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3. Proteomic and genetic analyses of influenza A viruses identify pan-viral host targets

Author

Haas, Kelsey M, McGregor, Michael J, Bouhaddou, Mehdi, Polacco, Benjamin J, Kim, Eun-Young, Nguyen, Thong T, Newton, Billy W, Urbanowski, Matthew, Kim, Heejin, Williams, Michael AP, Rezelj, Veronica V, Hardy, Alexandra, Fossati, Andrea, Stevenson, Erica J, Sukerman, Ellie, Kim, Tiffany, Penugonda, Sudhir, Moreno, Elena, Braberg, Hannes, Zhou, Yuan, Metreveli, Giorgi, Harjai, Bhavya, Tummino, Tia A, Melnyk, James E, Soucheray, Margaret, Batra, Jyoti, Pache, Lars, Martin-Sancho, Laura, Carlson-Stevermer, Jared, Jureka, Alexander S, Basler, Christopher F, Shokat, Kevan M, Shoichet, Brian K, Shriver, Leah P, Johnson, Jeffrey R, Shaw, Megan L, Chanda, Sumit K, Roden, Dan M, Carter, Tonia C, Kottyan, Leah C, Chisholm, Rex L, Pacheco, Jennifer A, Smith, Maureen E, Schrodi, Steven J, Albrecht, Randy A, Vignuzzi, Marco, Zuliani-Alvarez, Lorena, Swaney, Danielle L, Eckhardt, Manon, Wolinsky, Steven M, White, Kris M, Hultquist, Judd F, Kaake, Robyn M, García-Sastre, Adolfo, and Krogan, Nevan J

Subjects
Microbiology, Medical Microbiology, Biomedical and Clinical Sciences, Biological Sciences, Infectious Diseases, Prevention, Emerging Infectious Diseases, Vaccine Related, Influenza, Pneumonia & Influenza, Biodefense, Biotechnology, 2.1 Biological and endogenous factors, 2.2 Factors relating to the physical environment, Aetiology, Infection, Humans, Influenza A virus, Influenza, Human, Influenza A Virus, H5N1 Subtype, Influenza A Virus, H3N2 Subtype, Proteomics, Virus Replication, COVID-19, SARS-CoV-2, Antiviral Agents, Host-Pathogen Interactions
Abstract

Influenza A Virus (IAV) is a recurring respiratory virus with limited availability of antiviral therapies. Understanding host proteins essential for IAV infection can identify targets for alternative host-directed therapies (HDTs). Using affinity purification-mass spectrometry and global phosphoproteomic and protein abundance analyses using three IAV strains (pH1N1, H3N2, H5N1) in three human cell types (A549, NHBE, THP-1), we map 332 IAV-human protein-protein interactions and identify 13 IAV-modulated kinases. Whole exome sequencing of patients who experienced severe influenza reveals several genes, including scaffold protein AHNAK, with predicted loss-of-function variants that are also identified in our proteomic analyses. Of our identified host factors, 54 significantly alter IAV infection upon siRNA knockdown, and two factors, AHNAK and coatomer subunit COPB1, are also essential for productive infection by SARS-CoV-2. Finally, 16 compounds targeting our identified host factors suppress IAV replication, with two targeting CDK2 and FLT3 showing pan-antiviral activity across influenza and coronavirus families. This study provides a comprehensive network model of IAV infection in human cells, identifying functional host targets for pan-viral HDT.

Published
2023

5. Intravenous administration of BCG in mice promotes natural killer and T cell-mediated antitumor immunity in the lung

Author

Moreo, Eduardo, Jarit-Cabanillas, Aitor, Robles-Vera, Iñaki, Uranga, Santiago, Guerrero, Claudia, Gómez, Ana Belén, Mata-Martínez, Pablo, Minute, Luna, Araujo-Voces, Miguel, Felgueres, María José, Esteso, Gloria, Uranga-Murillo, Iratxe, Arias, Maykel, Pardo, Julián, Martín, Carlos, Valés-Gómez, Mar, del Fresno, Carlos, Sancho, David, and Aguiló, Nacho

Published
2023
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6. Identification of fatty acid amide hydrolase as a metastasis suppressor in breast cancer

