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Cancer Cell

Olivier Meurette, Patrick Mehlen
The Notch signaling pathway regulates many aspects of cancer biology. Most attention has been given to its role in the transformed cell. However, it is now clear that cancer progression and metastasis depend on the bidirectional interactions between cancer cells and their environment, forming the tumor microenvironment (TME). These interactions are mediated and constantly evolve through paracrine and juxtacrine signaling. In this review, we discuss how Notch signaling takes an important part in regulating the crosstalk between the different compartments of the TME...
August 14, 2018: Cancer Cell
Niraj Shenoy, Edward Creagan, Thomas Witzig, Mark Levine
Vitamin C (ascorbic acid, ascorbate), despite controversy, has re-emerged as a promising anti-cancer agent. Recent knowledge of intravenous ascorbate pharmacokinetics and discovery of unexpected mechanisms of ascorbate action have spawned many investigations. Two mechanisms of anti-cancer activity with ascorbate have gained prominence: hydrogen peroxide-induced oxidative stress and DNA demethylation mediated by ten-eleven translocation enzyme activation. Here, we highlight salient aspects of the evolution of ascorbate in cancer treatment, provide insights into the pharmacokinetics of ascorbate, describe mechanisms of its anti-cancer activity in relation to the pharmacokinetics, outline promising preclinical and clinical evidence, and recommend future directions...
August 13, 2018: Cancer Cell
Claire Vanpouille-Box, Sandra Demaria, Silvia C Formenti, Lorenzo Galluzzi
Besides constituting a first layer of defense against microbial challenges, the detection of cytosolic DNA is fundamental for mammalian organisms to control malignant transformation and tumor progression. The accumulation of DNA in the cytoplasm can initiate the proliferative inactivation (via cellular senescence) or elimination (via regulated cell death) of neoplastic cell precursors. Moreover, cytosolic DNA sensing is intimately connected to the secretion of cytokines that support innate and adaptive antitumor immunity...
September 10, 2018: Cancer Cell
Andrew Mancini, Ana Xavier-Magalhães, Wendy S Woods, Kien-Thiet Nguyen, Alexandra M Amen, Josie L Hayes, Christof Fellmann, Michael Gapinske, Andrew M McKinney, Chibo Hong, Lindsey E Jones, Kyle M Walsh, Robert J A Bell, Jennifer A Doudna, Bruno M Costa, Jun S Song, Pablo Perez-Pinera, Joseph F Costello
TERT promoter mutations reactivate telomerase, allowing for indefinite telomere maintenance and enabling cellular immortalization. These mutations specifically recruit the multimeric ETS factor GABP, which can form two functionally independent transcription factor species: a dimer or a tetramer. We show that genetic disruption of GABPβ1L (β1L), a tetramer-forming isoform of GABP that is dispensable for normal development, results in TERT silencing in a TERT promoter mutation-dependent manner. Reducing TERT expression by disrupting β1L culminates in telomere loss and cell death exclusively in TERT promoter mutant cells...
September 10, 2018: Cancer Cell
Lorenzo Brunetti, Michael C Gundry, Daniele Sorcini, Anna G Guzman, Yung-Hsin Huang, Raghav Ramabadran, Ilaria Gionfriddo, Federica Mezzasoma, Francesca Milano, Behnam Nabet, Dennis L Buckley, Steven M Kornblau, Charles Y Lin, Paolo Sportoletti, Maria Paola Martelli, Brunangelo Falini, Margaret A Goodell
NPM1 is the most frequently mutated gene in cytogenetically normal acute myeloid leukemia (AML). In AML cells, NPM1 mutations result in abnormal cytoplasmic localization of the mutant protein (NPM1c); however, it is unknown whether NPM1c is required to maintain the leukemic state. Here, we show that loss of NPM1c from the cytoplasm, either through nuclear relocalization or targeted degradation, results in immediate downregulation of homeobox (HOX) genes followed by differentiation. Finally, we show that XPO1 inhibition relocalizes NPM1c to the nucleus, promotes differentiation of AML cells, and prolongs survival of Npm1-mutated leukemic mice...
