25 results on '"Alyce A. Chen"'
Search Results
2. Supplementary Figure from The Spatial Landscape of Progression and Immunoediting in Primary Melanoma at Single-Cell Resolution
- Author
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Peter K. Sorger, Sandro Santagata, George F. Murphy, Christine G. Lian, Yu-An Chen, Raquel Arias-Camison, Clarence Yapp, Roxanne J. Pelletier, Connor A. Jacobson, Alyce A. Chen, Brian Quattrochi, Tuulia Vallius, Zoltan Maliga, and Ajit J. Nirmal
- Abstract
Supplementary Figure from The Spatial Landscape of Progression and Immunoediting in Primary Melanoma at Single-Cell Resolution
- Published
- 2023
3. Data from The Spatial Landscape of Progression and Immunoediting in Primary Melanoma at Single-Cell Resolution
- Author
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Peter K. Sorger, Sandro Santagata, George F. Murphy, Christine G. Lian, Yu-An Chen, Raquel Arias-Camison, Clarence Yapp, Roxanne J. Pelletier, Connor A. Jacobson, Alyce A. Chen, Brian Quattrochi, Tuulia Vallius, Zoltan Maliga, and Ajit J. Nirmal
- Abstract
Cutaneous melanoma is a highly immunogenic malignancy that is surgically curable at early stages but life-threatening when metastatic. Here we integrate high-plex imaging, 3D high-resolution microscopy, and spatially resolved microregion transcriptomics to study immune evasion and immunoediting in primary melanoma. We find that recurrent cellular neighborhoods involving tumor, immune, and stromal cells change significantly along a progression axis involving precursor states, melanoma in situ, and invasive tumor. Hallmarks of immunosuppression are already detectable in precursor regions. When tumors become locally invasive, a consolidated and spatially restricted suppressive environment forms along the tumor–stromal boundary. This environment is established by cytokine gradients that promote expression of MHC-II and IDO1, and by PD1–PDL1-mediated cell contacts involving macrophages, dendritic cells, and T cells. A few millimeters away, cytotoxic T cells synapse with melanoma cells in fields of tumor regression. Thus, invasion and immunoediting can coexist within a few millimeters of each other in a single specimen.Significance:The reorganization of the tumor ecosystem in primary melanoma is an excellent setting in which to study immunoediting and immune evasion. Guided by classic histopathology, spatial profiling of proteins and mRNA reveals recurrent morphologic and molecular features of tumor evolution that involve localized paracrine cytokine signaling and direct cell–cell contact.This article is highlighted in the In This Issue feature, p. 1397
- Published
- 2023
4. Supplementary Data from The Spatial Landscape of Progression and Immunoediting in Primary Melanoma at Single-Cell Resolution
- Author
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Peter K. Sorger, Sandro Santagata, George F. Murphy, Christine G. Lian, Yu-An Chen, Raquel Arias-Camison, Clarence Yapp, Roxanne J. Pelletier, Connor A. Jacobson, Alyce A. Chen, Brian Quattrochi, Tuulia Vallius, Zoltan Maliga, and Ajit J. Nirmal
- Abstract
Supplementary Data from The Spatial Landscape of Progression and Immunoediting in Primary Melanoma at Single-Cell Resolution
- Published
- 2023
5. The Spatial Landscape of Progression and Immunoediting in Primary Melanoma at Single-Cell Resolution
- Author
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Alyce A. Chen, Sandro Santagata, Yu-An Chen, Raquel Arias-Camison, Connor A. Jacobson, Christine G. Lian, Roxanne J. Pelletier, Brian Quattrochi, Peter K. Sorger, Ajit J. Nirmal, George F. Murphy, Clarence Yapp, Zoltan Maliga, and Tuulia Vallius
- Subjects
Stromal cell ,Skin Neoplasms ,Melanoma ,medicine.medical_treatment ,Cell ,Immunosuppression ,Biology ,medicine.disease ,Article ,Cytokine ,medicine.anatomical_structure ,Immune system ,Immunoediting ,Oncology ,Cutaneous melanoma ,Cancer research ,medicine ,Cytokines ,Humans ,Ecosystem - Abstract
Cutaneous melanoma is a highly immunogenic malignancy that is surgically curable at early stages but life-threatening when metastatic. Here we integrate high-plex imaging, 3D high-resolution microscopy, and spatially resolved microregion transcriptomics to study immune evasion and immunoediting in primary melanoma. We find that recurrent cellular neighborhoods involving tumor, immune, and stromal cells change significantly along a progression axis involving precursor states, melanoma in situ, and invasive tumor. Hallmarks of immunosuppression are already detectable in precursor regions. When tumors become locally invasive, a consolidated and spatially restricted suppressive environment forms along the tumor–stromal boundary. This environment is established by cytokine gradients that promote expression of MHC-II and IDO1, and by PD1–PDL1-mediated cell contacts involving macrophages, dendritic cells, and T cells. A few millimeters away, cytotoxic T cells synapse with melanoma cells in fields of tumor regression. Thus, invasion and immunoediting can coexist within a few millimeters of each other in a single specimen.Significance:The reorganization of the tumor ecosystem in primary melanoma is an excellent setting in which to study immunoediting and immune evasion. Guided by classic histopathology, spatial profiling of proteins and mRNA reveals recurrent morphologic and molecular features of tumor evolution that involve localized paracrine cytokine signaling and direct cell–cell contact.This article is highlighted in the In This Issue feature, p. 1397
- Published
- 2022
6. Supplementary Table S1 from Prevalence of Human Papillomavirus in Cancer of the Oropharynx by Gender
- Author
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Silvia Franceschi, Alyce A. Chen, and Jean-Damien Combes
- Abstract
Supplementary Table S1. Characteristics of 63 studies evaluated for the prevalence of HPV markers in men and women.
- Published
- 2023
7. Data from Prevalence of Human Papillomavirus in Cancer of the Oropharynx by Gender
- Author
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Silvia Franceschi, Alyce A. Chen, and Jean-Damien Combes
- Abstract
Oropharyngeal cancer (OPC) is more frequent in men than women mainly due to the heavier and longer duration of smoking in men. Human papillomavirus (HPV) has a role in the rising incidence of OPC in the United States and other high-income countries. To determine whether there is a difference in the proportion of HPV-attributable OPC between men and women, we systematically retrieved HPV prevalence data from 63 studies reporting separately on OPC by gender. The male/female (M/F) ratios of HPV prevalence in OPC across different countries and the corresponding M/F ratios of cumulative lung cancer risk (a proxy for smoking) were compared. The United States had the highest M/F ratios of HPV prevalence in OPC (1.5). The lowest M/F ratios (≤0.7) were found in Asia and some European countries (e.g., France). The countries in which the M/F ratio of HPV prevalence in OPC was ≥1.0 had the most similar lung cancer risks for men and women. When HPV prevalence data were applied to age-standardized OPC incidence rates in the United States, Australia, the United Kingdom, and France, the M/F ratio for the HPV-positive OPC incidence rates was rather stable (around 4) in all countries. In contrast, the M/F ratio for the HPV-negative OPC incidence rates reached 10.2 in France versus Cancer Epidemiol Biomarkers Prev; 23(12); 2954–8. ©2014 AACR.