Author

Tundidor, Isabel, Seijo-Vila, Marta, Blasco-Benito, Sandra, Rubert-Hernández, María, Adámez, Sandra, Andradas, Clara, Manzano, Sara, Álvarez-López, Isabel, Sarasqueta, Cristina, Villa-Morales, María, González-Lois, Carmen, Ramírez-Medina, Esther, Almoguera, Belén, Sánchez-López, Antonio J., Bindila, Laura, Hamann, Sigrid, Arnold, Norbert, Röcken, Christoph, Heras-Murillo, Ignacio, Sancho, David, Moreno-Bueno, Gema, Caffarel, María M., Guzmán, Manuel, Sánchez, Cristina, and Pérez-Gómez, Eduardo

Published
2023
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7. Author Correction: Defective HNF4alpha-dependent gene expression as a driver of hepatocellular failure in alcoholic hepatitis

Author

Argemi, Josepmaria, Latasa, Maria U., Atkinson, Stephen R., Blokhin, Ilya O., Massey, Veronica, Gue, Joel P., Cabezas, Joaquin, Lozano, Juan J., Van Booven, Derek, Bell, Aaron, Cao, Sheng, Vernetti, Lawrence A., Arab, Juan P., Ventura-Cots, Meritxell, Edmunds, Lia R., Fondevila, Constantino, Stärkel, Peter, Dubuquoy, Laurent, Louvet, Alexandre, Odena, Gemma, Gomez, Juan L., Aragon, Tomas, Altamirano, Jose, Caballeria, Juan, Jurczak, Michael J., Taylor, D. Lansing, Berasain, Carmen, Wahlestedt, Claes, Monga, Satdarshan P., Morgan, Marsha Y., Sancho-Bru, Pau, Mathurin, Philippe, Furuya, Shinji, Lackner, Carolin, Rusyn, Ivan, Shah, Vijay H., Thursz, Mark R., Mann, Jelena, Avila, Matias A., and Bataller, Ramon

Published
2023
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9. Gradual polyploid genome evolution revealed by pan-genomic analysis of Brachypodium hybridum and its diploid progenitors.

Author

Gordon, Sean P, Contreras-Moreira, Bruno, Levy, Joshua J, Djamei, Armin, Czedik-Eysenberg, Angelika, Tartaglio, Virginia S, Session, Adam, Martin, Joel, Cartwright, Amy, Katz, Andrew, Singan, Vasanth R, Goltsman, Eugene, Barry, Kerrie, Dinh-Thi, Vinh Ha, Chalhoub, Boulos, Diaz-Perez, Antonio, Sancho, Ruben, Lusinska, Joanna, Wolny, Elzbieta, Nibau, Candida, Doonan, John H, Mur, Luis AJ, Plott, Chris, Jenkins, Jerry, Hazen, Samuel P, Lee, Scott J, Shu, Shengqiang, Goodstein, David, Rokhsar, Daniel, Schmutz, Jeremy, Hasterok, Robert, Catalan, Pilar, and Vogel, John P

Subjects
Chromosomes, Plant, Retroelements, Hybridization, Genetic, Genomics, Evolution, Molecular, Phylogeny, Species Specificity, Diploidy, Polyploidy, Polymorphism, Single Nucleotide, Genome, Plant, Genome, Chloroplast, Brachypodium, Chromosomes, Plant, Hybridization, Genetic, Evolution, Molecular, Polymorphism, Single Nucleotide, Genome, Chloroplast
Abstract

Our understanding of polyploid genome evolution is constrained because we cannot know the exact founders of a particular polyploid. To differentiate between founder effects and post polyploidization evolution, we use a pan-genomic approach to study the allotetraploid Brachypodium hybridum and its diploid progenitors. Comparative analysis suggests that most B. hybridum whole gene presence/absence variation is part of the standing variation in its diploid progenitors. Analysis of nuclear single nucleotide variants, plastomes and k-mers associated with retrotransposons reveals two independent origins for B. hybridum, ~1.4 and ~0.14 million years ago. Examination of gene expression in the younger B. hybridum lineage reveals no bias in overall subgenome expression. Our results are consistent with a gradual accumulation of genomic changes after polyploidization and a lack of subgenome expression dominance. Significantly, if we did not use a pan-genomic approach, we would grossly overestimate the number of genomic changes attributable to post polyploidization evolution.

Published
2020

10. mRNA display with library of even-distribution reveals cellular interactors of influenza virus NS1.

