasive-bladder-cancer
#6
Kei Daizumoto, Tetsuro Yoshimaru, Yosuke Matsushita, Tomoya Fukawa, Hisaori Uehara, Masaya Ono, Masato Komatsu, Hiro-Omi Kanayama, Toyomasa Katagiri
The p53 and EGFR pathways are frequently altered in bladder cancers, yet their contributions to its progression remain elusive. Here we report that DEAD box polypeptide 31 (DDX31) plays a critical role in the multistep progression of muscle invasive bladder cancer (MIBC) through its sequential interactions with mutant p53 (mutp53) and EGFR. In early MIBC cells, nuclear DDX31 bound mutp53/SP1 and enhanced mutp53 transcriptional activation, leading to migration and invasion of MIBC. Cytoplasmic DDX31 also bound EGFR and phospho-nucleolin (p-NCL) in advanced MIBC, leading to EGFR-Akt signaling activation...
February 13, 2018: Cancer Research
https://www.readbyqxmd.com/read/29440145/the-fact-inhibitor-cbl0137-synergizes-with-cisplatin-in-small-cell-lung-cancer-by-increasing-notch1-expression-and-targeting-tumor-initiating-cells
#7
Sarmishtha De, Daniel J Lindner, Claire Coleman, Gary Wildey, Afshin Dowlati, George R Stark
Traditional treatments of small cell lung cancer (SCLC) with cisplatin, a standard of care therapy, spare the tumor-initiating cells (TIC) that mediate drug resistance. Here we report a novel therapeutic strategy that preferentially targets TIC in SCLC in which cisplatin is combined with CBL0137, an inhibitor of the histone chaperone facilitates chromatin transcription (FACT), which is highly expressed in TIC. Combination of cisplatin and CBL0137 killed patient-derived and murine SCLC cell lines synergistically...
February 13, 2018: Cancer Research
https://www.readbyqxmd.com/read/29440144/spon2-promotes-m1-like-macrophage-recruitment-and-inhibits-hepatocellular-carcinoma-metastasis-by-distinct-integrin-rho-gtpase-hippo-pathways
#8
Yan-Li Zhang, Qing Li, Xiao-Mei Yang, Fang Fang, Jun Li, Ya-Hui Wang, Qin Yang, Lei Zhu, Hui-Zhen Nie, Xue-Li Zhang, Ming-Xuan Feng, Shu-Heng Jiang, Guang-Ang Tian, Li-Peng Hu, Ho-Young Lee, Su-Jae Lee, Qiang Xia, Zhi-Gang Zhang
Tumor-associated macrophages (TAM) represent key regulators of the complex interplay between cancer and the immune microenvironment. Matricellular protein SPON2 is essential for recruiting lymphocytes and initiating immune responses. Recent studies have shown that SPON2 has complicated roles in cell migration and tumor progression. Here we report that, in the tumor microenvironment of hepatocellular carcinoma (HCC), SPON2 not only promotes infiltration of M1-like macrophages but also inhibits tumor metastasis...
February 13, 2018: Cancer Research
https://www.readbyqxmd.com/read/29440172/a-distinct-oncogenerative-multinucleated-cancer-cell-serves-as-a-source-of-stemness-and-tumor-heterogeneity
#9
David Diaz-Carballo, Sahitya Saka, Jacqueline Klein, Tobias Rennkamp, Ali Haydar Acikelli, Sascha Malak, Holger Jastrow, Gunther Wennemuth, Clemens B Tempfer, Inge Schmitz, Andrea Tannapfel, Dirk Strumberg
The effects of anticancer treatments on cell heterogeneity and their proliferative potential play an important role in tumor persistence and metastasis. However, little is known about de-polyploidization, cell fate, and physiological stemness of the resulting cell populations. Here we describe a distinctive cell type termed "pregnant" P1 cells found within chemotherapy refractory ovarian tumors, which generate and gestate daughter generation Gn-cells intracytoplasmically. Release of Gn-cells occurred by ejection through crevices in P1 cell membrane by body contractions or using a funiculus-like structure...