- Published
- 2023
8. The Human Tumor Atlas Network: Charting Tumor Transitions across Space and Time at Single-Cell Resolution
- Author
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Orit Rozenblatt-Rosen, Aviv Regev, Philipp Oberdoerffer, Tal Nawy, Anna Hupalowska, Jennifer E. Rood, Orr Ashenberg, Ethan Cerami, Robert J. Coffey, Emek Demir, Li Ding, Edward D. Esplin, James M. Ford, Jeremy Goecks, Sharmistha Ghosh, Joe W. Gray, Justin Guinney, Sean E. Hanlon, Shannon K. Hughes, E. Shelley Hwang, Christine A. Iacobuzio-Donahue, Judit Jané-Valbuena, Bruce E. Johnson, Ken S. Lau, Tracy Lively, Sarah A. Mazzilli, Dana Pe’er, Sandro Santagata, Alex K. Shalek, Denis Schapiro, Michael P. Snyder, Peter K. Sorger, Avrum E. Spira, Sudhir Srivastava, Kai Tan, Robert B. West, Elizabeth H. Williams, Denise Aberle, Samuel I. Achilefu, Foluso O. Ademuyiwa, Andrew C. Adey, Rebecca L. Aft, Rachana Agarwal, Ruben A. Aguilar, Fatemeh Alikarami, Viola Allaj, Christopher Amos, Robert A. Anders, Michael R. Angelo, Kristen Anton, Jon C. Aster, Ozgun Babur, Amir Bahmani, Akshay Balsubramani, David Barrett, Jennifer Beane, Diane E. Bender, Kathrin Bernt, Lynne Berry, Courtney B. Betts, Julie Bletz, Katie Blise, Adrienne Boire, Genevieve Boland, Alexander Borowsky, Kristopher Bosse, Matthew Bott, Ed Boyden, James Brooks, Raphael Bueno, Erik A. Burlingame, Qiuyin Cai, Joshua Campbell, Wagma Caravan, Hassan Chaib, Joseph M. Chan, Young Hwan Chang, Deyali Chatterjee, Ojasvi Chaudhary, Alyce A. Chen, Bob Chen, Changya Chen, Chia-hui Chen, Feng Chen, Yu-An Chen, Milan G. Chheda, Koei Chin, Roxanne Chiu, Shih-Kai Chu, Rodrigo Chuaqui, Jaeyoung Chun, Luis Cisneros, Graham A. Colditz, Kristina Cole, Natalie Collins, Kevin Contrepois, Lisa M. Coussens, Allison L. Creason, Daniel Crichton, Christina Curtis, Tanja Davidsen, Sherri R. Davies, Ino de Bruijn, Laura Dellostritto, Angelo De Marzo, David G. DeNardo, Dinh Diep, Sharon Diskin, Xengie Doan, Julia Drewes, Stephen Dubinett, Michael Dyer, Jacklynn Egger, Jennifer Eng, Barbara Engelhardt, Graham Erwin, Laura Esserman, Alex Felmeister, Heidi S. Feiler, Ryan C. Fields, Stephen Fisher, Keith Flaherty, Jennifer Flournoy, Angelo Fortunato, Allison Frangieh, Jennifer L. Frye, Robert S. Fulton, Danielle Galipeau, Siting Gan, Jianjiong Gao, Long Gao, Peng Gao, Vianne R. Gao, Tim Geiger, Ajit George, Gad Getz, Marios Giannakis, David L. Gibbs, William E. Gillanders, Simon P. Goedegebuure, Alanna Gould, Kate Gowers, William Greenleaf, Jeremy Gresham, Jennifer L. Guerriero, Tuhin K. Guha, Alexander R. Guimaraes, David Gutman, Nir Hacohen, Sean Hanlon, Casey R. Hansen, Olivier Harismendy, Kathleen A. Harris, Aaron Hata, Akimasa Hayashi, Cody Heiser, Karla Helvie, John M. Herndon, Gilliam Hirst, Frank Hodi, Travis Hollmann, Aaron Horning, James J. Hsieh, Shannon Hughes, Won Jae Huh, Stephen Hunger, Shelley E. Hwang, Heba Ijaz, Benjamin Izar, Connor A. Jacobson, Samuel Janes, Reyka G. Jayasinghe, Lihua Jiang, Brett E. Johnson, Bruce Johnson, Tao Ju, Humam Kadara, Klaus Kaestner, Jacob Kagan, Lukas Kalinke, Robert Keith, Aziz Khan, Warren Kibbe, Albert H. Kim, Erika Kim, Junhyong Kim, Annette Kolodzie, Mateusz Kopytra, Eran Kotler, Robert Krueger, Kostyantyn Krysan, Anshul Kundaje, Uri Ladabaum, Blue B. Lake, Huy Lam, Rozelle Laquindanum, Ashley M. Laughney, Hayan Lee, Marc Lenburg, Carina Leonard, Ignaty Leshchiner, Rochelle Levy, Jerry Li, Christine G. Lian, Kian-Huat Lim, Jia-Ren Lin, Yiyun Lin, Qi Liu, Ruiyang Liu, William J.R. Longabaugh, Teri Longacre, Cynthia X. Ma, Mary Catherine Macedonia, Tyler Madison, Christopher A. Maher, Anirban Maitra, Netta Makinen, Danika Makowski, Carlo Maley, Zoltan Maliga, Diego Mallo, John Maris, Nick Markham, Jeffrey Marks, Daniel Martinez, Robert J. Mashl, Ignas Masilionais, Jennifer Mason, Joan Massagué, Pierre Massion, Marissa Mattar, Richard Mazurchuk, Linas Mazutis, Eliot T. McKinley, Joshua F. McMichael, Daniel Merrick, Matthew Meyerson, Julia R. Miessner, Gordon B. Mills, Meredith Mills, Suman B. Mondal, Motomi Mori, Yuriko Mori, Elizabeth Moses, Yael Mosse, Jeremy L. Muhlich, George F. Murphy, Nicholas E. Navin, Michel Nederlof, Reid Ness, Stephanie Nevins, Milen Nikolov, Ajit Johnson Nirmal, Garry Nolan, Edward Novikov, Brendan O’Connell, Michael Offin, Stephen T. Oh, Anastasiya Olson, Alex Ooms, Miguel Ossandon, Kouros Owzar, Swapnil Parmar, Tasleema Patel, Gary J. Patti, Itsik Pe'er, Tao Peng, Daniel Persson, Marvin Petty, Hanspeter Pfister, Kornelia Polyak, Kamyar Pourfarhangi, Sidharth V. Puram, Qi Qiu, Álvaro Quintanal-Villalonga, Arjun Raj, Marisol Ramirez-Solano, Rumana Rashid, Ashley N. Reeb, Mary Reid, Adam Resnick, Sheila M. Reynolds, Jessica L. Riesterer, Scott Rodig, Joseph T. Roland, Sonia Rosenfield, Asaf Rotem, Sudipta Roy, Charles M. Rudin, Marc D. Ryser, Maria Santi-Vicini, Kazuhito Sato, Deborah Schrag, Nikolaus Schultz, Cynthia L. Sears, Rosalie C. Sears, Subrata Sen, Triparna Sen, Alex Shalek, Jeff Sheng, Quanhu Sheng, Kooresh I. Shoghi, Martha J. Shrubsole, Yu Shyr, Alexander B. Sibley, Kiara Siex, Alan J. Simmons, Dinah S. Singer, Shamilene Sivagnanam, Michal Slyper, Artem Sokolov, Sheng-Kwei Song, Austin Southard-Smith, Avrum Spira, Janet Stein, Phillip Storm, Elizabeth Stover, Siri H. Strand, Timothy Su, Damir Sudar, Ryan Sullivan, Lea Surrey, Mario Suvà, Nadezhda V. Terekhanova, Luke Ternes, Lisa Thammavong, Guillaume Thibault, George V. Thomas, Vésteinn Thorsson, Ellen Todres, Linh Tran, Madison Tyler, Yasin Uzun, Anil Vachani, Eliezer Van Allen, Simon Vandekar, Deborah J. Veis, Sébastien Vigneau, Arastoo Vossough, Angela Waanders, Nikhil Wagle, Liang-Bo Wang, Michael C. Wendl, Robert West, Chi-yun Wu, Hao Wu, Hung-Yi Wu, Matthew A. Wyczalkowski, Yubin Xie, Xiaolu Yang, Clarence Yapp, Wenbao Yu, Yinyin Yuan, Dadong Zhang, Kun Zhang, Mianlei Zhang, Nancy Zhang, Yantian Zhang, Yanyan Zhao, Daniel Cui Zhou, Zilu Zhou, Houxiang Zhu, Qin Zhu, Xiangzhu Zhu, Yuankun Zhu, and Xiaowei Zhuang
- Subjects
Cell ,Genomics ,Computational biology ,Tumor initiation ,Biology ,Article ,General Biochemistry, Genetics and Molecular Biology ,Metastasis ,03 medical and health sciences ,Atlases as Topic ,0302 clinical medicine ,Neoplasms ,Tumor Microenvironment ,medicine ,Humans ,Precision Medicine ,030304 developmental biology ,0303 health sciences ,Atlas (topology) ,Cancer ,medicine.disease ,3. Good health ,Human tumor ,Cell Transformation, Neoplastic ,medicine.anatomical_structure ,Single-Cell Analysis ,Single point ,030217 neurology & neurosurgery - Abstract