Author

Du, Yushen, Hultquist, Judd F, Zhou, Quan, Olson, Anders, Tseng, Yenwen, Zhang, Tian-Hao, Hong, Mengying, Tang, Kejun, Chen, Liubo, Meng, Xiangzhi, McGregor, Michael J, Dai, Lei, Gong, Danyang, Martin-Sancho, Laura, Chanda, Sumit, Li, Xinming, Bensenger, Steve, Krogan, Nevan J, and Sun, Ren

Subjects
Humans, Influenza A virus, Interferons, Viral Nonstructural Proteins, RNA, Messenger, Virus Replication, Protein Binding, Mutation, Gene Library, Lipid Metabolism, Fatty Acid Synthase, Type I, Gene Ontology, A549 Cells, Pneumonia & Influenza, Influenza, Genetics, Prevention
Abstract

A comprehensive examination of protein-protein interactions (PPIs) is fundamental for the understanding of cellular machineries. However, limitations in current methodologies often prevent the detection of PPIs with low abundance proteins. To overcome this challenge, we develop a mRNA display with library of even-distribution (md-LED) method that facilitates the detection of low abundance binders with high specificity and sensitivity. As a proof-of-principle, we apply md-LED to IAV NS1 protein. Complementary to AP-MS, md-LED enables us to validate previously described PPIs as well as to identify novel NS1 interactors. We show that interacting with FASN allows NS1 to directly regulate the synthesis of cellular fatty acids. We also use md-LED to identify a mutant of NS1, D92Y, results in a loss of interaction with CPSF1. The use of high-throughput sequencing as the readout for md-LED enables sensitive quantification of interactions, ultimately enabling massively parallel experimentation for the investigation of PPIs.

Published
2020

13. Jet stream position explains regional anomalies in European beech forest productivity and tree growth

Author

Dorado-Liñán, Isabel, Ayarzagüena, Blanca, Babst, Flurin, Xu, Guobao, Gil, Luis, Battipaglia, Giovanna, Buras, Allan, Čada, Vojtěch, Camarero, J. Julio, Cavin, Liam, Claessens, Hugues, Drobyshev, Igor, Garamszegi, Balázs, Grabner, Michael, Hacket-Pain, Andrew, Hartl, Claudia, Hevia, Andrea, Janda, Pavel, Jump, Alistair S., Kazimirovic, Marko, Keren, Srdjan, Kreyling, Juergen, Land, Alexander, Latte, Nicolas, Levanič, Tom, van der Maaten, Ernst, van der Maaten-Theunissen, Marieke, Martínez-Sancho, Elisabet, Menzel, Annette, Mikoláš, Martin, Motta, Renzo, Muffler, Lena, Nola, Paola, Panayotov, Momchil, Petritan, Any Mary, Petritan, Ion Catalin, Popa, Ionel, Prislan, Peter, Roibu, Catalin-Constantin, Rydval, Miloš, Sánchez-Salguero, Raul, Scharnweber, Tobias, Stajić, Branko, Svoboda, Miroslav, Tegel, Willy, Teodosiu, Marius, Toromani, Elvin, Trotsiuk, Volodymyr, Turcu, Daniel-Ond, Weigel, Robert, Wilmking, Martin, Zang, Christian, Zlatanov, Tzvetan, and Trouet, Valerie

Published
2022
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14. Establishment of human iPSC-based models for the study and targeting of glioma initiating cells.

Author

Sancho-Martinez, Ignacio, Nivet, Emmanuel, Xia, Yun, Hishida, Tomoaki, Aguirre, Aitor, Ocampo, Alejandro, Ma, Li, Morey, Robert, Krause, Marie N, Zembrzycki, Andreas, Ansorge, Olaf, Vazquez-Ferrer, Eric, Dubova, Ilir, Reddy, Pradeep, Lam, David, Hishida, Yuriko, Wu, Min-Zu, Esteban, Concepcion Rodriguez, O'Leary, Dennis, Wahl, Geoffrey M, Verma, Inder M, Laurent, Louise C, and Izpisua Belmonte, Juan Carlos

Subjects
Cell Line, Tumor, Humans, Glioma, Cell Transformation, Neoplastic, Tumor Stem Cell Assay, Female, Male, Neoplastic Stem Cells, SOXB1 Transcription Factors, Induced Pluripotent Stem Cells, Neural Stem Cells
Abstract