February 12, 2018: Cancer Research
https://www.readbyqxmd.com/read/29440171/crosstalk-signaling-between-her3-and-hpv16-e6-and-e7-mediates-resistance-to-pi3k-inhibitors-in-head-and-neck-cancer
#10
Toni M Brand, Stefan Hartmann, Neil E Bhola, Hua Li, Yan Zang, Rachel A O'Keefe, Max V Ranall, Sourav Bandyopadhyay, Margaret Soucheray, Nevan J Krogan, Carolyn Kemp, Umamaheswar Duvvuri, Theresa LaVallee, Daniel E Johnson, Michelle A Ozbun, Julie E Bauman, Jennifer R Grandis
Human papillomavirus (HPV) type 16 is implicated in approximately 75% of head and neck squamous cell carcinomas (HNSCC) that arise in the oropharynx, where viral expression of the E6 and E7 oncoproteins promote cellular transformation, tumor growth, and maintenance. An important oncogenic signaling pathway activated by E6 and E7 is the phosphatidylinositol 3-kinase (PI3K) pathway, a key driver of carcinogenesis. The PI3K pathway is also activated by mutation or amplification of PIK3CA in over half of HPV(+) HNSCC...
February 12, 2018: Cancer Research
https://www.readbyqxmd.com/read/29440170/rsk-regulates-pfk-2-activity-to-promote-metabolic-rewiring-in-melanoma
#11
Thibault Houles, Simon-Pierre Gravel, Geneviève Lavoie, Sejeong Shin, Mathilde Savall, Antoine Méant, Benoit Grondin, Louis Gaboury, Sang-Oh Yoon, Julie St-Pierre, Philippe P Roux
Metabolic reprogramming is a hallmark of cancer that includes increased glucose uptake and accelerated aerobic glycolysis. This phenotype is required to fulfill anabolic demands associated with aberrant cell proliferation and is often mediated by oncogenic drivers such as activated BRAF. In this study, we show that the MAPK-activated p90 ribosomal S6 kinase (RSK) is necessary to maintain glycolytic metabolism in BRAF-mutated melanoma cells. RSK directly phosphorylated the regulatory domain of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2 (PFKFB2), an enzyme that catalyzes the synthesis of fructose-2,6-bisphosphate during glycolysis...
February 12, 2018: Cancer Research
https://www.readbyqxmd.com/read/29440169/oncogenic-kinase-induced-pkm2-tyrosine-105-phosphorylation-converts-non-oncogenic-pkm2-to-a-tumor-promoter-and-induces-cancer-stem-like-cells
#12
Zhifen Zhou, Min Li, Lin Zhang, Hong Zhao, Özgür Şahin, Jing Chen, Jean J Zhao, Zhou Songyang, Dihua Yu
The role of pyruvate kinase M2 isoform (PKM2) in tumor progression has been controversial. Previous studies showed that PKM2 promoted tumor growth in xenograft models; however, depletion of PKM2 in the Brca1-loss-driven mammary tumor mouse model accelerates tumor formation. Since oncogenic kinases are frequently activated in tumors and PKM2 phosphorylation promotes tumor growth, we hypothesized that phosphorylation of PKM2 by activated kinases in tumor cells confers PKM2 oncogenic function, whereas non-phosphorylated PKM2 is non-oncogenic...
February 12, 2018: Cancer Research
https://www.readbyqxmd.com/read/29440168/foxo-transcription-factors-both-suppress-and-support-breast-cancer-progression
#13
Marten Hornsveld, Lydia M Smits, Maaike Meerlo, Miranda van Amersfoort, Marian J Groot Koerkamp, Dik van Leenen, David E Kloet, Frank C Holstege, Patrick W B Derksen, Boudewijn M T Burgering, Tobias B Dansen
FOXO transcription factors are regulators of cellular homeostasis and putative tumor suppressors, yet the role of FOXO in cancer progression remains to be determined. The data on FOXO function, particularly for epithelial cancers, are fragmentary and come from studies that focused on isolated aspects of cancer. To clarify the role of FOXO in epithelial cancer progression, we characterized the effects of inducible FOXO activation and loss in a mouse model of metastatic invasive lobular carcinoma. Strikingly, either activation or loss of FOXO function suppressed tumor growth and metastasis...
