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Cancer Cell

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https://www.readbyqxmd.com/read/29706454/a-to-i-rna-editing-contributes-to-proteomic-diversity-in-cancer
#1
Xinxin Peng, Xiaoyan Xu, Yumeng Wang, David H Hawke, Shuangxing Yu, Leng Han, Zhicheng Zhou, Kamalika Mojumdar, Kang Jin Jeong, Marilyne Labrie, Yiu Huen Tsang, Minying Zhang, Yiling Lu, Patrick Hwu, Kenneth L Scott, Han Liang, Gordon B Mills
Adenosine (A) to inosine (I) RNA editing introduces many nucleotide changes in cancer transcriptomes. However, due to the complexity of post-transcriptional regulation, the contribution of RNA editing to proteomic diversity in human cancers remains unclear. Here, we performed an integrated analysis of TCGA genomic data and CPTAC proteomic data. Despite limited site diversity, we demonstrate that A-to-I RNA editing contributes to proteomic diversity in breast cancer through changes in amino acid sequences. We validate the presence of editing events at both RNA and protein levels...
April 23, 2018: Cancer Cell
https://www.readbyqxmd.com/read/29731394/tumor-mutational-burden-and-efficacy-of-nivolumab-monotherapy-and-in-combination-with-ipilimumab-in-small-cell-lung-cancer
#2
Matthew D Hellmann, Margaret K Callahan, Mark M Awad, Emiliano Calvo, Paolo A Ascierto, Akin Atmaca, Naiyer A Rizvi, Fred R Hirsch, Giovanni Selvaggi, Joseph D Szustakowski, Ariella Sasson, Ryan Golhar, Patrik Vitazka, Han Chang, William J Geese, Scott J Antonia
Durable responses and encouraging survival have been demonstrated with immune checkpoint inhibitors in small-cell lung cancer (SCLC), but predictive markers are unknown. We used whole exome sequencing to evaluate the impact of tumor mutational burden on efficacy of nivolumab monotherapy or combined with ipilimumab in patients with SCLC from the nonrandomized or randomized cohorts of CheckMate 032. Patients received nivolumab (3 mg/kg every 2 weeks) or nivolumab plus ipilimumab (1 mg/kg plus 3 mg/kg every 3 weeks for four cycles, followed by nivolumab 3 mg/kg every 2 weeks)...
April 21, 2018: Cancer Cell
https://www.readbyqxmd.com/read/29706455/extrinsic-phagocyte-dependent-sting-signaling-dictates-the-immunogenicity-of-dying-cells
#3
Jeonghyun Ahn, Tianli Xia, Ailem Rabasa Capote, Dillon Betancourt, Glen N Barber
The ability of dying cells to activate antigen-presenting cells (APCs) is carefully controlled to avoid unwarranted inflammatory responses. Here, we show that engulfed cells containing cytosolic double-stranded DNA species (viral or synthetic) or cyclic di-nucleotides (CDNs) are able to stimulate APCs via extrinsic STING (stimulator of interferon genes) signaling, to promote antigen cross-presentation. In the absence of STING agonists, dying cells were ineffectual in the stimulation of APCs in trans. Cytosolic STING activators, including CDNs, constitute cellular danger-associated molecular patterns (DAMPs) only generated by viral infection or following DNA damage events that rendered tumor cells highly immunogenic...