Glioma tumour-initiating cells (GTICs) can originate upon the transformation of neural progenitor cells (NPCs). Studies on GTICs have focused on primary tumours from which GTICs could be isolated and the use of human embryonic material. Recently, the somatic genomic landscape of human gliomas has been reported. RTK (receptor tyrosine kinase) and p53 signalling were found dysregulated in ∼90% and 86% of all primary tumours analysed, respectively. Here we report on the use of human-induced pluripotent stem cells (hiPSCs) for modelling gliomagenesis. Dysregulation of RTK and p53 signalling in hiPSC-derived NPCs (iNPCs) recapitulates GTIC properties in vitro. In vivo transplantation of transformed iNPCs leads to highly aggressive tumours containing undifferentiated stem cells and their differentiated derivatives. Metabolic modulation compromises GTIC viability. Last, screening of 101 anti-cancer compounds identifies three molecules specifically targeting transformed iNPCs and primary GTICs. Together, our results highlight the potential of hiPSCs for studying human tumourigenesis.

Published
2016

15. A single cell characterisation of human embryogenesis identifies pluripotency transitions and putative anterior hypoblast centre

Author

Molè, Matteo A., Coorens, Tim H. H., Shahbazi, Marta N., Weberling, Antonia, Weatherbee, Bailey A. T., Gantner, Carlos W., Sancho-Serra, Carmen, Richardson, Lucy, Drinkwater, Abbie, Syed, Najma, Engley, Stephanie, Snell, Philip, Christie, Leila, Elder, Kay, Campbell, Alison, Fishel, Simon, Behjati, Sam, Vento-Tormo, Roser, and Zernicka-Goetz, Magdalena

Published
2021
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16. Exploiting oxidative phosphorylation to promote the stem and immunoevasive properties of pancreatic cancer stem cells

Author

Valle, Sandra, Alcalá, Sonia, Martin-Hijano, Laura, Cabezas-Sáinz, Pablo, Navarro, Diego, Muñoz, Edurne Ramos, Yuste, Lourdes, Tiwary, Kanishka, Walter, Karolin, Ruiz-Cañas, Laura, Alonso-Nocelo, Marta, Rubiolo, Juan A., González-Arnay, Emilio, Heeschen, Christopher, Garcia-Bermejo, Laura, Hermann, Patrick C., Sánchez, Laura, Sancho, Patricia, Fernández-Moreno, Miguel Ángel, and Sainz, Jr, Bruno

Published
2020
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18. Cancer associated fibroblast FAK regulates malignant cell metabolism

Author

Demircioglu, Fevzi, Wang, Jun, Candido, Juliana, Costa, Ana S. H., Casado, Pedro, de Luxan Delgado, Beatriz, Reynolds, Louise E., Gomez-Escudero, Jesus, Newport, Emma, Rajeeve, Vinothini, Baker, Ann-Marie, Roy-Luzarraga, Marina, Graham, Trevor A., Foster, Julie, Wang, Yu, Campbell, James J., Singh, Rajinder, Zhang, Penglie, Schall, Thomas J., Balkwill, Frances R., Sosabowski, Jane, Cutillas, Pedro R., Frezza, Christian, Sancho, Patricia, and Hodivala-Dilke, Kairbaan

Published
2020
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19. An Abl-FBP17 mechanosensing system couples local plasma membrane curvature and stress fiber remodeling during mechanoadaptation

Author

Echarri, Asier, Pavón, Dácil M., Sánchez, Sara, García-García, María, Calvo, Enrique, Huerta-López, Carla, Velázquez-Carreras, Diana, Viaris de Lesegno, Christine, Ariotti, Nicholas, Lázaro-Carrillo, Ana, Strippoli, Raffaele, De Sancho, David, Alegre-Cebollada, Jorge, Lamaze, Christophe, Parton, Robert G., and Del Pozo, Miguel A.

Published
2019
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20. Defective HNF4alpha-dependent gene expression as a driver of hepatocellular failure in alcoholic hepatitis

Author

Argemi, Josepmaria, Latasa, Maria U., Atkinson, Stephen R., Blokhin, Ilya O., Massey, Veronica, Gue, Joel P., Cabezas, Joaquin, Lozano, Juan J., Van Booven, Derek, Bell, Aaron, Cao, Sheng, Vernetti, Lawrence A., Arab, Juan P., Ventura-Cots, Meritxell, Edmunds, Lia R., Fondevila, Constantino, Stärkel, Peter, Dubuquoy, Laurent, Louvet, Alexandre, Odena, Gemma, Gomez, Juan L., Aragon, Tomas, Altamirano, Jose, Caballeria, Juan, Jurczak, Michael J., Taylor, D. Lansing, Berasain, Carmen, Wahlestedt, Claes, Monga, Satdarshan P., Morgan, Marsha Y., Sancho-Bru, Pau, Mathurin, Philippe, Furuya, Shinji, Lackner, Carolin, Rusyn, Ivan, Shah, Vijay H., Thursz, Mark R., Mann, Jelena, Avila, Matias A., and Bataller, Ramon