Crucial transitions in cancer-including tumor initiation, local expansion, metastasis, and therapeutic resistance-involve complex interactions between cells within the dynamic tumor ecosystem. Transformative single-cell genomics technologies and spatial multiplex in situ methods now provide an opportunity to interrogate this complexity at unprecedented resolution. The Human Tumor Atlas Network (HTAN), part of the National Cancer Institute (NCI) Cancer Moonshot Initiative, will establish a clinical, experimental, computational, and organizational framework to generate informative and accessible three-dimensional atlases of cancer transitions for a diverse set of tumor types. This effort complements both ongoing efforts to map healthy organs and previous large-scale cancer genomics approaches focused on bulk sequencing at a single point in time. Generating single-cell, multiparametric, longitudinal atlases and integrating them with clinical outcomes should help identify novel predictive biomarkers and features as well as therapeutically relevant cell types, cell states, and cellular interactions across transitions. The resulting tumor atlases should have a profound impact on our understanding of cancer biology and have the potential to improve cancer detection, prevention, and therapeutic discovery for better precision-medicine treatments of cancer patients and those at risk for cancer.
- Published
- 2020
9. The spatial landscape of progression and immunoediting in primary melanoma at single cell resolution
- Author
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Alyce A. Chen, George F. Murphy, Sandro Santagata, Clarence Yapp, Peter K. Sorger, Christine G. Lian, Raquel Arias-Camison, Ajit J. Nirmal, Tuulia Vallius, Connor A. Jacobson, Zoltan Maliga, Brian Quattrochi, Roxanne J. Pelletier, and Yu-An Chen
- Subjects
Stromal cell ,Myeloid ,Melanoma ,medicine.medical_treatment ,Biology ,medicine.disease ,CTL ,Cytokine ,medicine.anatomical_structure ,Immune system ,Immunoediting ,Cutaneous melanoma ,medicine ,Cancer research - Abstract
Cutaneous melanoma is a highly immunogenic malignancy, surgically curable at early stages, but life- threatening when metastatic. Here we integrate high-plex imaging, 3D high-resolution microscopy, and spatially-resolved micro-region transcriptomics to study immune evasion and immunoediting in primary melanoma. We find that recurrent cellular neighborhoods involving tumor, immune, and stromal cells change significantly along a progression axis involving precursor states, melanoma in situ, and invasive tumor. Hallmarks of immunosuppression are already detectable in precursor regions. When tumors become locally invasive, a consolidated and spatially restricted suppressive environment forms along the tumor-stromal boundary. This environment is established by cytokine gradients that promote expression of MHC-II and IDO1, and by PD1-PDL1 mediated cell contacts involving macrophages, dendritic cells, and T cells. A few millimeters away, cytotoxic T cells synapse with melanoma cells in fields of tumor regression. Thus, invasion and immunoediting can co-exist within a few millimeters of each other in a single specimen.STATEMENT OF SIGNIFICANCEThe reorganization of the tumor ecosystem in primary melanoma is an excellent setting in which to study immunoediting and immune evasion. Guided by classical histopathology, spatial profiling of proteins and mRNA reveals recurrent morphological and molecular features of tumor evolution that involve localized paracrine cytokine signaling and direct cell-cell contact.
- Published
- 2021
10. Micro-region transcriptomics of fixed human tissue using Pick-Seq
- Author
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Alyce A. Chen, Sandro Santagata, Eric P. Kaldjian, Lance U’Ren, Jennifer Chow, Sarah A. Boswell, David M. Weinstock, Ajit J. Nirmal, Nolan G. Ericson, George F. Murphy, Yu-An Chen, Peter K. Sorger, Christine G. Lian, Rebecca Podyminogin, and Zoltan Maliga
- Subjects
Transcriptome ,Diagnostic specimens ,Cancer cell ,Archival tissue ,Human melanoma ,Histology ,Computational biology ,Biology ,Parallel imaging - Abstract
Spatial transcriptomics and multiplexed imaging are complementary methods for studying tissue biology and disease. Recently developed spatial transcriptomic methods use fresh-frozen specimens but most diagnostic specimens, clinical trials, and tissue archives rely on formaldehyde-fixed tissue. Here we describe the Pick-Seq method for deep spatial transcriptional profiling of fixed tissue. Pick-Seq is a form of micro-region sequencing in which small regions of tissue, containing 5-20 cells, are mechanically isolated on a microscope and then sequenced. We demonstrate the use of Pick-Seq with several different fixed and frozen human specimens. Application of Pick-Seq to a human melanoma with complex histology reveals significant differences in transcriptional programs associated with tumor invasion, proliferation, and immuno-editing. Parallel imaging confirms changes in immuno-phenotypes and cancer cell states. This work demonstrates the ability of Pick-Seq to generate deep spatial transcriptomic data from fixed and archival tissue with multiplexed imaging in parallel.
- Published
- 2021
11. A motive for killing: effector functions of regulated lytic cell death
- Author
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Meghan Bliss-Moreau, Alyce A. Chen, Akshay A. D’Cruz, and Ben A. Croker
- Subjects
Cytotoxicity, Immunologic ,0301 basic medicine ,Chemokine ,Programmed cell death ,Inflammasomes ,Necroptosis ,Immunology ,Apoptosis ,Inflammation ,Extracellular Traps ,Article ,Proinflammatory cytokine ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Immunity ,medicine ,Animals ,Humans ,Immunology and Allergy ,Bacteria ,biology ,Pyroptosis ,Cell Biology ,Cell biology ,030104 developmental biology ,Caspases ,biology.protein ,medicine.symptom ,030215 immunology - Abstract
Immunological responses activated by pathogen recognition come in many guises. The proliferation, differentiation and recruitment of immune cells, and the production of inflammatory cytokines and chemokines are central to lifelong immunity. Cell death serves as a key function in the resolution of innate and adaptive immune responses. It also coordinates cell-intrinsic effector functions to restrict infection. Necrosis was formally considered a passive form of cell death or a consequence of pathogen virulence factor expression, and necrotic tissue is frequently associated with infection. However, there is now emerging evidence that points to a role for regulated forms of necrosis, such as pyroptosis and necroptosis, driving inflammation and shaping the immune response.
- Published
- 2016
12. Ptpn6 inhibits caspase-8- and Ripk3/Mlkl-dependent inflammation
- Author
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Paul R Lakin, Mary Speir, Heather Patsiouras, Ben A. Croker, Roman Othmar Braun, Shu Wang, Rowena S. Lewis, Razq Hakem, Akshay A. D’Cruz, Nathan E. Lewis, Andrew W. Roberts, Kate E. Lawlor, Anca I. Stoica, Louise H. Cengia, Isaac Shamie, Joanne A. O’Donnell, Edie Weller, Inbar Shlomovitz, Motti Gerlic, Meghan Bliss-Moreau, Jeffrey J. Babon, Lorraine A. O'Reilly, Alyce A. Chen, Cameron J. Nowell, and Michelle A. Kelliher
- Subjects
0301 basic medicine ,Programmed cell death ,Neutrophils ,Necroptosis ,Immunology ,Interleukin-1beta ,Shp1 ,necroptosis ,Inflammation ,Apoptosis ,Caspase 8 ,p38 Mitogen-Activated Protein Kinases ,Article ,caspase-8 ,03 medical and health sciences ,RIPK1 ,Mice ,0302 clinical medicine ,Tumor necrosis factor production ,Interleukin-1alpha ,Ripk1 ,medicine ,Immunology and Allergy ,Animals ,Ripk3 ,Cells, Cultured ,Mlkl ,Mice, Knockout ,Receptors, Interleukin-1 Type I ,Ptpn6 ,Chemistry ,Tumor Necrosis Factor-alpha ,Protein Tyrosine Phosphatase, Non-Receptor Type 6 ,neutrophil ,NFKB1 ,Mice, Inbred C57BL ,030104 developmental biology ,cell death ,Receptor-Interacting Protein Serine-Threonine Kinases ,Cancer research ,Tumor necrosis factor alpha ,medicine.symptom ,Protein Kinases ,Gene Deletion ,030215 immunology ,Interleukin-1 - Abstract
Ptpn6 is a cytoplasmic phosphatase that functions to prevent autoimmune and interleukin-1 (IL-1) receptor-dependent, caspase-1-independent inflammatory disease. Conditional deletion of Ptpn6 in neutrophils (Ptpn6∆PMN) is sufficient to initiate IL-1 receptor-dependent cutaneous inflammatory disease, but the source of IL-1 and the mechanisms behind IL-1 release remain unclear. Here, we investigate the mechanisms controlling IL-1α/β release from neutrophils by inhibiting caspase-8-dependent apoptosis and Ripk1-Ripk3-Mlkl-regulated necroptosis. Loss of Ripk1 accelerated disease onset, whereas combined deletion of caspase-8 and either Ripk3 or Mlkl strongly protected Ptpn6∆PMN mice. Ptpn6∆PMN neutrophils displayed increased p38 mitogen-activated protein kinase-dependent Ripk1-independent IL-1 and tumor necrosis factor production, and were prone to cell death. Together, these data emphasize dual functions for Ptpn6 in the negative regulation of p38 mitogen-activated protein kinase activation to control tumor necrosis factor and IL-1α/β expression, and in maintaining Ripk1 function to prevent caspase-8- and Ripk3-Mlkl-dependent cell death and concomitant IL-1α/β release.
- Published
- 2018
13. Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing
- Author
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Dawit Balcha, Lila Ghamsari, Andrew MacWilliams, Aaron Richardson, Alyce A. Chen, Song Yi, Benoit Charloteaux, Tong Hao, Jasmin Coulombe-Huntington, Kerstin Spirohn, Shelly A. Trigg, Bridget E. Begg, Quan Zhong, Marc Vidal, Brenda J. Andrews, Frederick P. Roth, Yu Xia, Michael Costanzo, Guihong Tan, David E. Hill, Gloria M. Sheynkman, Yun A. Shen, Samuel J. Pevzner, Nidhi Sahni, Shuli Kang, Michael A. Calderwood, Kourosh Salehi-Ashtiani, Maria D. Rodriguez, Song Sun, Lilia M. Iakoucheva, Patrick Aloy, Ryan R. Murray, Fan Yang, Xinping Yang, Xianghong Jasmine Zhou, Charles Boone, Stanley Tam, and Miquel Duran-Frigola
- Subjects
Models, Molecular ,0301 basic medicine ,Protein isoform ,Gene isoform ,Proteome ,Genomics ,Computational biology ,Biology ,Interactome ,General Biochemistry, Genetics and Molecular Biology ,Evolution, Molecular ,Open Reading Frames ,03 medical and health sciences ,Animals ,Humans ,Protein Isoforms ,Protein Interaction Domains and Motifs ,Protein Interaction Maps ,Cloning, Molecular ,Gene ,Genetics ,Biochemistry, Genetics and Molecular Biology(all) ,Alternative splicing ,Alternative Splicing ,030104 developmental biology ,Human genome - Abstract
While alternative splicing is known to diversify the functional characteristics of some genes, the extent to which protein isoforms globally contribute to functional complexity on a proteomic scale remains unknown. To address this systematically, we cloned full-length open reading frames of alternatively spliced transcripts for a large number of human genes and used protein-protein interaction profiling to functionally compare hundreds of protein isoform pairs. The majority of isoform pairs share less than 50% of their interactions. In the global context of interactome network maps, alternative isoforms tend to behave like distinct proteins rather than minor variants of each other. Interaction partners specific to alternative isoforms tend to be expressed in a highly tissue-specific manner and belong to distinct functional modules. Our strategy, applicable to other functional characteristics, reveals a widespread expansion of protein interaction capabilities through alternative splicing and suggests that many alternative "isoforms" are functionally divergent (i.e., "functional alloforms").