September 10, 2018: Cancer Cell
Allison L Boyd, Lili Aslostovar, Jennifer Reid, Wendy Ye, Borko Tanasijevic, Deanna P Porras, Zoya Shapovalova, Mohammed Almakadi, Ronan Foley, Brian Leber, Anargyros Xenocostas, Mickie Bhatia
Despite successful remission induction, recurrence of acute myeloid leukemia (AML) remains a clinical obstacle thought to be caused by the retention of dormant leukemic stem cells (LSCs). Using chemotherapy-treated AML xenografts and patient samples, we have modeled patient remission and relapse kinetics to reveal that LSCs are effectively depleted via cell-cycle recruitment, leaving the origins of relapse unclear. Post-chemotherapy, in vivo characterization at the onset of disease relapse revealed a unique molecular state of leukemic-regenerating cells (LRCs) responsible for disease re-growth...
September 10, 2018: Cancer Cell
Paola Brescia, Christof Schneider, Antony B Holmes, Qiong Shen, Shafinaz Hussein, Laura Pasqualucci, Katia Basso, Riccardo Dalla-Favera
The gene encoding the MEF2B transcription factor is mutated in germinal center (GC)-derived B cell lymphomas, but its role in GC development and lymphomagenesis is unknown. We demonstrate that Mef2b deletion reduces GC formation in mice and identify MEF2B transcriptional targets in GC, with roles in cell proliferation, apoptosis, GC confinement, and differentiation. The most common lymphoma-associated MEF2B mutant (MEF2BD83V ) is hypomorphic, yet escapes binding and negative regulation by components of the HUCA complex and class IIa HDACs...
September 10, 2018: Cancer Cell
Shunsuke Kitajima, Hajime Asahina, Ting Chen, Sujuan Guo, Laura Gutierrez Quiceno, Jillian D Cavanaugh, Ashley A Merlino, Shoichiro Tange, Hideki Terai, Jong Wook Kim, Xiaoen Wang, Shan Zhou, Man Xu, Stephen Wang, Zehua Zhu, Tran C Thai, Chiaki Takahashi, Yujin Wang, Richard Neve, Susanna Stinson, Pablo Tamayo, Hideo Watanabe, Paul T Kirschmeier, Kwok-Kin Wong, David A Barbie
Despite extensive efforts, oncogenic KRAS remains resistant to targeted therapy. Combined downstream RAL-TBK1 and MEK inhibition induces only transient lung tumor shrinkage in KRAS-driven genetically engineered mouse models (GEMMs). Using the sensitive KRAS;LKB1 (KL) mutant background, we identify YAP1 upregulation and a therapy-induced secretome as mediators of acquired resistance. This program is reversible, associated with H3K27 promoter acetylation, and suppressed by BET inhibition, resensitizing resistant KL cells to TBK1/MEK inhibition...
September 10, 2018: Cancer Cell
Pedram Razavi, Matthew T Chang, Guotai Xu, Chaitanya Bandlamudi, Dara S Ross, Neil Vasan, Yanyan Cai, Craig M Bielski, Mark T A Donoghue, Philip Jonsson, Alexander Penson, Ronglai Shen, Fresia Pareja, Ritika Kundra, Sumit Middha, Michael L Cheng, Ahmet Zehir, Cyriac Kandoth, Ruchi Patel, Kety Huberman, Lillian M Smyth, Komal Jhaveri, Shanu Modi, Tiffany A Traina, Chau Dang, Wen Zhang, Britta Weigelt, Bob T Li, Marc Ladanyi, David M Hyman, Nikolaus Schultz, Mark E Robson, Clifford Hudis, Edi Brogi, Agnes Viale, Larry Norton, Maura N Dickler, Michael F Berger, Christine A Iacobuzio-Donahue, Sarat Chandarlapaty, Maurizio Scaltriti, Jorge S Reis-Filho, David B Solit, Barry S Taylor, José Baselga
We integrated the genomic sequencing of 1,918 breast cancers, including 1,501 hormone receptor-positive tumors, with detailed clinical information and treatment outcomes. In 692 tumors previously exposed to hormonal therapy, we identified an increased number of alterations in genes involved in the mitogen-activated protein kinase (MAPK) pathway and in the estrogen receptor transcriptional machinery. Activating ERBB2 mutations and NF1 loss-of-function mutations were more than twice as common in endocrine resistant tumors...