Published
2019
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22. Single cell analysis of human foetal liver captures the transcriptional profile of hepatobiliary hybrid progenitors

Author

Segal, Joe M., Kent, Deniz, Wesche, Daniel J., Ng, Soon Seng, Serra, Maria, Oulès, Bénédicte, Kar, Gozde, Emerton, Guy, Blackford, Samuel J. I., Darmanis, Spyros, Miquel, Rosa, Luong, Tu Vinh, Yamamoto, Ryo, Bonham, Andrew, Jassem, Wayel, Heaton, Nigel, Vigilante, Alessandra, King, Aileen, Sancho, Rocio, Teichmann, Sarah, Quake, Stephen R., Nakauchi, Hiromitsu, and Rashid, S. Tamir

Published
2019
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24. Live imaging of airway epithelium reveals that mucociliary clearance modulates SARS-CoV-2 spread

Author

Mark E. Becker, Laura Martin-Sancho, Lacy M. Simons, Michael D. McRaven, Sumit K. Chanda, Judd F. Hultquist, and Thomas J. Hope

Subjects
Science
Abstract

Abstract SARS-CoV-2 initiates infection in the conducting airways, where mucociliary clearance inhibits pathogen penetration. However, it is unclear how mucociliary clearance impacts SARS-CoV-2 spread after infection is established. To investigate viral spread at this site, we perform live imaging of SARS-CoV-2 infected differentiated primary human bronchial epithelium cultures for up to 12 days. Using a fluorescent reporter virus and markers for cilia and mucus, we longitudinally monitor mucus motion, ciliary motion, and infection. Infected cell numbers peak at 4 days post infection, forming characteristic foci that tracked mucus movement. Inhibition of MCC using physical and genetic perturbations limits foci. Later in infection, mucociliary clearance deteriorates. Increased mucus secretion accompanies ciliary motion defects, but mucociliary clearance and vectorial infection spread resume after mucus removal, suggesting that mucus secretion may mediate MCC deterioration. Our work shows that while MCC can facilitate SARS-CoV-2 spread after initial infection, subsequent MCC decreases inhibit spread, revealing a complex interplay between SARS-CoV-2 and MCC.

Published
2024
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25. A versatile microbial platform as a tunable whole-cell chemical sensor

Author

Javier M. Hernández-Sancho, Arnaud Boudigou, Maria V. G. Alván-Vargas, Dekel Freund, Jenny Arnling Bååth, Peter Westh, Kenneth Jensen, Lianet Noda-García, Daniel C. Volke, and Pablo I. Nikel

Subjects
Science
Abstract

Abstract Biosensors are used to detect and quantify chemicals produced in industrial microbiology with high specificity, sensitivity, and portability. Most biosensors, however, are limited by the need for transcription factors engineered to recognize specific molecules. In this study, we overcome the limitations typically associated with traditional biosensors by engineering Pseudomonas putida for whole-cell sensing of a variety of chemicals. Our approach integrates fluorescent reporters with synthetic auxotrophies within central metabolism that can be complemented by target analytes in growth-coupled setups. This platform enables the detection of a wide array of structurally diverse chemicals under various conditions, including co-cultures of producer cell factories and sensor strains. We also demonstrate the applicability of this versatile biosensor platform for monitoring complex biochemical processes, including plastic degradation by either purified hydrolytic enzymes or engineered bacteria. This microbial system provides a rapid, sensitive, and readily adaptable tool for monitoring cell factory performance and for environmental analyzes.