February 12, 2018: Cancer Research
https://www.readbyqxmd.com/read/29438991/genetic-hitchhiking-and-population-bottlenecks-contribute-to-prostate-cancer-disparities-in-men-of-african-descent
#14
Joseph Lachance, Ali J Berens, Matthew E B Hansen, Andrew K Teng, Sarah A Tishkoff, Timothy R Rebbeck
Prostate cancer (CaP) incidence and mortality rates in African and African American men are greatly elevated compared to other ethnicities. This disparity is likely explained by a combination of social, environmental, and genetic factors. A large number of susceptibility loci have been reported by genome-wide association studies (GWAS), but the contribution of these loci to CaP disparities is unclear. Here we investigated the population structure of 68 previously reported GWAS loci and calculated Genetic Disparity Contribution (GDC) statistics to identify SNPs that contribute the most to differences in CaP risk across populations...
February 8, 2018: Cancer Research
https://www.readbyqxmd.com/read/29438990/nuclear-receptor-lrh-1-functions-to-promote-castration-resistant-growth-of-prostate-cancer-via-its-promotion-of-intratumoral-androgen-biosynthesis
#15
Lijia Xiao, Yuliang Wang, Kexin Xu, Hao Hu, Zhenyu Xu, Dinglan Wu, Zhu Wang, Wenxing You, Chi-Fai Ng, Shan Yu, Franky Leung Chan
Targeting of steroidogenic enzymes (e.g. abiraterone acetate targeting CYP17A1) has been developed as a novel therapeutic strategy against metastatic castration-resistant prostate cancer (CRPC). However, resistance to steroidal inhibitors inevitably develops in patients, the mechanisms of which remain largely unknown. Liver receptor homolog-1 (LRH-1, NR5A2) is a nuclear receptor, originally characterized as an important regulator of some liver-specific metabolic genes. Here we report that LRH-1, which exhibited an increased expression pattern in high-grade prostate cancer and CRPC xenograft models, functions to promote de novo androgen biosynthesis via its direct transactivation of several key steroidogenic enzyme genes, elevating intratumoral androgen levels and reactivating AR signaling in CRPC xenografts as well as abiraterone-treated CRPC tumors...
February 8, 2018: Cancer Research
https://www.readbyqxmd.com/read/29438989/mitotic-phosphorylation-of-senp3-regulates-de-sumoylation-of-chromosome-associated-proteins-and-chromosome-stability
#16
Bo Wei, Chao Huang, Bin Liu, Yang Wang, Nansong Xia, Qiuju Fan, Guo-Qiang Chen, Jinke Cheng
Progression of mitotic cell cycle as well as chromosome condensation and segregation are controlled by posttranslational protein modifications such as phosphorylation and SUMOylation. However, how SUMO isopeptidases (SENP) regulate cell mitotic procession is largely unknown. Here we demonstrate that precise phosphorylation of SENP3 during mitosis suppresses SENP3 de-SUMOylation activity towards chromosome-associated proteins including Topoisomerase IIα (Topo IIα). Cyclin B-dependent kinases 1 (CDK1) and protein phosphatase 1α (PP1α) were identified as the kinase and phosphatase in control of mitotic SENP3 phosphorylation, respectively...
