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Cancer Cell

Sarah M Greenblatt, Na Man, Pierre-Jacques Hamard, Takashi Asai, Daniel Karl, Concepcion Martinez, Daniel Bilbao, Vasileios Stathias, Anna McGrew-Jermacowicz, Stephanie Duffort, Madhavi Tadi, Ezra Blumenthal, Samantha Newman, Ly Vu, Ye Xu, Fan Liu, Stephan C Schurer, Michael T McCabe, Ryan G Kruger, Mingjiang Xu, Feng-Chun Yang, Daniel Tenen, Justin Watts, Francisco Vega, Stephen D Nimer
No abstract text is available yet for this article.
November 12, 2018: Cancer Cell
Bernhard W Renz, Ryota Takahashi, Takayuki Tanaka, Marina Macchini, Yoku Hayakawa, Zahra Dantes, H Carlo Maurer, Xiaowei Chen, Zhengyu Jiang, C Benedikt Westphalen, Matthias Ilmer, Giovanni Valenti, Sarajo K Mohanta, Andreas J R Habenicht, Moritz Middelhoff, Timothy Chu, Karan Nagar, Yagnesh Tailor, Riccardo Casadei, Mariacristina Di Marco, Axel Kleespies, Richard A Friedman, Helen Remotti, Maximilian Reichert, Daniel L Worthley, Jens Neumann, Jens Werner, Alina C Iuga, Kenneth P Olive, Timothy C Wang
No abstract text is available yet for this article.
November 12, 2018: Cancer Cell
Hai Wang, Lin Tian, Jun Liu, Amit Goldstein, Igor Bado, Weijie Zhang, Benjamin R Arenkiel, Zonghai Li, Meng Yang, Shiyu Du, Hong Zhao, David R Rowley, Stephen T C Wong, Zbigniew Gugala, Xiang H-F Zhang
The fate of disseminated tumor cells is largely determined by microenvironment (ME) niche. The osteogenic niche promotes cancer cell proliferation and bone metastasis progression. We investigated the underlying mechanisms using pre-clinical models and analyses of clinical data. We discovered that the osteogenic niche serves as a calcium (Ca) reservoir for cancer cells through gap junctions. Cancer cells cannot efficiently absorb Ca from ME, but depend on osteogenic cells to increase intracellular Ca concentration...
November 12, 2018: Cancer Cell
Angelina V Vaseva, Devon R Blake, Thomas S K Gilbert, Serina Ng, Galen Hostetter, Salma H Azam, Irem Ozkan-Dagliyan, Prson Gautam, Kirsten L Bryant, Kenneth H Pearce, Laura E Herring, Haiyong Han, Lee M Graves, Agnieszka K Witkiewicz, Erik S Knudsen, Chad V Pecot, Naim Rashid, Peter J Houghton, Krister Wennerberg, Adrienne D Cox, Channing J Der
Our recent ERK1/2 inhibitor analyses in pancreatic ductal adenocarcinoma (PDAC) indicated ERK1/2-independent mechanisms maintaining MYC protein stability. To identify these mechanisms, we determined the signaling networks by which mutant KRAS regulates MYC. Acute KRAS suppression caused rapid proteasome-dependent loss of MYC protein, through both ERK1/2-dependent and -independent mechanisms. Surprisingly, MYC degradation was independent of PI3K-AKT-GSK3β signaling and the E3 ligase FBWX7. We then established and applied a high-throughput screen for MYC protein degradation and performed a kinome-wide proteomics screen...
November 12, 2018: Cancer Cell
Aung Naing, Jeffrey R Infante, Kyriakos P Papadopoulos, Ivan H Chan, Cong Shen, Navneet P Ratti, Bianca Rojo, Karen A Autio, Deborah J Wong, Manish R Patel, Patrick A Ott, Gerald S Falchook, Shubham Pant, Annie Hung, Kara L Pekarek, Victoria Wu, Matthew Adamow, Scott McCauley, John B Mumm, Phillip Wong, Peter Van Vlasselaer, Joseph Leveque, Nizar M Tannir, Martin Oft
Tumor-reactive T cell exhaustion prevents the success of immune therapies. Pegilodecakin activates intratumoral CD8+ T cells in mice and induces objective tumor responses in patients. Here we report that pegilodecakin induces hallmarks of CD8+ T cell immunity in cancer patients, including elevation of interferon-γ and GranzymeB, expansion and activation of intratumoral CD8+ T cells, and proliferation and expansion of LAG-3+ PD-1+ CD8+ T cells. On pegilodecakin, newly expanded T cell clones, undetectable at baseline, become 1%-10% of the total T cell repertoire in the blood...