- Published
- 2016
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14. The pseudokinase MLKL activates PAD4-dependent NET formation in necroptotic neutrophils
- Author
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Mathilde Gavillet, Shu Wang, Ben A. Croker, David A. Williams, Michelle A. Kelliher, Meghan Bliss-Moreau, Sylvia Dietrich, Manolis Pasparakis, Alyce A. Chen, Akshay A. D’Cruz, Mary Speir, James E Vince, Arshed Al-Obeidi, Kate E. Lawlor, Maria Ericsson, and Razq Hakem
- Subjects
0301 basic medicine ,Methicillin-Resistant Staphylococcus aureus ,Programmed cell death ,Neutrophils ,Apoptosis ,Biochemistry ,Cytoplast ,Extracellular Traps ,Article ,Histones ,03 medical and health sciences ,RIPK1 ,Microscopy, Electron, Transmission ,Protein-Arginine Deiminase Type 4 ,Animals ,Humans ,Viability assay ,Molecular Biology ,Cells, Cultured ,Mice, Knockout ,Caspase 8 ,biology ,Chemistry ,Cell Biology ,Neutrophil extracellular traps ,Cell biology ,Mice, Inbred C57BL ,030104 developmental biology ,Histone ,Cytoplasm ,Receptor-Interacting Protein Serine-Threonine Kinases ,biology.protein ,Protein-Arginine Deiminases ,Protein Kinases - Abstract
Neutrophil extracellular trap (NET) formation can generate short-term, functional anucleate cytoplasts and trigger loss of cell viability. We demonstrated that the necroptotic cell death effector mixed lineage kinase domain–like (MLKL) translocated from the cytoplasm to the plasma membrane and stimulated downstream NADPH oxidase– independent ROS production, loss of cytoplasmic granules, breakdown of the nuclear membrane, chromatin decondensation, histone hypercitrullination, and extrusion of bacteriostatic NETs. This process was coordinated by receptor-interacting protein kinase-1 (RIPK1), which activated the caspase-8–dependent apoptotic or RIPK3/ MLKL-dependent necroptotic death of mouse and human neutrophils. Genetic deficiency of RIPK3 and MLKL prevented NET formation but did not prevent cell death, which was because of residual caspase-8–dependent activity. Peptidylarginine deiminase 4 (PAD4) was activated downstream of RIPK1/RIPK3/MLKL and was required for maximal histone hypercitrullination and NET extrusion. This work defines a distinct signaling network that activates PAD4-dependent NET release for the control of methicillin-resistant Staphylococcus aureus (MRSA) infection.
- Published
- 2018
15. Prevalence of Human Papillomavirus in Cancer of the Oropharynx by Gender
- Author
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Alyce A. Chen, Silvia Franceschi, and Jean-Damien Combes
- Subjects
Male ,medicine.medical_specialty ,Lung Neoplasms ,Epidemiology ,Smoking habit ,Hpv prevalence ,Prevalence ,Humans ,Medicine ,Human papillomavirus ,Papillomaviridae ,Lung cancer ,Gender identity ,biology ,business.industry ,Incidence (epidemiology) ,Papillomavirus Infections ,Smoking ,Gender Identity ,medicine.disease ,biology.organism_classification ,Surgery ,Oropharyngeal Neoplasms ,stomatognathic diseases ,nervous system ,Oncology ,Female ,business ,Demography - Abstract
Oropharyngeal cancer (OPC) is more frequent in men than women mainly due to the heavier and longer duration of smoking in men. Human papillomavirus (HPV) has a role in the rising incidence of OPC in the United States and other high-income countries. To determine whether there is a difference in the proportion of HPV-attributable OPC between men and women, we systematically retrieved HPV prevalence data from 63 studies reporting separately on OPC by gender. The male/female (M/F) ratios of HPV prevalence in OPC across different countries and the corresponding M/F ratios of cumulative lung cancer risk (a proxy for smoking) were compared. The United States had the highest M/F ratios of HPV prevalence in OPC (1.5). The lowest M/F ratios (≤0.7) were found in Asia and some European countries (e.g., France). The countries in which the M/F ratio of HPV prevalence in OPC was ≥1.0 had the most similar lung cancer risks for men and women. When HPV prevalence data were applied to age-standardized OPC incidence rates in the United States, Australia, the United Kingdom, and France, the M/F ratio for the HPV-positive OPC incidence rates was rather stable (around 4) in all countries. In contrast, the M/F ratio for the HPV-negative OPC incidence rates reached 10.2 in France versus
- Published
- 2014
16. Human Papillomavirus 45 Genetic Variation and Cervical Cancer Risk Worldwide
- Author
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Alyce A, Chen, Daniëlle A M, Heideman, Debby, Boon, Tarik, Gheit, Peter J F, Snijders, Massimo, Tommasino, Silvia, Franceschi, Gary M, Clifford, I H, Frazer, Pathology, and CCA - Oncogenesis
- Subjects
Immunology ,Molecular Sequence Data ,Papillomavirus Infections ,Genetic Variation ,Uterine Cervical Neoplasms ,Oncogene Proteins, Viral ,Alphapapillomavirus ,Global Health ,Microbiology ,Genetic Diversity and Evolution ,Virology ,Insect Science ,Case-Control Studies ,Humans ,Female ,Phylogeny - Abstract
Human papillomavirus 45 (HPV45) is a member of the HPV18-related alpha-7 species and accounts for approximately 5% of all cervical cancer cases worldwide. This study evaluated the genetic diversity of HPV45 and the association of HPV45 variants with the risk of cervical cancer by sequencing the entire E6 and E7 open reading frames of 300 HPV45-positive cervical samples from 36 countries. A total of 43 HPV45 sequence variants were identified that formed 5 phylogenetic sublineages, A1, A2, A3, B1, and B2, the distribution of which varied by geographical region. Among 192 cases of cervical cancer and 101 controls, the B2 sublineage was significantly overrepresented in cervical cancer, both overall and in Africa and Europe separately. We show that the sequence analysis of E6 and E7 allows the classification of HPV45 variants and that the risk of cervical cancer may differ by HPV45 variant sublineage. IMPORTANCE This work describes the largest study to date of human papillomavirus 45 (HPV45)-positive cervical samples and provides a comprehensive reference for phylogenetic classification for use in epidemiological studies of the carcinogenicity of HPV45 genetic variants, particularly as our findings suggest that the B2 sublineage of HPV45 is associated with a higher risk of cervical cancer.
- Published
- 2014
17. Ptpn6 inhibits Caspase-8- and Ripk3/Mlkl-dependent inflammation
- Author
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Ben A Croker, Mary Speir, Cameron J Nowell, Alyce A Chen, Joanne A O’Donnell, Akshay A D’Cruz, Meghan Bliss-Moreau, Shu Wang, Michelle A Kelliher, Razq Hakem, and Motti Gerlic
- Subjects
Immunology ,Immunology and Allergy - Abstract
Neutrophilic dermatoses are a group of inflammatory skin disorders characterized by sterile infiltrates of neutrophils. These syndromes include pyoderma gangrenosum (PG) and Sweet’s syndrome (SS), and they are associated with an increased incidence of inflammatory bowel disease, rheumatoid arthritis, and acute myeloid leukemia. IL-1β is detectable in skin lesions, and IL-1 neutralizing therapies have met with success in some patients. Splicing variants and promoter region deletions of protein tyrosine phosphatase-6 (PTPN6) are a feature of SS and PG. Mice lacking Ptpn6 develop a cutaneous inflammatory disease that is dependent on the IL-1 receptor, G-CSF, and neutrophils, but the source of IL-1 and the mechanisms of IL-1 release remain unclear. Here, we investigated the mechanisms controlling IL-1α/β release specifically from neutrophils (Ptpn6ΔPMN) by inhibiting Caspase-8-dependent apoptosis and Ripk1/Ripk3/Mlkl-regulated necroptosis. Loss of Ripk1 from neutrophils accelerated disease onset, whereas combined deletion of caspase-8 and either Ripk3 or Mlkl strongly protected Ptpn6ΔPMN mice. Ptpn6ΔPMN neutrophils displayed increased p38-dependent Ripk1-independent IL-1 and TNF production, and were prone to cell death. Together, these data emphasize dual functions for Ptpn6 in the negative regulation of p38 MAP kinase activation to control TNF and IL-1α/β transcription, and in maintaining Ripk1 function to prevent caspase-8- and Ripk3/Mlkl-dependent cell death and concomitant IL-1α/β release. These findings implicate neutrophils as the dominant producers of IL-1 in neutrophilic dermatoses, and identify novel therapeutic targets for the treatment of these skin disorders.
- Published
- 2019
18. Padi4 Regulates NET Formation and Inflammatory Cell Death Downstream of Mlkl
- Author
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James E Vince, David A. Williams, Michelle A. Kelliher, Manolis Pasparakis, Maria Ericsson, Sylvia Dietrich, Meghan Bliss-Moreau, Akshay A. D’Cruz, Alyce A. Chen, Ben A. Croker, Razq Hakem, Mary Speir, Mathilde Gavillet, and Kate E. Lawlor
- Subjects
Programmed cell death ,Chemistry ,Necroptosis ,Immunology ,Cell Biology ,Hematology ,Neutrophil extracellular traps ,Inhibitor of apoptosis ,Biochemistry ,Cell biology ,Cell membrane ,RIPK1 ,medicine.anatomical_structure ,medicine ,Signal transduction ,Kinase activity - Abstract
Neutrophil extracellular trap (NET) formation can generate short-term functional anucleate cytoplasts and can trigger loss of cell viability. We examined the role of non-apoptotic cell death signaling in NET formation by studying necroptotic human and mouse neutrophils. Necroptotic cell death signaling was activated by caspase-8 inhibition and pharmacological targeting of inhibitor of apoptosis proteins (IAPs). The specificity of cell death was confirmed using neutrophils from mice deficient in receptor-interacting protein kinase-3 (Ripk3), Ripk1 kinase activity (Ripk1D138N/D138N), caspase-8, or the plasma membrane-disrupting effector protein mixed lineage kinase domain-like (Mlkl). NETs were investigated with a combination of imaging and quantitative flow cytometry, immunogold electron microscopy, immunofluorescence microscopy, and ex vivo microbicidal assays to demonstrate functionality of NETs. In response to necroptotic stimuli, Mlkl translocates to the plasma membrane in neutrophils, and is required for downstream NADPH oxidase-independent reactive oxygen species production, loss of cytoplasmic granules, breakdown of the nuclear membrane, chromatin decondensation, histone hypercitrullination, and extrusion of bacteriostatic NETs. Neutrophils expressing a kinase-dead form of Ripk1 (Ripk1D138N/D138N) were unable to generate Ripk3/Mlkl-dependent NETs, or to undergo necroptosis or caspase-8-dependent apoptosis. NET formation that is triggered by necroptotic stimuli is dependent on TNF production, can be differentially modulated by the actions of G-CSF and IFNγ, and occurs concomitantly with the production, processing and release of IL-1α/β. Human necroptotic neutrophils also release NETs that kill S.aureus. Necroptotic NETs contain components of canonical NETs including dsDNA, hypercitrullinated histones, and neutrophil elastase, but also non-canonical components including Mlkl and membranes. Peptidylarginine deiminase 4 (Padi4) is required for extrusion of necroptotic NETs but not for chromatin decondensation. Padi4-deficient neutrophils are hypersensitive to necroptotic stimuli despite normal levels of phosphorylated Mlkl, indicating that Padi4 acts downstream of Mlkl activation. The failure of Padi4-deficient neutrophils to generate necroptotic NETs in the presence of membrane-associated Mlkl, suggests that the removal of Mlkl membrane-disrupting complexes by NETs can facilitate membrane repair and control the kinetics of neutrophil necroptosis. This work defines a distinct cell death signaling network downstream of Mlkl that promotes Padi4-dependent necroptotic NET release. Disclosures No relevant conflicts of interest to declare.
- Published
- 2018
19. Ptpn6 Inhibits IL-1 Release from Neutrophils By Regulation of Caspase-8- and Ripk3/Mlkl-Dependent Forms of Cell Death
- Author
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Ben A. Croker, Akshay A. D’Cruz, Alyce A. Chen, Joanne A. O’Donnell, and Mary Speir
- Subjects
Programmed cell death ,biology ,Chemistry ,Necroptosis ,medicine.medical_treatment ,Immunology ,Interleukin ,Inflammation ,Recombinant Granulocyte Colony-Stimulating Factor ,Cell Biology ,Hematology ,Caspase 8 ,Biochemistry ,Cell biology ,Cytokine ,medicine ,biology.protein ,medicine.symptom ,Caspase - Abstract
Neutrophilic dermatoses are a group of inflammatory skin disorders characterized by sterile infiltrates of neutrophils. These syndromes include pyoderma gangrenosum (PG) and Sweet's syndrome (SS), and they are associated with an increased risk of inflammatory bowel disease, rheumatoid arthritis, and hematologic malignancy, particularly monocytic or myelomonocytic leukemia (AML). IL-1 was first proposed in 1987 as a factor in SS, and the presence of "fragmented neutrophil nuclei" was hypothesized to contribute to disease. IL-1 has subsequently been reported at high levels in lesions of SS, and IL-1 neutralizing therapies have met with success in some SS patients. PG is also reported to be responsive to IL-1 neutralizing therapy, including PG patients with psoriatic arthritis. Splicing variants and promoter region deletions of protein tyrosine phosphatase-6 (PTPN6, or Src homology region 2 domain-containing phosphatase-1, SHP1) are a feature of SS and PG, consistent with the findings that mutations in Ptpn6 drive spontaneous IL-1R-dependent skin inflammation in mice. Mice lacking Ptpn6 develop a cutaneous inflammatory disease that is dependent on the IL-1 receptor (IL-1R), G-CSF, and neutrophils. We hypothesized that production of IL-1 by dying neutrophils drives skin inflammation in the setting of Ptpn6 deficiency. To investigate the mechanisms controlling pathogenic IL-1 release in mice lacking Ptpn6 specifically in neutrophils (Ptpn6∆PMN), we looked directly at cytokine production from neutrophils undergoing inflammatory forms of cell death. We found that stimuli engaging Ripk3/Mlkl-dependent necroptotic forms of cell death result in transcription, processing, and release of bioactive IL-1α and IL-1β from neutrophils. Production of IL-1α and IL-1β were increased in Ptpn6∆PMN neutrophils treated to undergo necroptosis. Ptpn6∆PMN neutrophils displayed increased rates of spontaneous cell death in the presence of G-CSF or IFN-γ alone, and were hypersensitive to necroptotic stimuli. These cell death abnormalities were absent in Ptpn6∆PMN Casp8∆PMN Mlkl-/- neutrophils, demonstrating that Ptpn6 regulates both apoptosis and necroptosis to prevent IL-1 release. We next examined the contribution of apoptosis and necroptosis in the development of spontaneous cutaneous inflammatory disease in Ptpn6∆PMN mice. Loss of either the Caspase-8-dependent apoptotic pathway or the Ripk3/Mlkl-dependent necroptotic pathway was not sufficient to prevent inflammation in mice. However, combined deletion of Caspase-8 and Ripk3/Mlkl protected Ptpn6∆PMN mice (Ptpn6∆PMN Casp8∆PMN Ripk3-/- and Ptpn6∆PMN Casp8∆PMN Mlkl-/- mice). Ripk1 is known to act as a physiological negative regulator of both Caspase-8-dependent apoptosis and Ripk3/Mlkl-dependent necroptosis. We found that the absence of Ripk1 in neutrophils in Ptpn6∆PMN Ripk1∆PMN mice resulted in heightened sensitivity of neutrophils to cell death and accelerated onset of cutaneous inflammatory disease. These results reveal Ripk1 as a critical physiological negative regulator of neutrophil inflammatory cell death and IL-1 production, and cutaneous inflammation. Together, these data emphasize dual functions for Ptpn6 in negative regulation of IL-1α/β transcription, and to prevent Caspase-8- and Ripk3/Mlkl-dependent cell death and concomitant IL-1α/β processing and release. These findings implicate neutrophils as the dominant producers of IL-1 in neutrophilic dermatoses, and identify novel therapeutic targets that could be exploited to control inflammatory forms of cell death in these skin disorders. Disclosures No relevant conflicts of interest to declare.