February 8, 2018: Cancer Research
https://www.readbyqxmd.com/read/29436427/pyruvate-dehydrogenase-pdh-e1%C3%AE-controls-tumor-progression-by-altering-the-metabolic-status-of-cancer-cells
#17
Ryo Yonashiro, Kayoko Eguchi, Masaki Wake, Norihiko Takeda, Koh Nakayama
Downregulation of pyruvate dehydrogenase (PDH) is critical for the aberrant preferential activation of glycolysis in cancer cells under normoxic conditions. Phosphorylation-dependent inhibition of PDH is a relevant event in this process, but it is not durable since it relies on PDH kinases which are activated ordinarily under hypoxic conditions. Thus, it remains unclear how PDH is durably downregulated in cancer cells that are not hypoxic. Building on evidence that PDH activity depends on the stability of a multi-protein PDH complex, we found that the PDH-E1β subunit of the PDH complex is downregulated to inhibit PDH activity under conditions of prolonged hypoxia...
February 7, 2018: Cancer Research
https://www.readbyqxmd.com/read/29437708/expression-of-adipocyte-macrophage-fatty-acid-binding-protein-in-tumor-associated-macrophages-promotes-breast-cancer-progression
#18
Jiaqing Hao, Fei Yan, Yuwen Zhang, Ashley Triplett, Ying Zhang, Debra A Schultz, Yanwen Sun, Jun Zeng, Kevin A T Silverstein, Qi Zheng, David A Bernlohr, Margot P Cleary, Nejat K Egilmez, Edward Sauter, Shujun Liu, Jill Suttles, Bing Li
Tumor associated macrophages (TAM) play a critical role in cancer development and progression. However, the heterogeneity of TAM presents a major challenge to identify clinically-relevant markers for pro-tumor TAM. Here, we report that expression of adipocyte/macrophage fatty acid binding protein (A-FABP) in TAM promotes breast cancer progression. While upregulation of A-FABP was inversely associated with breast cancer survival, deficiency of A-FABP significantly reduced mammary tumor growth and metastasis...
February 6, 2018: Cancer Research
https://www.readbyqxmd.com/read/29437707/proteolytic-release-of-the-p75ntr-intracellular-domain-by-adam10-promotes-metastasis-and-resistance-to-anoikis
#19
Xin Bao, Jianbo Shi, Furong Xie, Zengying Liu, Jingshuang Yu, Wan-Tao Chen, Zhiyuan Zhang, Qin Xu
Resistance to anoikis allows cancer cells to survive during systemic circulation, however, the mechanism underlying anoikis resistance remains unclear. Here we show that A disintegrin and metalloprotease 10 (ADAM10)-mediated cleavage of p75 neurotrophin receptor (p75NTR) and subsequent generation of the p75NTR intracellular domain (ICD) endows cancer cells with resistance to anoikis. p75NTR ICD promoted expression of TNF receptor associated factor 6 (TRAF6), a critical intermediary in p75NTR ICD-mediated signal transduction, at the translational level...
February 6, 2018: Cancer Research
https://www.readbyqxmd.com/read/29437706/targeting-cyclin-d-cdk4-6-sensitizes-immune-refractory-cancer-by-blocking-the-scp3-nanog-axis
#20
Se Jin Oh, Hanbyoul Cho, Suhyun Kim, Kyung Hee Noh, Kwon-Ho Song, Hyo-Jung Lee, Seon Rang Woo, Suyeon Kim, Chel Hun Choi, Joon-Yong Chung, Stephen M Hewitt, Jae-Hoon Kim, Seungki Baek, Kyung-Mi Lee, Cassian Yee, Hae-Chul Park, Tae Woo Kim
Immune editing caused by anti-tumor immunity drives tumor cells to acquire refractory phenotypes. We demonstrated previously that tumor antigen-specific T cells edit these cells such that they become resistant to CTL killing and enrich NANOGhigh cancer stem cell-like (CSC-like) cells. In the current study, we show that synaptonemal complex protein 3 (SCP3), a member of the Cor1 family, is overexpressed in immune-edited cells and upregulates NANOG by hyperactivating the Cyclin D1-CDK4/6 axis. The SCP3-Cyclin D1-CDK4/6 axis was preserved across various types of human cancer, and correlated negatively with progression-free survival of cervical cancer patients...
February 6, 2018: Cancer Research
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