November 12, 2018: Cancer Cell
Wei Wang, Jill M Marinis, Allison M Beal, Shivraj Savadkar, Yue Wu, Mohammed Khan, Pardeep S Taunk, Nan Wu, Wenyu Su, Jingjing Wu, Aarif Ahsan, Emma Kurz, Ting Chen, Inedouye Yaboh, Fei Li, Johana Gutierrez, Brian Diskin, Mautin Hundeyin, Michael Reilly, John D Lich, Philip A Harris, Mukesh K Mahajan, James H Thorpe, Pamela Nassau, Julie E Mosley, Joshua Leinwand, Juan A Kochen Rossi, Ankita Mishra, Berk Aykut, Michael Glacken, Atsuo Ochi, Narendra Verma, Jacqueline I Kim, Varshini Vasudevaraja, Dennis Adeegbe, Christina Almonte, Ece Bagdatlioglu, Deirdre J Cohen, Kwok-Kin Wong, John Bertin, George Miller
Pancreatic ductal adenocarcinoma (PDA) is characterized by immune tolerance and immunotherapeutic resistance. We discovered upregulation of receptor-interacting serine/threonine protein kinase 1 (RIP1) in tumor-associated macrophages (TAMs) in PDA. To study its role in oncogenic progression, we developed a selective small-molecule RIP1 inhibitor with high in vivo exposure. Targeting RIP1 reprogrammed TAMs toward an MHCIIhi TNFα+ IFNγ+ immunogenic phenotype in a STAT1-dependent manner. RIP1 inhibition in TAMs resulted in cytotoxic T cell activation and T helper cell differentiation toward a mixed Th1/Th17 phenotype, leading to tumor immunity in mice and in organotypic models of human PDA...
November 12, 2018: Cancer Cell
Hamza Celik, Won Kyun Koh, Ashley C Kramer, Elizabeth L Ostrander, Cates Mallaney, Daniel A C Fisher, Jingyu Xiang, William C Wilson, Andrew Martens, Alok Kothari, Gregory Fishberger, Eric Tycksen, Darja Karpova, Eric J Duncavage, Youngsook Lee, Stephen T Oh, Grant A Challen
How specific genetic lesions contribute to transformation of non-malignant myeloproliferative neoplasms (MPNs) and myelodysplastic syndromes (MDSs) to secondary acute myeloid leukemia (sAML) are poorly understood. JARID2 is lost by chromosomal deletions in a proportion of MPN/MDS cases that progress to sAML. In this study, genetic mouse models and patient-derived xenografts demonstrated that JARID2 acts as a tumor suppressor in chronic myeloid disorders. Genetic deletion of Jarid2 either reduced overall survival of animals with MPNs or drove transformation to sAML, depending on the timing and context of co-operating mutations...
November 12, 2018: Cancer Cell
Courtney L Jones, Brett M Stevens, Angelo D'Alessandro, Julie A Reisz, Rachel Culp-Hill, Travis Nemkov, Shanshan Pei, Nabilah Khan, Biniam Adane, Haobin Ye, Anna Krug, Dominik Reinhold, Clayton Smith, James DeGregori, Daniel A Pollyea, Craig T Jordan
In this study we interrogated the metabolome of human acute myeloid leukemia (AML) stem cells to elucidate properties relevant to therapeutic intervention. We demonstrate that amino acid uptake, steady-state levels, and catabolism are all elevated in the leukemia stem cell (LSC) population. Furthermore, LSCs isolated from de novo AML patients are uniquely reliant on amino acid metabolism for oxidative phosphorylation and survival. Pharmacological inhibition of amino acid metabolism reduces oxidative phosphorylation and induces cell death...