Published
2024
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26. Mechanistic insights into glycoside 3-oxidases involved in C-glycoside metabolism in soil microorganisms

Author

André Taborda, Tomás Frazão, Miguel V. Rodrigues, Xavier Fernández-Luengo, Ferran Sancho, Maria Fátima Lucas, Carlos Frazão, Eduardo P. Melo, M. Rita Ventura, Laura Masgrau, Patrícia T. Borges, and Lígia O. Martins

Subjects
Science
Abstract

Abstract C-glycosides are natural products with important biological activities but are recalcitrant to degradation. Glycoside 3-oxidases (G3Oxs) are recently identified bacterial flavo-oxidases from the glucose-methanol-coline (GMC) superfamily that catalyze the oxidation of C-glycosides with the concomitant reduction of O2 to H2O2. This oxidation is followed by C-C acid/base-assisted bond cleavage in two-step C-deglycosylation pathways. Soil and gut microorganisms have different oxidative enzymes, but the details of their catalytic mechanisms are largely unknown. Here, we report that PsG3Ox oxidizes at 50,000-fold higher specificity (k cat/Km) the glucose moiety of mangiferin to 3-keto-mangiferin than free D-glucose to 2-keto-glucose. Analysis of PsG3Ox X-ray crystal structures and PsG3Ox in complex with glucose and mangiferin, combined with mutagenesis and molecular dynamics simulations, reveal distinctive features in the topology surrounding the active site that favor catalytically competent conformational states suitable for recognition, stabilization, and oxidation of the glucose moiety of mangiferin. Furthermore, their distinction to pyranose 2-oxidases (P2Oxs) involved in wood decay and recycling is discussed from an evolutionary, structural, and functional viewpoint.

Published
2023
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27. Intravenous administration of BCG in mice promotes natural killer and T cell-mediated antitumor immunity in the lung

Author

Eduardo Moreo, Aitor Jarit-Cabanillas, Iñaki Robles-Vera, Santiago Uranga, Claudia Guerrero, Ana Belén Gómez, Pablo Mata-Martínez, Luna Minute, Miguel Araujo-Voces, María José Felgueres, Gloria Esteso, Iratxe Uranga-Murillo, Maykel Arias, Julián Pardo, Carlos Martín, Mar Valés-Gómez, Carlos del Fresno, David Sancho, and Nacho Aguiló

Subjects
Science
Abstract

Abstract Intravesical administration of Bacillus Calmette-Guérin (BCG) was one of the first FDA-approved immunotherapies and remains a standard treatment for bladder cancer. Previous studies have demonstrated that intravenous (IV) administration of BCG is well-tolerated and effective in preventing tuberculosis infection in animals. Here, we examine IV BCG in several preclinical lung tumor models. Our findings demonstrate that BCG inoculation reduced tumor growth and prolonged mouse survival in models of lung melanoma metastasis and orthotopic lung adenocarcinoma. Moreover, IV BCG treatment was well-tolerated with no apparent signs of acute toxicity. Mechanistically, IV BCG induced tumor-specific CD8+ T cell responses, which were dependent on type 1 conventional dendritic cells, as well as NK cell-mediated immunity. Lastly, we also show that IV BCG has an additive effect on anti-PD-L1 checkpoint inhibitor treatment in mouse lung tumors that are otherwise resistant to anti-PD-L1 as monotherapy. Overall, our study demonstrates the potential of systemic IV BCG administration in the treatment of lung tumors, highlighting its ability to enhance immune responses and augment immune checkpoint blockade efficacy.

Published
2023
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28. Proteomic and genetic analyses of influenza A viruses identify pan-viral host targets

Author

Kelsey M. Haas, Michael J. McGregor, Mehdi Bouhaddou, Benjamin J. Polacco, Eun-Young Kim, Thong T. Nguyen, Billy W. Newton, Matthew Urbanowski, Heejin Kim, Michael A. P. Williams, Veronica V. Rezelj, Alexandra Hardy, Andrea Fossati, Erica J. Stevenson, Ellie Sukerman, Tiffany Kim, Sudhir Penugonda, Elena Moreno, Hannes Braberg, Yuan Zhou, Giorgi Metreveli, Bhavya Harjai, Tia A. Tummino, James E. Melnyk, Margaret Soucheray, Jyoti Batra, Lars Pache, Laura Martin-Sancho, Jared Carlson-Stevermer, Alexander S. Jureka, Christopher F. Basler, Kevan M. Shokat, Brian K. Shoichet, Leah P. Shriver, Jeffrey R. Johnson, Megan L. Shaw, Sumit K. Chanda, Dan M. Roden, Tonia C. Carter, Leah C. Kottyan, Rex L. Chisholm, Jennifer A. Pacheco, Maureen E. Smith, Steven J. Schrodi, Randy A. Albrecht, Marco Vignuzzi, Lorena Zuliani-Alvarez, Danielle L. Swaney, Manon Eckhardt, Steven M. Wolinsky, Kris M. White, Judd F. Hultquist, Robyn M. Kaake, Adolfo García-Sastre, and Nevan J. Krogan