April 17, 2018: Cancer Cell
https://www.readbyqxmd.com/read/29681510/germline-genetic-ikzf1-variation-and-predisposition-to-childhood-acute-lymphoblastic-leukemia
#4
Michelle L Churchman, Maoxiang Qian, Geertruy Te Kronnie, Ranran Zhang, Wenjian Yang, Hui Zhang, Tobia Lana, Paige Tedrick, Rebekah Baskin, Katherine Verbist, Jennifer L Peters, Meenakshi Devidas, Eric Larsen, Ian M Moore, Zhaohui Gu, Chunxu Qu, Hiroki Yoshihara, Shaina N Porter, Shondra M Pruett-Miller, Gang Wu, Elizabeth Raetz, Paul L Martin, W Paul Bowman, Naomi Winick, Elaine Mardis, Robert Fulton, Martin Stanulla, William E Evans, Mary V Relling, Ching-Hon Pui, Stephen P Hunger, Mignon L Loh, Rupert Handgretinger, Kim E Nichols, Jun J Yang, Charles G Mullighan
Somatic genetic alterations of IKZF1, which encodes the lymphoid transcription factor IKAROS, are common in high-risk B-progenitor acute lymphoblastic leukemia (ALL) and are associated with poor prognosis. Such alterations result in the acquisition of stem cell-like features, overexpression of adhesion molecules causing aberrant cell-cell and cell-stroma interaction, and decreased sensitivity to tyrosine kinase inhibitors. Here we report coding germline IKZF1 variation in familial childhood ALL and 0.9% of presumed sporadic B-ALL, identifying 28 unique variants in 45 children...
April 16, 2018: Cancer Cell
https://www.readbyqxmd.com/read/29657128/genomic-features-of-response-to-combination-immunotherapy-in-patients-with-advanced-non-small-cell-lung-cancer
#5
Matthew D Hellmann, Tavi Nathanson, Hira Rizvi, Benjamin C Creelan, Francisco Sanchez-Vega, Arun Ahuja, Ai Ni, Jacki B Novik, Levi M B Mangarin, Mohsen Abu-Akeel, Cailian Liu, Jennifer L Sauter, Natasha Rekhtman, Eliza Chang, Margaret K Callahan, Jamie E Chaft, Martin H Voss, Megan Tenet, Xue-Mei Li, Kelly Covello, Andrea Renninger, Patrik Vitazka, William J Geese, Hossein Borghaei, Charles M Rudin, Scott J Antonia, Charles Swanton, Jeff Hammerbacher, Taha Merghoub, Nicholas McGranahan, Alexandra Snyder, Jedd D Wolchok
Combination immune checkpoint blockade has demonstrated promising benefit in lung cancer, but predictors of response to combination therapy are unknown. Using whole-exome sequencing to examine non-small-cell lung cancer (NSCLC) treated with PD-1 plus CTLA-4 blockade, we found that high tumor mutation burden (TMB) predicted improved objective response, durable benefit, and progression-free survival. TMB was independent of PD-L1 expression and the strongest feature associated with efficacy in multivariable analysis...
April 12, 2018: Cancer Cell
https://www.readbyqxmd.com/read/29731395/cdk4-6-inhibitors-the-mechanism-of-action-may-not-be-as-simple-as-once-thought
#6
REVIEW
Mary E Klein, Marta Kovatcheva, Lara E Davis, William D Tap, Andrew Koff
CDK4/6 inhibitors are among a new generation of therapeutics. Building upon the striking success of the combination of CDK4/6 inhibitors and the hormone receptor antagonist letrozole in breast cancer, many other combinations have recently entered clinical trials in multiple diseases. To achieve maximal benefit with CDK4/6 inhibitors it will be critical to understand the cellular mechanisms by which they act. Here we highlight the mechanisms by which CDK4/6 inhibitors can exert their anti-tumor activities beyond simply enforcing cytostatic growth arrest, and discuss how this knowledge may inform new combinations, improve outcomes, and modify dosing schedules in the future...
April 10, 2018: Cancer Cell
https://www.readbyqxmd.com/read/29681511/a-glial-signature-and-wnt7-signaling-regulate-glioma-vascular-interactions-and-tumor-microenvironment
#7
Amelie Griveau, Giorgio Seano, Samuel J Shelton, Robert Kupp, Arman Jahangiri, Kirsten Obernier, Shanmugarajan Krishnan, Olle R Lindberg, Tracy J Yuen, An-Chi Tien, Jennifer K Sabo, Nancy Wang, Ivy Chen, Jonas Kloepper, Louis Larrouquere, Mitrajit Ghosh, Itay Tirosh, Emmanuelle Huillard, Arturo Alvarez-Buylla, Michael C Oldham, Anders I Persson, William A Weiss, Tracy T Batchelor, Anat Stemmer-Rachamimov, Mario L Suvà, Joanna J Phillips, Manish K Aghi, Shwetal Mehta, Rakesh K Jain, David H Rowitch
Gliomas comprise heterogeneous malignant glial and stromal cells. While blood vessel co-option is a potential mechanism to escape anti-angiogenic therapy, the relevance of glial phenotype in this process is unclear. We show that Olig2+ oligodendrocyte precursor-like glioma cells invade by single-cell vessel co-option and preserve the blood-brain barrier (BBB). Conversely, Olig2-negative glioma cells form dense perivascular collections and promote angiogenesis and BBB breakdown, leading to innate immune cell activation...