November 12, 2018: Cancer Cell
Andrew Volk, Kaiwei Liang, Praveen Suraneni, Xinyu Li, Jianyun Zhao, Marinka Bulic, Stacy Marshall, Kirthi Pulakanti, Sebastien Malinge, Jeffrey Taub, Yubin Ge, Sridhar Rao, Elizabeth Bartom, Ali Shilatifard, John D Crispino
CHAF1B is the p60 subunit of the chromatin assembly factor (CAF1) complex, which is responsible for assembly of histones H3.1/H4 heterodimers at the replication fork during S phase. Here we report that CHAF1B is required for normal hematopoiesis while its overexpression promotes leukemia. CHAF1B has a pro-leukemia effect by binding chromatin at discrete sites and interfering with occupancy of transcription factors that promote myeloid differentiation, such as CEBPA. Reducing Chaf1b activity by either heterozygous deletion or overexpression of a CAF1 dominant negative allele is sufficient to suppress leukemogenesis in vivo without impairing normal hematopoiesis...
November 12, 2018: Cancer Cell
Emily Z Keung, Christina L Roland
In this issue of Cancer Cell, Saudemont et al. describe the real-time ex vivo molecular diagnosis and histologic subtyping of canine soft tissue sarcomas using SpiderMass, a technology using water-assisted laser desorption/ionization mass spectrometry. In the future, SpiderMass has the potential to aid in diagnosis and intraoperative margin assessment.
November 12, 2018: Cancer Cell
Boaz Nachmias, Aaron D Schimmer
In this issue of Cancer Cell, Jones et al. demonstrate that LSCs are metabolically inflexible. LSCs rely on amino acid metabolism to fuel oxidative phosphorylation and cannot compensate with other fuel sources following amino acid depletion. Combined venetoclax and azacitidine reduces amino acid uptake, partly explaining the anti-LSC effects.
November 12, 2018: Cancer Cell
Qing Li, Xu Zhang, Zhiguo Zhang
In this issue of Cancer Cell, Volk et al. report that overexpression of CHAF1B displaces myeloid transcription factors from chromatin, and deletion of CHAF1B promotes differentiation of leukemia cells and suppresses leukemogenesis in a murine model, revealing a causal role of and an unexpected mechanism for CHAF1B overexpression in tumorigenesis.
November 12, 2018: Cancer Cell
Craig M Bielski, Mark T A Donoghue, Mayur Gadiya, Aphrothiti J Hanrahan, Helen H Won, Matthew T Chang, Philip Jonsson, Alexander V Penson, Alexander Gorelick, Christopher Harris, Alison M Schram, Aijazuddin Syed, Ahmet Zehir, Paul B Chapman, David M Hyman, David B Solit, Kevin Shannon, Sarat Chandarlapaty, Michael F Berger, Barry S Taylor
Driver mutations in oncogenes encode proteins with gain-of-function properties that enhance fitness. Heterozygous mutations are thus viewed as sufficient for tumorigenesis. We describe widespread oncogenic mutant allele imbalance in 13,448 prospectively characterized cancers. Imbalance was selected for through modest dosage increases of gain-of-fitness mutations. Negative selection targeted haplo-essential effectors of the spliceosome. Loss of the normal allele comprised a distinct class of imbalance driven by competitive fitness, which correlated with enhanced response to targeted therapies...
November 12, 2018: Cancer Cell
Philippe Saudemont, Jusal Quanico, Yves-Marie Robin, Anna Baud, Julia Balog, Benoit Fatou, Dominique Tierny, Quentin Pascal, Kevin Minier, Mélissa Pottier, Cristian Focsa, Michael Ziskind, Zoltan Takats, Michel Salzet, Isabelle Fournier
Histopathological diagnosis of biopsy samples and margin assessment of surgical specimens are challenging aspects in sarcoma. Using dog patient tissues, we assessed the performance of a recently developed technology for fast ex vivo molecular lipid-based diagnosis of sarcomas. The instrument is based on mass spectrometry (MS) molecular analysis through a laser microprobe operating under ambient conditions using excitation of endogenous water molecules. Classification models based on cancer/normal/necrotic, tumor grade, and subtypes showed a minimum of 97...
November 12, 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...