Subjects
Science
Abstract

Abstract Influenza A Virus (IAV) is a recurring respiratory virus with limited availability of antiviral therapies. Understanding host proteins essential for IAV infection can identify targets for alternative host-directed therapies (HDTs). Using affinity purification-mass spectrometry and global phosphoproteomic and protein abundance analyses using three IAV strains (pH1N1, H3N2, H5N1) in three human cell types (A549, NHBE, THP-1), we map 332 IAV-human protein-protein interactions and identify 13 IAV-modulated kinases. Whole exome sequencing of patients who experienced severe influenza reveals several genes, including scaffold protein AHNAK, with predicted loss-of-function variants that are also identified in our proteomic analyses. Of our identified host factors, 54 significantly alter IAV infection upon siRNA knockdown, and two factors, AHNAK and coatomer subunit COPB1, are also essential for productive infection by SARS-CoV-2. Finally, 16 compounds targeting our identified host factors suppress IAV replication, with two targeting CDK2 and FLT3 showing pan-antiviral activity across influenza and coronavirus families. This study provides a comprehensive network model of IAV infection in human cells, identifying functional host targets for pan-viral HDT.

Published
2023
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29. Identification of fatty acid amide hydrolase as a metastasis suppressor in breast cancer

Author

Isabel Tundidor, Marta Seijo-Vila, Sandra Blasco-Benito, María Rubert-Hernández, Sandra Adámez, Clara Andradas, Sara Manzano, Isabel Álvarez-López, Cristina Sarasqueta, María Villa-Morales, Carmen González-Lois, Esther Ramírez-Medina, Belén Almoguera, Antonio J. Sánchez-López, Laura Bindila, Sigrid Hamann, Norbert Arnold, Christoph Röcken, Ignacio Heras-Murillo, David Sancho, Gema Moreno-Bueno, María M. Caffarel, Manuel Guzmán, Cristina Sánchez, and Eduardo Pérez-Gómez

Subjects
Science
Abstract

Abstract Clinical management of breast cancer (BC) metastasis remains an unmet need as it accounts for 90% of BC-associated mortality. Although the luminal subtype, which represents >70% of BC cases, is generally associated with a favorable outcome, it is susceptible to metastatic relapse as late as 15 years after treatment discontinuation. Seeking therapeutic approaches as well as screening tools to properly identify those patients with a higher risk of recurrence is therefore essential. Here, we report that the lipid-degrading enzyme fatty acid amide hydrolase (FAAH) is a predictor of long-term survival in patients with luminal BC, and that it blocks tumor progression and lung metastasis in cell and mouse models of BC. Together, our findings highlight the potential of FAAH as a biomarker with prognostic value in luminal BC and as a therapeutic target in metastatic disease.

Published
2023
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30. USP7 controls NGN3 stability and pancreatic endocrine lineage development

Author

Teodora Manea, Jessica Kristine Nelson, Cristina Maria Garrone, Karin Hansson, Ian Evans, Axel Behrens, and Rocio Sancho

Subjects
Science
Abstract

Abstract Understanding the factors and mechanisms involved in beta-cell development will guide therapeutic efforts to generate fully functional beta cells for diabetes. Neurogenin 3 (NGN3) is the key transcription factor that marks endocrine progenitors and drives beta-cell differentiation. Here we screen for binding partners of NGN3 and identify the deubiquitylating enzyme USP7 as a key regulator of NGN3 stability. Mechanistically, USP7 interacts with, deubiquitinates and stabilizes NGN3. In vivo, conditional knockout of Usp7 in the mouse embryonic pancreas causes a dramatic reduction in islet formation and hyperglycemia in adult mice, due to impaired NGN3-mediated endocrine specification during pancreatic development. Furthermore, pharmacological inhibition of USP7 during endocrine specification in human iPSC models of beta-cell differentiation decreases NGN3 expressing progenitor cell numbers and impairs beta cell differentiation. Thus, the USP7-NGN3 axis is an essential mechanism for driving endocrine development and beta-cell differentiation, which can be therapeutically exploited.