April 6, 2018: Cancer Cell
https://www.readbyqxmd.com/read/29731393/nrf2-and-the-hallmarks-of-cancer
#8
REVIEW
Montserrat Rojo de la Vega, Eli Chapman, Donna D Zhang
The transcription factor NRF2 is the master regulator of the cellular antioxidant response. Though recognized originally as a target of chemopreventive compounds that help prevent cancer and other maladies, accumulating evidence has established the NRF2 pathway as a driver of cancer progression, metastasis, and resistance to therapy. Recent studies have identified new functions for NRF2 in the regulation of metabolism and other essential cellular functions, establishing NRF2 as a truly pleiotropic transcription factor...
April 5, 2018: Cancer Cell
https://www.readbyqxmd.com/read/29657129/multi-stage-differentiation-defines-melanoma-subtypes-with-differential-vulnerability-to-drug-induced-iron-dependent-oxidative-stress
#9
Jennifer Tsoi, Lidia Robert, Kim Paraiso, Carlos Galvan, Katherine M Sheu, Johnson Lay, Deborah J L Wong, Mohammad Atefi, Roksana Shirazi, Xiaoyan Wang, Daniel Braas, Catherine S Grasso, Nicolaos Palaskas, Antoni Ribas, Thomas G Graeber
Malignant transformation can result in melanoma cells that resemble different stages of their embryonic development. Our gene expression analysis of human melanoma cell lines and patient tumors revealed that melanoma follows a two-dimensional differentiation trajectory that can be subclassified into four progressive subtypes. This differentiation model is associated with subtype-specific sensitivity to iron-dependent oxidative stress and cell death known as ferroptosis. Receptor tyrosine kinase-mediated resistance to mitogen-activated protein kinase targeted therapies and activation of the inflammatory signaling associated with immune therapy involves transitions along this differentiation trajectory, which lead to increased sensitivity to ferroptosis...
April 3, 2018: Cancer Cell
https://www.readbyqxmd.com/read/29622466/comparative-molecular-analysis-of-gastrointestinal-adenocarcinomas
#10
Yang Liu, Nilay S Sethi, Toshinori Hinoue, Barbara G Schneider, Andrew D Cherniack, Francisco Sanchez-Vega, Jose A Seoane, Farshad Farshidfar, Reanne Bowlby, Mirazul Islam, Jaegil Kim, Walid Chatila, Rehan Akbani, Rupa S Kanchi, Charles S Rabkin, Joseph E Willis, Kenneth K Wang, Shannon J McCall, Lopa Mishra, Akinyemi I Ojesina, Susan Bullman, Chandra Sekhar Pedamallu, Alexander J Lazar, Ryo Sakai, Vésteinn Thorsson, Adam J Bass, Peter W Laird
We analyzed 921 adenocarcinomas of the esophagus, stomach, colon, and rectum to examine shared and distinguishing molecular characteristics of gastrointestinal tract adenocarcinomas (GIACs). Hypermutated tumors were distinct regardless of cancer type and comprised those enriched for insertions/deletions, representing microsatellite instability cases with epigenetic silencing of MLH1 in the context of CpG island methylator phenotype, plus tumors with elevated single-nucleotide variants associated with mutations in POLE...