- Published
- 2018
20. Human papillomavirus 33 worldwide genetic variation and associated risk of cervical cancer
- Author
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Alyce A. Chen, Daniëlle A.M. Heideman, Silvia Franceschi, Zigui Chen, Gary M. Clifford, Hugo De Vuyst, Peter J.F. Snijders, Debby Boon, Massimo Tommasino, Robert D. Burk, Tarik Gheit, Pathology, and CCA - Oncogenesis
- Subjects
HPV ,Asia ,Lineage (genetic) ,Molecular Sequence Data ,Uterine Cervical Neoplasms ,Cancer Biobank ,Alphapapillomavirus ,Biology ,Article ,03 medical and health sciences ,0302 clinical medicine ,Phylogenetics ,Virology ,Genetic variation ,medicine ,Humans ,Amino Acid Sequence ,Human papillomavirus ,Phylogeny ,030304 developmental biology ,Genetics ,Cervical cancer ,0303 health sciences ,Genetic diversity ,Base Sequence ,Phylogenetic tree ,Papillomavirus Infections ,Variants ,Genetic Variation ,Oncogene Proteins, Viral ,South America ,medicine.disease ,3. Good health ,Europe ,030220 oncology & carcinogenesis ,Africa ,Female ,Sequence Alignment - Abstract
Human papillomavirus (HPV) 33, a member of the HPV16-related alpha-9 species group, is found in approximately 5% of cervical cancers worldwide. The current study aimed to characterize the genetic diversity of HPV33 and to explore the association of HPV33 variants with the risk for cervical cancer. Taking advantage of the International Agency for Research on Cancer biobank, we sequenced the entire E6 and E7 open reading frames of 213 HPV33-positive cervical samples from 30 countries. We identified 28 HPV33 variants that formed 5 phylogenetic groups: the previously identified A1, A2, and B (sub)lineages and the novel A3 and C (sub)lineages. The A1 sublineage was strongly over-represented in cervical cases compared to controls in both Africa and Europe. In conclusion, we provide a classification system for HPV33 variants based on the sequence of E6 and E7 and suggest that the association of HPV33 with cervical cancer may differ by variant (sub)lineage.
- Published
- 2014
21. Human Papillomavirus: Pathogenesis and Host Immune Response
- Author
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Karl Münger, Jennifer M. Spangle, and Alyce A. Chen
- Subjects
Viral pathogenesis ,virus diseases ,Cell cycle ,Biology ,medicine.disease_cause ,Virology ,female genital diseases and pregnancy complications ,Vaccination ,Immune system ,Viral life cycle ,Viral entry ,medicine ,Epigenetics ,Carcinogenesis - Abstract
Our understanding of the biology of the human papillomavirus (HPV) has grown considerably over the last quarter century. While advances have been made in prevention with the development of vaccines, there remains a need for further research to help those who are already infected and those for whom vaccination is not an option. Additionally, the mechanism of HPV-associated oncogenesis can provide mechanistic clues for other, non-HPV-associated cancers. This chapter discusses the life cycle of the virus, including a review of the current theories of viral entry into the host cell, and the functions of each of the HPV proteins, including the well-characterized HPV E6 and E7. The HPV-mediated disruption of normal cellular functions including cell cycle, metabolism, epigenetics, immune surveillance, and DNA replication, and how these disruptions can lead to cellular transformation are described in detail.
- Published
- 2014
22. Interpreting cancer genomes using systematic host network perturbations by tumour virus proteins
- Author
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Alyce A. Chen, David E. Hill, Amy M. Holthaus, Theodore R. Pak, Mariet C.W. Feltkamp, Danielle Byrdsong, James A. DeCaprio, Rachel Franchi, Melissa Duarte, Saurav Singh, Manor Askenazi, Orit Rozenblatt-Rosen, Jennifer M. Spangle, Rameen Beroukhim, Larisa Litovchick, Natali Gulbahce, Sam Pevzner, Miranda Grace, Sabrina Rabello, Karl Münger, Elliott Kieff, Anne-Ruxandra Carvunis, Yun Shen, Scott B. Ficarro, Thomas Rolland, Tong Hao, Brijesh K. Garg, Michael A. Calderwood, Anna Korkhin, Renee Rubio, Jessica C. Mar, Maria Tavares, Shelly Wanamaker, Murat Tasan, Frederick P. Roth, Fieda Abderazzaq, Robert James, James T. Webber, Albert-László Barabási, Jarrod A. Marto, Mick Correll, Changyu Fan, John Quackenbush, Megha Padi, Guillaume Adelmant, Rahul C. Deo, Amélie Dricot, Marc Vidal, Jingwei Cheng, Michael E. Cusick, Jennifer Roecklein-Canfield, and Eric Johannsen
- Subjects
Herpesvirus 4, Human ,Biology ,Interactome ,Genome ,Adenoviridae ,Open Reading Frames ,Viral Proteins ,03 medical and health sciences ,0302 clinical medicine ,Germline mutation ,Neoplasms ,Two-Hybrid System Techniques ,Humans ,Papillomaviridae ,030304 developmental biology ,Genetics ,0303 health sciences ,Multidisciplinary ,Receptors, Notch ,Genome, Human ,Gene Expression Profiling ,Human genetics ,3. Good health ,Gene Expression Regulation, Neoplastic ,Gene expression profiling ,030220 oncology & carcinogenesis ,Host-Pathogen Interactions ,Human genome ,Oncogenic Viruses ,Polyomavirus ,Functional genomics ,Oncovirus ,Genes, Neoplasm ,Signal Transduction - Abstract
Genotypic differences greatly influence susceptibility and resistance to disease. Understanding genotype-phenotype relationships requires that phenotypes be viewed as manifestations of network properties, rather than simply as the result of individual genomic variations. Genome sequencing efforts have identified numerous germline mutations, and large numbers of somatic genomic alterations, associated with a predisposition to cancer. However, it remains difficult to distinguish background, or 'passenger', cancer mutations from causal, or 'driver', mutations in these data sets. Human viruses intrinsically depend on their host cell during the course of infection and can elicit pathological phenotypes similar to those arising from mutations. Here we test the hypothesis that genomic variations and tumour viruses may cause cancer through related mechanisms, by systematically examining host interactome and transcriptome network perturbations caused by DNA tumour virus proteins. The resulting integrated viral perturbation data reflects rewiring of the host cell networks, and highlights pathways, such as Notch signalling and apoptosis, that go awry in cancer. We show that systematic analyses of host targets of viral proteins can identify cancer genes with a success rate on a par with their identification through functional genomics and large-scale cataloguing of tumour mutations. Together, these complementary approaches increase the specificity of cancer gene identification. Combining systems-level studies of pathogen-encoded gene products with genomic approaches will facilitate the prioritization of cancer-causing driver genes to advance the understanding of the genetic basis of human cancer.
- Published
- 2012
23. Viral perturbations of host networks reflect disease etiology
- Author
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Han Yan, Karin Hellner, Marc Vidal, Jarrod A. Marto, Megha Padi, Jessica C. Mar, Amy Baldwin, Amélie Dricot, Danielle Byrdsong, Nicolas Simonis, Nicholas A. Christakis, Bo Zhao, David E. Hill, Alyce A. Chen, Karl Münger, Renee Rubio, Elliott Kieff, Frederick P. Roth, John Quackenbush, Michael A. Calderwood, Albert-László Barabási, Michael E. Cusick, Rachel Franchi, Deok-Sun Lee, Pascal Braun, Natali Gulbahce, Miranda Grace, Balaji Santhanam, Orit Rozenblatt-Rosen, Jennifer Roecklein-Canfield, James A. DeCaprio, and Kyung-Won Huh
- Subjects
Herpesvirus 4, Human ,Viral Proteins -- metabolism ,Microarrays ,Viral pathogenesis ,viruses ,Disease ,Virologie générale ,medicine.disease_cause ,Interactome ,0302 clinical medicine ,Fanconi anemia ,Protein Interaction Maps ,Biology (General) ,Genetics ,Human papillomavirus 16 ,0303 health sciences ,Ecology ,Systems Biology ,Fanconi Anemia -- etiology -- genetics -- virology ,Herpesvirus 4, Human -- metabolism -- pathogenicity ,Computational Theory and Mathematics ,Virus Diseases ,030220 oncology & carcinogenesis ,Modeling and Simulation ,Host-Pathogen Interactions ,Human papillomavirus 16 -- metabolism -- pathogenicity ,Disease -- etiology -- genetics ,DNA microarray ,Virus Diseases -- complications ,Research Article ,QH301-705.5 ,Biology ,Models, Biological ,Virus ,Host-Pathogen Interactions -- genetics -- physiology ,Viral Proteins ,Metabolic Networks ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Informatique mathématique ,medicine ,Théorie des graphes ,Humans ,Genetic Predisposition to Disease ,Molecular Biology ,Gene ,Ecology, Evolution, Behavior and Systematics ,030304 developmental biology ,Virologie médicale ,Biologie moléculaire ,Computational Biology ,medicine.disease ,Virology ,Epstein–Barr virus ,Fanconi Anemia - Abstract
Many human diseases, arising from mutations of disease susceptibility genes (genetic diseases), are also associated with viral infections (virally implicated diseases), either in a directly causal manner or by indirect associations. Here we examine whether viral perturbations of host interactome may underlie such virally implicated disease relationships. Using as models two different human viruses, Epstein-Barr virus (EBV) and human papillomavirus (HPV), we find that host targets of viral proteins reside in network proximity to products of disease susceptibility genes. Expression changes in virally implicated disease tissues and comorbidity patterns cluster significantly in the network vicinity of viral targets. The topological proximity found between cellular targets of viral proteins and disease genes was exploited to uncover a novel pathway linking HPV to Fanconi anemia., Journal Article, Research Support, N.I.H. Extramural, Research Support, Non-U.S. Gov't, SCOPUS: ar.j, info:eu-repo/semantics/published
- Published
- 2012
24. Genetic variation in the vitamin C transporter, SLC23A2, modifies the risk of HPV16-associated head and neck cancer.
- Author
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Alyce A. Chen, Carmen J. Marsit, Brock C. Christensen, E.Andrés Houseman, Michael D. McClean, Judith F. Smith, Janine T. Bryan, Marshall R. Posner, Heather H. Nelson, and Karl T. Kelsey
- Subjects
- *
PHYSIOLOGICAL effects of vitamin C , *HUMAN genetic variation , *HEAD & neck cancer , *CANCER risk factors , *PAPILLOMAVIRUS diseases , *SQUAMOUS cell carcinoma , *ETIOLOGY of cancer ,CANCER susceptibility - Abstract
Human papillomavirus (HPV) type 16 infection is an etiologic factor in a subset of head and neck squamous cell carcinomas (HNSCC). It is unknown if host genetic susceptibility modifies the HPV16–HNSCC association. DNA samples collected as part of a Boston area case–control study of HNSCC were genotyped for single-nucleotide polymorphisms (SNPs) from the National Cancer Institutes SNP500Cancer database. Analysis of demographic, phenotypic and genotypic data for 319 HNSCC cases and 495 frequency-matched controls was performed using unconditional logistic regression. All reported P-values are two sided. We identified a polymorphism in the sodium-dependent vitamin C transporter SLC23A2 that modifies the risk of HNSCC associated with HPV16 infection. Among those with a wild-type allele at SLC23A2, the risk of HNSCC associated with HPV16-positive serology was 5.0 (95% confidence interval (CI) = 3.2–7.8). However, among those with a homozygous variant genotype, the risk of HNSCC associated with HPV16 was attenuated [odds ratio (OR) = 2.8; 95% CI = 1.2–6.2]. Further, when we tested whether genotype modified the interaction between citrus exposure, HPV16, and HNSCC, we found a dramatically increased risk of HNSCC for those with a wild-type SLC23A2 allele, HPV16-positive serology and high citrus intake (OR = 7.4; 95% CI = 3.6–15.1). These results suggest that SLC23A2 genetic variation alters HPV16-associated HNSCC while also highlighting the important role of citrus exposure in this disease. [ABSTRACT FROM AUTHOR]
- Published
- 2009
- Full Text
- View/download PDF
25. Viral perturbations of host networks reflect disease etiology.
- Author
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Gulbahce N, Yan H, Dricot A, Padi M, Byrdsong D, Franchi R, Lee DS, Rozenblatt-Rosen O, Mar JC, Calderwood MA, Baldwin A, Zhao B, Santhanam B, Braun P, Simonis N, Huh KW, Hellner K, Grace M, Chen A, Rubio R, Marto JA, Christakis NA, Kieff E, Roth FP, Roecklein-Canfield J, Decaprio JA, Cusick ME, Quackenbush J, Hill DE, Münger K, Vidal M, and Barabási AL
- Subjects
- Computational Biology, Disease genetics, Fanconi Anemia etiology, Fanconi Anemia genetics, Fanconi Anemia virology, Genetic Predisposition to Disease, Herpesvirus 4, Human metabolism, Herpesvirus 4, Human pathogenicity, Host-Pathogen Interactions genetics, Host-Pathogen Interactions physiology, Human papillomavirus 16 metabolism, Human papillomavirus 16 pathogenicity, Humans, Protein Interaction Maps, Viral Proteins metabolism, Disease etiology, Models, Biological, Virus Diseases complications
- Abstract
Many human diseases, arising from mutations of disease susceptibility genes (genetic diseases), are also associated with viral infections (virally implicated diseases), either in a directly causal manner or by indirect associations. Here we examine whether viral perturbations of host interactome may underlie such virally implicated disease relationships. Using as models two different human viruses, Epstein-Barr virus (EBV) and human papillomavirus (HPV), we find that host targets of viral proteins reside in network proximity to products of disease susceptibility genes. Expression changes in virally implicated disease tissues and comorbidity patterns cluster significantly in the network vicinity of viral targets. The topological proximity found between cellular targets of viral proteins and disease genes was exploited to uncover a novel pathway linking HPV to Fanconi anemia.
- Published
- 2012
- Full Text
- View/download PDF
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