Published
2023
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31. Robust temporal map of human in vitro myelopoiesis using single-cell genomics

Author

Clara Alsinet, Maria Nascimento Primo, Valentina Lorenzi, Erica Bello, Iva Kelava, Carla P. Jones, Roser Vilarrasa-Blasi, Carmen Sancho-Serra, Andrew J. Knights, Jong-Eun Park, Beata S. Wyspianska, Gosia Trynka, David F. Tough, Andrew Bassett, Daniel J. Gaffney, Damiana Alvarez-Errico, and Roser Vento-Tormo

Subjects
Science
Abstract

The myeloid lineage is central to homeostasis and immunity. The authors provide an atlas of human iPSC-to-myeloid cell differentiation and demonstrate that the in vitro system recapitulates yolk sac differentiation, opening new avenues to human myelopoiesis.

Published
2022
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32. Stress-induced protein disaggregation in the endoplasmic reticulum catalysed by BiP

Author

Eduardo Pinho Melo, Tasuku Konno, Ilaria Farace, Mosab Ali Awadelkareem, Lise R. Skov, Fernando Teodoro, Teresa P. Sancho, Adrienne W. Paton, James C. Paton, Matthew Fares, Pedro M. R. Paulo, Xin Zhang, and Edward Avezov

Subjects
Science
Abstract

Aggregation of misfolded proteins underlie dementias. Here, the authors show that stressed cells activate an innate mechanism to resolve aggregates of defective proteins in the endoplasmic reticulum, where a third of cellular proteins are produced.

Published
2022
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33. Jet stream position explains regional anomalies in European beech forest productivity and tree growth

Author

Isabel Dorado-Liñán, Blanca Ayarzagüena, Flurin Babst, Guobao Xu, Luis Gil, Giovanna Battipaglia, Allan Buras, Vojtěch Čada, J. Julio Camarero, Liam Cavin, Hugues Claessens, Igor Drobyshev, Balázs Garamszegi, Michael Grabner, Andrew Hacket-Pain, Claudia Hartl, Andrea Hevia, Pavel Janda, Alistair S. Jump, Marko Kazimirovic, Srdjan Keren, Juergen Kreyling, Alexander Land, Nicolas Latte, Tom Levanič, Ernst van der Maaten, Marieke van der Maaten-Theunissen, Elisabet Martínez-Sancho, Annette Menzel, Martin Mikoláš, Renzo Motta, Lena Muffler, Paola Nola, Momchil Panayotov, Any Mary Petritan, Ion Catalin Petritan, Ionel Popa, Peter Prislan, Catalin-Constantin Roibu, Miloš Rydval, Raul Sánchez-Salguero, Tobias Scharnweber, Branko Stajić, Miroslav Svoboda, Willy Tegel, Marius Teodosiu, Elvin Toromani, Volodymyr Trotsiuk, Daniel-Ond Turcu, Robert Weigel, Martin Wilmking, Christian Zang, Tzvetan Zlatanov, and Valerie Trouet

Subjects
Science
Abstract

Here the authors show that extremes in the summer jet stream position over Europe create a beech forest productivity dipole between northwestern and southeastern Europe and can result in regional anomalies in forest carbon uptake and growth.

Published
2022
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34. A single cell characterisation of human embryogenesis identifies pluripotency transitions and putative anterior hypoblast centre

Author

Matteo A. Molè, Tim H. H. Coorens, Marta N. Shahbazi, Antonia Weberling, Bailey A. T. Weatherbee, Carlos W. Gantner, Carmen Sancho-Serra, Lucy Richardson, Abbie Drinkwater, Najma Syed, Stephanie Engley, Philip Snell, Leila Christie, Kay Elder, Alison Campbell, Simon Fishel, Sam Behjati, Roser Vento-Tormo, and Magdalena Zernicka-Goetz

Subjects
Science
Abstract

Single cell analysis of early human embryos identifies key changes in pluripotency, the requirement of FGF signalling for embryo survival, and defines a putative anterior-like region of hypoblast cells, providing insights into how early human development is regulated.

Published
2021
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35. Exploiting oxidative phosphorylation to promote the stem and immunoevasive properties of pancreatic cancer stem cells

Author

Sandra Valle, Sonia Alcalá, Laura Martin-Hijano, Pablo Cabezas-Sáinz, Diego Navarro, Edurne Ramos Muñoz, Lourdes Yuste, Kanishka Tiwary, Karolin Walter, Laura Ruiz-Cañas, Marta Alonso-Nocelo, Juan A. Rubiolo, Emilio González-Arnay, Christopher Heeschen, Laura Garcia-Bermejo, