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Cancer Cell

Lin Shan, Xing Zhou, Xinhua Liu, Yue Wang, Dongxue Su, Yongqiang Hou, Na Yu, Chao Yang, Beibei Liu, Jie Gao, Yang Duan, Jianguo Yang, Wanjin Li, Jing Liang, Luyang Sun, Kexin Chen, Chenghao Xuan, Lei Shi, Yan Wang, Yongfeng Shang
Although clinically associated with severe developmental defects, the biological function of FOXK2 remains poorly explored. Here we report that FOXK2 interacts with transcription corepressor complexes NCoR/SMRT, SIN3A, NuRD, and REST/CoREST to repress a cohort of genes including HIF1β and EZH2 and to regulate several signaling pathways including the hypoxic response. We show that FOXK2 inhibits the proliferation and invasion of breast cancer cells and suppresses the growth and metastasis of breast cancer. Interestingly, FOXK2 is transactivated by ERα and transrepressed via reciprocal successive feedback by HIF1β/EZH2...
October 14, 2016: Cancer Cell
Genaro R Villa, Jonathan J Hulce, Ciro Zanca, Junfeng Bi, Shiro Ikegami, Gabrielle L Cahill, Yuchao Gu, Kenneth M Lum, Kenta Masui, Huijun Yang, Xin Rong, Cynthia Hong, Kristen M Turner, Feng Liu, Gary C Hon, David Jenkins, Michael Martini, Aaron M Armando, Oswald Quehenberger, Timothy F Cloughesy, Frank B Furnari, Webster K Cavenee, Peter Tontonoz, Timothy C Gahman, Andrew K Shiau, Benjamin F Cravatt, Paul S Mischel
Small-molecule inhibitors targeting growth factor receptors have failed to show efficacy for brain cancers, potentially due to their inability to achieve sufficient drug levels in the CNS. Targeting non-oncogene tumor co-dependencies provides an alternative approach, particularly if drugs with high brain penetration can be identified. Here we demonstrate that the highly lethal brain cancer glioblastoma (GBM) is remarkably dependent on cholesterol for survival, rendering these tumors sensitive to Liver X receptor (LXR) agonist-dependent cell death...
October 13, 2016: Cancer Cell
Wen-Lian Chen, Yue-Ying Wang, Aihua Zhao, Li Xia, Guoxiang Xie, Mingming Su, Linjing Zhao, Jiajian Liu, Chun Qu, Runmin Wei, Cynthia Rajani, Yan Ni, Zhen Cheng, Zhu Chen, Sai-Juan Chen, Wei Jia
Rapidly proliferating leukemic progenitor cells consume substantial glucose, which may lead to glucose insufficiency in bone marrow. We show that acute myeloid leukemia (AML) cells are prone to fructose utilization with an upregulated fructose transporter GLUT5, which compensates for glucose deficiency. Notably, AML patients with upregulated transcription of the GLUT5-encoding gene SLC2A5 or increased fructose utilization have poor outcomes. Pharmacological blockage of fructose uptake ameliorates leukemic phenotypes and potentiates the cytotoxicity of the antileukemic agent, Ara-C...
September 28, 2016: Cancer Cell
Ilaria Marigo, Serena Zilio, Giacomo Desantis, Bernhard Mlecnik, Andrielly H R Agnellini, Stefano Ugel, Maria Stella Sasso, Joseph E Qualls, Franz Kratochvill, Paola Zanovello, Barbara Molon, Carola H Ries, Valeria Runza, Sabine Hoves, Amélie M Bilocq, Gabriela Bindea, Emilia M C Mazza, Silvio Bicciato, Jérôme Galon, Peter J Murray, Vincenzo Bronte
No abstract text is available yet for this article.
October 10, 2016: Cancer Cell
Nidal E Muvarak, Khadiza Chowdhury, Limin Xia, Carine Robert, Eun Yong Choi, Yi Cai, Marina Bellani, Ying Zou, Zeba N Singh, Vu H Duong, Tyler Rutherford, Pratik Nagaria, Søren M Bentzen, Michael M Seidman, Maria R Baer, Rena G Lapidus, Stephen B Baylin, Feyruz V Rassool
Poly (ADP-ribose) polymerase inhibitors (PARPis) are clinically effective predominantly for BRCA-mutant tumors. We introduce a mechanism-based strategy to enhance PARPi efficacy based on DNA damage-related binding between DNA methyltransferases (DNMTs) and PARP1. In acute myeloid leukemia (AML) and breast cancer cells, DNMT inhibitors (DNMTis) alone covalently bind DNMTs into DNA and increase PARP1 tightly bound into chromatin. Low doses of DNMTis plus PARPis, versus each drug alone, increase PARPi efficacy, increasing amplitude and retention of PARP1 directly at laser-induced DNA damage sites...
October 10, 2016: Cancer Cell
Phuong-Hien Nguyen, Oleg Fedorchenko, Natascha Rosen, Maximilian Koch, Romy Barthel, Tomasz Winarski, Alexandra Florin, F Thomas Wunderlich, Nina Reinart, Michael Hallek
Survival of chronic lymphocytic leukemia (CLL) cells strictly depends on the support of an appropriate tumor microenvironment. Here, we demonstrate that LYN kinase is essential for CLL progression. Lyn deficiency results in a significantly reduced CLL burden in vivo. Loss of Lyn within leukemic cells reduces B cell receptor (BCR) signaling including BTK phosphorylation, but surprisingly does not affect leukemic cell expansion. Instead, syngeneic CLL transplantation of CLL cells into Lyn- or Btk-deficient recipients results in a strongly delayed leukemic progression and prolonged survival...
October 10, 2016: Cancer Cell
Angeles Duran, Eloy D Hernandez, Miguel Reina-Campos, Elias A Castilla, Shankar Subramaniam, Sindhu Raghunandan, Lewis R Roberts, Tatiana Kisseleva, Michael Karin, Maria T Diaz-Meco, Jorge Moscat
Hepatic stellate cells (HSCs) play critical roles in liver fibrosis and hepatocellular carcinoma (HCC). Vitamin D receptor (VDR) activation in HSCs inhibits liver inflammation and fibrosis. We found that p62/SQSTM1, a protein upregulated in liver parenchymal cells but downregulated in HCC-associated HSCs, negatively controls HSC activation. Total body or HSC-specific p62 ablation potentiates HSCs and enhances inflammation, fibrosis, and HCC progression. p62 directly interacts with VDR and RXR promoting their heterodimerization, which is critical for VDR:RXR target gene recruitment...
October 10, 2016: Cancer Cell
Etienne Dardenne, Himisha Beltran, Matteo Benelli, Kaitlyn Gayvert, Adeline Berger, Loredana Puca, Joanna Cyrta, Andrea Sboner, Zohal Noorzad, Theresa MacDonald, Cynthia Cheung, Ka Shing Yuen, Dong Gao, Yu Chen, Martin Eilers, Juan-Miguel Mosquera, Brian D Robinson, Olivier Elemento, Mark A Rubin, Francesca Demichelis, David S Rickman
The transition from castration-resistant prostate adenocarcinoma (CRPC) to neuroendocrine prostate cancer (NEPC) has emerged as an important mechanism of treatment resistance. NEPC is associated with overexpression and gene amplification of MYCN (encoding N-Myc). N-Myc is an established oncogene in several rare pediatric tumors, but its role in prostate cancer progression is not well established. Integrating a genetically engineered mouse model and human prostate cancer transcriptome data, we show that N-Myc overexpression leads to the development of poorly differentiated, invasive prostate cancer that is molecularly similar to human NEPC...
October 10, 2016: Cancer Cell
Tobias Eggert, Katharina Wolter, Juling Ji, Chi Ma, Tetyana Yevsa, Sabrina Klotz, José Medina-Echeverz, Thomas Longerich, Marshonna Forgues, Florian Reisinger, Mathias Heikenwalder, Xin Wei Wang, Lars Zender, Tim F Greten
Oncogene-induced senescence causes hepatocytes to secrete cytokines, which induce their immune-mediated clearance to prevent tumor initiation, a process termed "senescence surveillance." However, senescent hepatocytes give rise to hepatocellular carcinomas (HCCs), if the senescence program is bypassed or if senescent cells are not cleared. Here, we show context-specific roles for CCR2(+) myeloid cells in liver cancer. Senescence surveillance requires the recruitment and maturation of CCR2(+) myeloid cells, and CCR2 ablation caused outgrowth of HCC...
October 10, 2016: Cancer Cell
Giustina Ferone, Ji-Ying Song, Kate D Sutherland, Rajith Bhaskaran, Kim Monkhorst, Jan-Paul Lambooij, Natalie Proost, Gaetano Gargiulo, Anton Berns
Lung squamous cell carcinoma (LSCC) is a devastating malignancy with no effective treatments, due to its complex genomic profile. Therefore, preclinical models mimicking its salient features are urgently needed. Here we describe mouse models bearing various combinations of genetic lesions predominantly found in human LSCC. We show that SOX2 but not FGFR1 overexpression in tracheobronchial basal cells combined with Cdkn2ab and Pten loss results in LSCC closely resembling the human counterpart. Interestingly, Sox2;Pten;Cdkn2ab mice develop LSCC with a more peripheral location when Club or Alveolar type 2 (AT2) cells are targeted...
October 10, 2016: Cancer Cell
Christopher J Ricketts, Daniel R Crooks, W Marston Linehan
In two recent studies, the HIF2α antagonist, PT2399, decreased HIF2α-dependent transcription and tumor growth in selected VHL-deficient clear-cell renal cell carcinoma (ccRCC) models. These studies validate HIF2α as a therapeutic target in ccRCC, reveal variable sensitivity to HIF2α antagonism, and provide the foundation for predictive biomarker-driven clinical trials.
October 10, 2016: Cancer Cell
Stephen Bohlman, James J Manfredi
In this issue of Cancer Cell, Gu et al. characterize small molecules that inhibit the interaction of Mdm2 with the mRNA that encodes the anti-apoptotic XIAP, simultaneously decreasing expression of both proteins. This represents a novel approach that has relevance in tumor cells independent of p53 status.