April 2, 2018: Cancer Cell
https://www.readbyqxmd.com/read/29622464/a-comprehensive-pan-cancer-molecular-study-of-gynecologic-and-breast-cancers
#11
Ashton C Berger, Anil Korkut, Rupa S Kanchi, Apurva M Hegde, Walter Lenoir, Wenbin Liu, Yuexin Liu, Huihui Fan, Hui Shen, Visweswaran Ravikumar, Arvind Rao, Andre Schultz, Xubin Li, Pavel Sumazin, Cecilia Williams, Pieter Mestdagh, Preethi H Gunaratne, Christina Yau, Reanne Bowlby, A Gordon Robertson, Daniel G Tiezzi, Chen Wang, Andrew D Cherniack, Andrew K Godwin, Nicole M Kuderer, Janet S Rader, Rosemary E Zuna, Anil K Sood, Alexander J Lazar, Akinyemi I Ojesina, Clement Adebamowo, Sally N Adebamowo, Keith A Baggerly, Ting-Wen Chen, Hua-Sheng Chiu, Steve Lefever, Liang Liu, Karen MacKenzie, Sandra Orsulic, Jason Roszik, Carl Simon Shelley, Qianqian Song, Christopher P Vellano, Nicolas Wentzensen, John N Weinstein, Gordon B Mills, Douglas A Levine, Rehan Akbani
We analyzed molecular data on 2,579 tumors from The Cancer Genome Atlas (TCGA) of four gynecological types plus breast. Our aims were to identify shared and unique molecular features, clinically significant subtypes, and potential therapeutic targets. We found 61 somatic copy-number alterations (SCNAs) and 46 significantly mutated genes (SMGs). Eleven SCNAs and 11 SMGs had not been identified in previous TCGA studies of the individual tumor types. We found functionally significant estrogen receptor-regulated long non-coding RNAs (lncRNAs) and gene/lncRNA interaction networks...
April 1, 2018: Cancer Cell
https://www.readbyqxmd.com/read/29622465/lncrna-epigenetic-landscape-analysis-identifies-epic1-as-an-oncogenic-lncrna-that-interacts-with-myc-and-promotes-cell-cycle-progression-in-cancer
#12
Zehua Wang, Bo Yang, Min Zhang, Weiwei Guo, Zhiyuan Wu, Yue Wang, Lin Jia, Song Li, Wen Xie, Da Yang
We characterized the epigenetic landscape of genes encoding long noncoding RNAs (lncRNAs) across 6,475 tumors and 455 cancer cell lines. In stark contrast to the CpG island hypermethylation phenotype in cancer, we observed a recurrent hypomethylation of 1,006 lncRNA genes in cancer, including EPIC1 (epigenetically-induced lncRNA1). Overexpression of EPIC1 is associated with poor prognosis in luminal B breast cancer patients and enhances tumor growth in vitro and in vivo. Mechanistically, EPIC1 promotes cell-cycle progression by interacting with MYC through EPIC1's 129-283 nt region...
March 31, 2018: Cancer Cell
https://www.readbyqxmd.com/read/29622463/genomic-and-functional-approaches-to-understanding-cancer-aneuploidy
#13
Alison M Taylor, Juliann Shih, Gavin Ha, Galen F Gao, Xiaoyang Zhang, Ashton C Berger, Steven E Schumacher, Chen Wang, Hai Hu, Jianfang Liu, Alexander J Lazar, Andrew D Cherniack, Rameen Beroukhim, Matthew Meyerson
Aneuploidy, whole chromosome or chromosome arm imbalance, is a near-universal characteristic of human cancers. In 10,522 cancer genomes from The Cancer Genome Atlas, aneuploidy was correlated with TP53 mutation, somatic mutation rate, and expression of proliferation genes. Aneuploidy was anti-correlated with expression of immune signaling genes, due to decreased leukocyte infiltrates in high-aneuploidy samples. Chromosome arm-level alterations show cancer-specific patterns, including loss of chromosome arm 3p in squamous cancers...