November 12, 2018: Cancer Cell
Roberta Zappasodi, Sadna Budhu, Matthew D Hellmann, Michael A Postow, Yasin Senbabaoglu, Sasikanth Manne, Billel Gasmi, Cailian Liu, Hong Zhong, Yanyun Li, Alexander C Huang, Daniel Hirschhorn-Cymerman, Katherine S Panageas, E John Wherry, Taha Merghoub, Jedd D Wolchok
No abstract text is available yet for this article.
October 8, 2018: Cancer Cell
Roberta Zappasodi, Taha Merghoub, Jedd D Wolchok
No abstract text is available yet for this article.
October 8, 2018: Cancer Cell
Natalia Martinez-Soria, Lynsey McKenzie, Julia Draper, Anetta Ptasinska, Hasan Issa, Sandeep Potluri, Helen J Blair, Anna Pickin, Asmida Isa, Paulynn Suyin Chin, Ricky Tirtakusuma, Daniel Coleman, Sirintra Nakjang, Salam Assi, Victoria Forster, Mojgan Reza, Ed Law, Philip Berry, Dorothee Mueller, Alex Elder, Simon N Bomken, Deepali Pal, James M Allan, Gareth J Veal, Peter N Cockerill, Christian Wichmann, Josef Vormoor, Georges Lacaud, Constanze Bonifer, Olaf Heidenreich
Oncogenic transcription factors such as the leukemic fusion protein RUNX1/ETO, which drives t(8;21) acute myeloid leukemia (AML), constitute cancer-specific but highly challenging therapeutic targets. We used epigenomic profiling data for an RNAi screen to interrogate the transcriptional network maintaining t(8;21) AML. This strategy identified Cyclin D2 (CCND2) as a crucial transmitter of RUNX1/ETO-driven leukemic propagation. RUNX1/ETO cooperates with AP-1 to drive CCND2 expression. Knockdown or pharmacological inhibition of CCND2 by an approved drug significantly impairs leukemic expansion of patient-derived AML cells and engraftment in immunodeficient murine hosts...
October 8, 2018: Cancer Cell
Ivana Yen, Frances Shanahan, Mark Merchant, Christine Orr, Thomas Hunsaker, Matthew Durk, Hank La, Xiaolin Zhang, Scott E Martin, Eva Lin, John Chan, Yihong Yu, Dhara Amin, Richard M Neve, Amy Gustafson, Avinashnarayan Venkatanarayan, Scott A Foster, Joachim Rudolph, Christiaan Klijn, Shiva Malek
Targeting KRAS mutant tumors through inhibition of individual downstream pathways has had limited clinical success. Here we report that RAF inhibitors exhibit little efficacy in KRAS mutant tumors. In combination drug screens, MEK and PI3K inhibitors synergized with pan-RAF inhibitors through an RAS-GTP-dependent mechanism. Broad cell line profiling with RAF/MEK inhibitor combinations revealed synergistic efficacy in KRAS mutant and wild-type tumors, with KRASG13D mutants exhibiting greater synergy versus KRASG12 mutant tumors...
October 8, 2018: Cancer Cell
Antonia Rotolo, Valentina S Caputo, Monika Holubova, Nicoleta Baxan, Olivier Dubois, Mohammed Suhail Chaudhry, Xiaolin Xiao, Katerina Goudevenou, David S Pitcher, Kyriaki Petevi, Carolina Kachramanoglou, Sandra Iles, Kikkeri Naresh, John Maher, Anastasios Karadimitris
Chimeric antigen receptor anti-CD19 (CAR19)-T cell immunotherapy-induced clinical remissions in CD19+ B cell lymphomas are often short lived. We tested whether CAR19-engineering of the CD1d-restricted invariant natural killer T (iNKT) cells would result in enhanced anti-lymphoma activity. CAR19-iNKT cells co-operatively activated by CD1d- and CAR19-CD19-dependent interactions are more effective than CAR19-T cells against CD1d-expressing lymphomas in vitro and in vivo. The swifter in vivo anti-lymphoma activity of CAR19-iNKT cells and their enhanced ability to eradicate brain lymphomas underpinned an improved tumor-free and overall survival...
October 8, 2018: Cancer Cell
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