October 10, 2016: Cancer Cell
Shuai Dong, John C Byrd
The role of Lyn, both a positive and a negative regulator of B and myeloid cells, in chronic lymphocytic leukemia (CLL) has not been well characterized. In this issue of Cancer Cell, Nguyen et al. demonstrated that Lyn in macrophages rather than in CLL cells is critical for the malignancy.
October 10, 2016: Cancer Cell
Zexi Hu, Lars Zender
The multidomain adaptor protein p62 has been suggested to exert pro-oncogenic functions in hepatocytes and other epithelial cells. In this issue of Cancer Cell, Duran et al. show that p62 acts as a non-cell-autonomous tumor suppressor in liver cancer by counteracting the activation of hepatic stellate cells.
October 10, 2016: Cancer Cell
Susana Llanos, Manuel Serrano
Senescent cells and cancer cells recruit immunosuppressive myeloid cells. In this issue of Cancer Cell, Eggert et al. report that senescent cells recruit immature myeloid cells (iMCs) through the secretion of the CCL2 cytokine and that these iMCs have pro- or anti-tumorigenic activities, depending on the cellular context.
October 10, 2016: Cancer Cell
Nicole R Murray, Verline Justilien, Alan P Fields
In this issue of Cancer Cell, Ferone et al. demonstrate that SOX2 not only drives lung tumor formation but also restricts tumor lineage to squamous cell carcinoma (LSCC), regardless of cell of origin. This novel LSCC model should facilitate identification of key oncogenic drivers and treatment strategies for this lung cancer subtype.
October 10, 2016: Cancer Cell
Chiara Bardella, Osama Al-Dalahmah, Daniel Krell, Pijus Brazauskas, Khalid Al-Qahtani, Marketa Tomkova, Julie Adam, Sébastien Serres, Helen Lockstone, Luke Freeman-Mills, Inga Pfeffer, Nicola Sibson, Robert Goldin, Benjamin Schuster-Böeckler, Patrick J Pollard, Tomoyoshi Soga, James S McCullagh, Christopher J Schofield, Paul Mulholland, Olaf Ansorge, Skirmantas Kriaucionis, Peter J Ratcliffe, Francis G Szele, Ian Tomlinson
Isocitrate dehydrogenase 1 mutations drive human gliomagenesis, probably through neomorphic enzyme activity that produces D-2-hydroxyglutarate. To model this disease, we conditionally expressed Idh1(R132H) in the subventricular zone (SVZ) of the adult mouse brain. The mice developed hydrocephalus and grossly dilated lateral ventricles, with accumulation of 2-hydroxyglutarate and reduced α-ketoglutarate. Stem and transit amplifying/progenitor cell populations were expanded, and proliferation increased. Cells expressing SVZ markers infiltrated surrounding brain regions...
October 10, 2016: Cancer Cell
Elisa Matas-Rico, Michiel van Veen, Daniela Leyton-Puig, Jeroen van den Berg, Jan Koster, Katarzyna M Kedziora, Bas Molenaar, Marjolein J A Weerts, Iris de Rink, René H Medema, Ben N G Giepmans, Anastassis Perrakis, Kees Jalink, Rogier Versteeg, Wouter H Moolenaar
Neuroblastoma is a pediatric embryonal malignancy characterized by impaired neuronal differentiation. A better understanding of neuroblastoma differentiation is essential for developing new therapeutic approaches. GDE2 (encoded by GDPD5) is a six-transmembrane-domain glycerophosphodiesterase that promotes embryonic neurogenesis. We find that high GDPD5 expression is strongly associated with favorable outcome in neuroblastoma. GDE2 induces differentiation of neuroblastoma cells, suppresses cell motility, and opposes RhoA-driven neurite retraction...
October 10, 2016: Cancer Cell
Lubing Gu, Hailong Zhang, Tao Liu, Sheng Zhou, Yuhong Du, Jing Xiong, Sha Yi, Cheng-Kui Qu, Haian Fu, Muxiang Zhou
MDM2 and XIAP are mutually regulated. Binding of MDM2 RING protein to the IRES region on XIAP mRNA results in MDM2 protein stabilization and enhanced XIAP translation. In this study, we developed a protein-RNA fluorescence polarization (FP) assay for high-throughput screening (HTS) of chemical libraries. Our FP-HTS identified eight inhibitors that blocked the MDM2 protein-XIAP RNA interaction, leading to MDM2 degradation. The compound-induced MDM2 downregulation resulted not only in inhibition of XIAP expression, but also in activation of p53, which contributed to cancer cell apoptosis in vitro and inhibition of cancer cell proliferation in vivo...
October 10, 2016: Cancer Cell
Zoi Karoulia, Yang Wu, Tamer A Ahmed, Qisheng Xin, Julien Bollard, Clemens Krepler, Xuewei Wu, Chao Zhang, Gideon Bollag, Meenhard Herlyn, James A Fagin, Amaia Lujambio, Evripidis Gavathiotis, Poulikos I Poulikakos
No abstract text is available yet for this article.
September 12, 2016: Cancer Cell
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