March 31, 2018: Cancer Cell
https://www.readbyqxmd.com/read/29606349/angiogenin-ribonuclease-5-is-an-egfr-ligand-and-a-serum-biomarker-for-erlotinib-sensitivity-in-pancreatic-cancer
#14
Ying-Nai Wang, Heng-Huan Lee, Chao-Kai Chou, Wen-Hao Yang, Yongkun Wei, Chun-Te Chen, Jun Yao, Jennifer L Hsu, Cihui Zhu, Haoqiang Ying, Yuanqing Ye, Wei-Jan Wang, Seung-Oe Lim, Weiya Xia, How-Wen Ko, Xiuping Liu, Chang-Gong Liu, Xifeng Wu, Huamin Wang, Donghui Li, Laura R Prakash, Matthew H Katz, Yaan Kang, Michael Kim, Jason B Fleming, David Fogelman, Milind Javle, Anirban Maitra, Mien-Chie Hung
Pancreatic ribonuclease (RNase) is a secreted enzyme critical for host defense. We discover an intrinsic RNase function, serving as a ligand for epidermal growth factor receptor (EGFR), a member of receptor tyrosine kinase (RTK), in pancreatic ductal adenocarcinoma (PDAC). The closely related bovine RNase A and human RNase 5 (angiogenin [ANG]) can trigger oncogenic transformation independently of their catalytic activities via direct association with EGFR. Notably, high plasma ANG level in PDAC patients is positively associated with response to EGFR inhibitor erlotinib treatment...
March 29, 2018: Cancer Cell
https://www.readbyqxmd.com/read/29657130/the-platelet-lifeline-to-cancer-challenges-and-opportunities
#15
REVIEW
Monika Haemmerle, Rebecca L Stone, David G Menter, Vahid Afshar-Kharghan, Anil K Sood
Besides their function in limiting blood loss and promoting wound healing, experimental evidence has highlighted platelets as active players in all steps of tumorigenesis including tumor growth, tumor cell extravasation, and metastasis. Additionally, thrombocytosis in cancer patients is associated with adverse patient survival. Due to the secretion of large amounts of microparticles and exosomes, platelets are well positioned to coordinate both local and distant tumor-host crosstalk. Here, we present a review of recent discoveries in the field of platelet biology and the role of platelets in cancer progression as well as challenges in targeting platelets for cancer treatment...
March 19, 2018: Cancer Cell
https://www.readbyqxmd.com/read/29657127/the-intestinal-microbiota-in-colorectal-cancer
#16
REVIEW
Herbert Tilg, Timon E Adolph, Romana R Gerner, Alexander R Moschen
Experimental evidence from the past years highlights a key role for the intestinal microbiota in inflammatory and malignant gastrointestinal diseases. Diet exhibits a strong impact on microbial composition and provides risk for developing colorectal carcinoma (CRC). Large metagenomic studies in human CRC associated microbiome signatures with the colorectal adenoma-carcinoma sequence, suggesting a fundamental role of the intestinal microbiota in the evolution of gastrointestinal malignancy. Basic science established a critical function for the intestinal microbiota in promoting tumorigenesis...
March 19, 2018: Cancer Cell
https://www.readbyqxmd.com/read/29606348/gkap-acts-as-a-genetic-modulator-of-nmdar-signaling-to-govern-invasive-tumor-growth
#17
Leanne Li, Qiqun Zeng, Arjun Bhutkar, José A Galván, Eva Karamitopoulou, Daan Noordermeer, Mei-Wen Peng, Alessandra Piersigilli, Aurel Perren, Inti Zlobec, Hugh Robinson, M Luisa Iruela-Arispe, Douglas Hanahan
Genetic linkage analysis previously suggested that GKAP, a scaffold protein of the N-methyl-D-aspartate receptor (NMDAR), was a potential modifier of invasion in a mouse model of pancreatic neuroendocrine tumor (PanNET). Here, we establish that GKAP governs invasive growth and treatment response to NMDAR inhibitors of PanNET via its pivotal role in regulating NMDAR pathway activity. Combining genetic knockdown of GKAP and pharmacological inhibition of NMDAR, we implicate as downstream effectors FMRP and HSF1, which along with GKAP demonstrably support invasiveness of PanNET and pancreatic ductal adenocarcinoma cancer cells...
March 9, 2018: Cancer Cell
https://www.readbyqxmd.com/read/29576375/fc-effector-function-contributes-to-the-activity-of-human-anti-ctla-4-antibodies
#18
Frederick Arce Vargas, Andrew J S Furness, Kevin Litchfield, Kroopa Joshi, Rachel Rosenthal, Ehsan Ghorani, Isabelle Solomon, Marta H Lesko, Nora Ruef, Claire Roddie, Jake Y Henry, Lavinia Spain, Assma Ben Aissa, Andrew Georgiou, Yien Ning Sophia Wong, Myles Smith, Dirk Strauss, Andrew Hayes, David Nicol, Tim O'Brien, Linda Mårtensson, Anne Ljungars, Ingrid Teige, Björn Frendéus, Martin Pule, Teresa Marafioti, Martin Gore, James Larkin, Samra Turajlic, Charles Swanton, Karl S Peggs, Sergio A Quezada
With the use of a mouse model expressing human Fc-gamma receptors (FcγRs), we demonstrated that antibodies with isotypes equivalent to ipilimumab and tremelimumab mediate intra-tumoral regulatory T (Treg) cell depletion in vivo, increasing the CD8+ to Treg cell ratio and promoting tumor rejection. Antibodies with improved FcγR binding profiles drove superior anti-tumor responses and survival. In patients with advanced melanoma, response to ipilimumab was associated with the CD16a-V158F high affinity polymorphism...
March 8, 2018: Cancer Cell
https://www.readbyqxmd.com/read/29576376/complex-interplay-between-epitope-specificity-and-isotype-dictates-the-biological-activity-of-anti-human-cd40-antibodies
#19
Xiaojie Yu, H T Claude Chan, Christian M Orr, Osman Dadas, Steven G Booth, Lekh N Dahal, Christine A Penfold, Lyn O'Brien, C Ian Mockridge, Ruth R French, Patrick Duriez, Leon R Douglas, Arwen R Pearson, Mark S Cragg, Ivo Tews, Martin J Glennie, Ann L White
Anti-CD40 monoclonal antibodies (mAbs) that promote or inhibit receptor function hold promise as therapeutics for cancer and autoimmunity. Rules governing their diverse range of functions, however, are lacking. Here we determined characteristics of nine hCD40 mAbs engaging epitopes throughout the CD40 extracellular region expressed as varying isotypes. All mAb formats were strong agonists when hyper-crosslinked; however, only those binding the membrane-distal cysteine-rich domain 1 (CRD1) retained agonistic activity with physiological Fc gamma receptor crosslinking or as human immunoglobulin G2 isotype; agonistic activity decreased as epitopes drew closer to the membrane...
March 3, 2018: Cancer Cell
https://www.readbyqxmd.com/read/29551594/dysregulated-il-18-is-a-key-driver-of-immunosuppression-and-a-possible-therapeutic-target-in-the-multiple-myeloma-microenvironment
#20
Kyohei Nakamura, Sahar Kassem, Alice Cleynen, Marie-Lorraine Chrétien, Camille Guillerey, Eva Maria Putz, Tobias Bald, Irmgard Förster, Slavica Vuckovic, Geoffrey R Hill, Seth L Masters, Marta Chesi, P Leif Bergsagel, Hervé Avet-Loiseau, Ludovic Martinet, Mark J Smyth
Tumor-promoting inflammation and avoiding immune destruction are hallmarks of cancer. Here, we demonstrate that the pro-inflammatory cytokine interleukin (IL)-18 is critically involved in these hallmarks in multiple myeloma (MM). Mice deficient for IL-18 were remarkably protected from Vk∗ MYC MM progression in a CD8+ T cell-dependent manner. The MM-niche-derived IL-18 drove generation of myeloid-derived suppressor cells (MDSCs), leading to accelerated disease progression. A global transcriptome analysis of the immune microenvironment in 73 MM patients strongly supported the negative impact of IL-18-driven MDSCs on T cell responses...
March 1, 2018: Cancer Cell
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