September 10, 2018: Cancer Cell
Tenley C Archer, Tobias Ehrenberger, Filip Mundt, Maxwell P Gold, Karsten Krug, Clarence K Mah, Elizabeth L Mahoney, Colin J Daniel, Alexander LeNail, Divya Ramamoorthy, Philipp Mertins, D R Mani, Hailei Zhang, Michael A Gillette, Karl Clauser, Michael Noble, Lauren C Tang, Jessica Pierre-François, Jacob Silterra, James Jensen, Pablo Tamayo, Andrey Korshunov, Stefan M Pfister, Marcel Kool, Paul A Northcott, Rosalie C Sears, Jonathan O Lipton, Steven A Carr, Jill P Mesirov, Scott L Pomeroy, Ernest Fraenkel
There is a pressing need to identify therapeutic targets in tumors with low mutation rates such as the malignant pediatric brain tumor medulloblastoma. To address this challenge, we quantitatively profiled global proteomes and phospho-proteomes of 45 medulloblastoma samples. Integrated analyses revealed that tumors with similar RNA expression vary extensively at the post-transcriptional and post-translational levels. We identified distinct pathways associated with two subsets of SHH tumors, and found post-translational modifications of MYC that are associated with poor outcomes in group 3 tumors...
September 10, 2018: Cancer Cell
Antoine Forget, Loredana Martignetti, Stéphanie Puget, Laurence Calzone, Sebastian Brabetz, Daniel Picard, Arnau Montagud, Stéphane Liva, Alexandre Sta, Florent Dingli, Guillaume Arras, Jaime Rivera, Damarys Loew, Aurore Besnard, Joëlle Lacombe, Mélanie Pagès, Pascale Varlet, Christelle Dufour, Hua Yu, Audrey L Mercier, Emilie Indersie, Anaïs Chivet, Sophie Leboucher, Laura Sieber, Kevin Beccaria, Michael Gombert, Frauke D Meyer, Nan Qin, Jasmin Bartl, Lukas Chavez, Konstantin Okonechnikov, Tanvi Sharma, Venu Thatikonda, Franck Bourdeaut, Celio Pouponnot, Vijay Ramaswamy, Andrey Korshunov, Arndt Borkhardt, Guido Reifenberger, Patrick Poullet, Michael D Taylor, Marcel Kool, Stefan M Pfister, Daisuke Kawauchi, Emmanuel Barillot, Marc Remke, Olivier Ayrault
The current consensus recognizes four main medulloblastoma subgroups (wingless, Sonic hedgehog, group 3 and group 4). While medulloblastoma subgroups have been characterized extensively at the (epi-)genomic and transcriptomic levels, the proteome and phosphoproteome landscape remain to be comprehensively elucidated. Using quantitative (phospho)-proteomics in primary human medulloblastomas, we unravel distinct posttranscriptional regulation leading to highly divergent oncogenic signaling and kinase activity profiles in groups 3 and 4 medulloblastomas...
September 10, 2018: Cancer Cell
Gilbert J Rahme, Elizabeth Gaskell, Bradley E Bernstein
TERT catalyzes telomere maintenance. While silenced in most normal somatic cells, TERT is expressed in cancer, often due to promoter mutations, facilitating replicative immortality. In this issue of Cancer Cell, Mancini et al. demonstrate that GABPβ1L is required for mutant TERT promoter activity, thus identifying a potential therapeutic target.
September 10, 2018: Cancer Cell
Hannah J Uckelmann, Scott A Armstrong, Richard M Stone
In this issue of Cancer Cell, Brunetti and colleagues elucidate the role of mutant NPM1c and its cytoplasmic mislocalization in acute myeloid leukemia. They demonstrate how mutant-specific degradation or relocalization leads to a loss of the stem cell signature characteristic of these leukemias and induces their differentiation.
September 10, 2018: Cancer Cell
Ly P Vu, Michael G Kharas
One of the biggest challenges in treating acute myeloid leukemia (AML) is relapse of aggressive disease after treatment. In this issue of Cancer Cell, Boyd et al. characterize a molecularly distinct population of chemotherapy-induced transient leukemic regenerating cells (LRCs), which can be exploited to prevent AML recurrence.
September 10, 2018: Cancer Cell
Eric P Rahmann, Richard J Gilbertson
Epigenomics and transcriptomics of medulloblastoma-an important childhood brain tumor-segregate the disease into four clinically relevant subtypes. In this issue of Cancer Cell, Archer et al. and Forget et al. add the proteome to our multiomic map of this disease, revealing posttranscriptional and posttranslational variations with potential therapeutic implications.
September 10, 2018: Cancer Cell
Christopher Dravis, Chi-Yeh Chung, Nikki K Lytle, Jaslem Herrera-Valdez, Gidsela Luna, Christy L Trejo, Tannishtha Reya, Geoffrey M Wahl
Cell state reprogramming during tumor progression complicates accurate diagnosis, compromises therapeutic effectiveness, and fuels metastatic dissemination. We used chromatin accessibility assays and transcriptional profiling during mammary development as an agnostic approach to identify factors that mediate cancer cell state interconversions. We show that fetal and adult basal cells share epigenetic features consistent with multi-lineage differentiation potential. We find that DNA-binding motifs for SOX transcription factors are enriched in chromatin that is accessible in stem/progenitor cells and inaccessible in differentiated cells...
September 10, 2018: Cancer Cell
Elizabeth Stewart, Justina McEvoy, Hong Wang, Xiang Chen, Victoria Honnell, Monica Ocarz, Brittney Gordon, Jason Dapper, Kaley Blankenship, Yanling Yang, Yuxin Li, Timothy I Shaw, Ji-Hoon Cho, Xusheng Wang, Beisi Xu, Pankaj Gupta, Yiping Fan, Yu Liu, Michael Rusch, Lyra Griffiths, Jongrye Jeon, Burgess B Freeman, Michael R Clay, Alberto Pappo, John Easton, Sheila Shurtleff, Anang Shelat, Xin Zhou, Kristy Boggs, Heather Mulder, Donald Yergeau, Armita Bahrami, Elaine R Mardis, Richard K Wilson, Jinghui Zhang, Junmin Peng, James R Downing, Michael A Dyer
Personalized cancer therapy targeting somatic mutations in patient tumors is increasingly being incorporated into practice. Other therapeutic vulnerabilities resulting from changes in gene expression due to tumor specific epigenetic perturbations are progressively being recognized. These genomic and epigenomic changes are ultimately manifest in the tumor proteome and phosphoproteome. We integrated transcriptomic, epigenomic, and proteomic/phosphoproteomic data to elucidate the cellular origins and therapeutic vulnerabilities of rhabdomyosarcoma (RMS)...
September 10, 2018: Cancer Cell
Carolyn Hurst, Jonathan Rosenberg, Margaret Knowles
Bladder cancers, the majority of which are urothelial carcinoma, are the most common urinary tract cancers. There are two major disease types, muscle-invasive and non-muscle-invasive, with distinct pathogenesis pathways, molecular features, and clinical outcomes. Recent genomic and transcriptomic data have significantly improved tumor sub-classification and prognostication for both patient groups and are informing improved approaches to treatment of muscle-invasive disease. To view this SnapShot, open or download the PDF...
August 13, 2018: Cancer Cell
Ana Banito, Xiang Li, Aimée N Laporte, Jae-Seok Roe, Francisco Sanchez-Vega, Chun-Hao Huang, Amanda R Dancsok, Katerina Hatzi, Chi-Chao Chen, Darjus F Tschaharganeh, Rohit Chandwani, Nilgun Tasdemir, Kevin B Jones, Mario R Capecchi, Christopher R Vakoc, Nikolaus Schultz, Marc Ladanyi, Torsten O Nielsen, Scott W Lowe
No abstract text is available yet for this article.
August 13, 2018: Cancer Cell
Gururaj Shivange, Karol Urbanek, Piotr Przanowski, Justin S A Perry, James Jones, Robert Haggart, Christina Kostka, Tejal Patki, Edward Stelow, Yuliya Petrova, Danielle Llaneza, Marty Mayo, Kodi S Ravichandran, Charles N Landen, Sanchita Bhatnagar, Jogender Tushir-Singh
Therapeutic antibodies targeting ovarian cancer (OvCa)-enriched receptors have largely been disappointing due to limited tumor-specific antibody-dependent cellular cytotoxicity. Here we report a symbiotic approach that is highly selective and superior compared with investigational clinical antibodies. This bispecific-anchored cytotoxicity activator antibody is rationally designed to instigate "cis" and "trans" cytotoxicity by combining specificities against folate receptor alpha-1 (FOLR1) and death receptor 5 (DR5)...
August 13, 2018: Cancer Cell
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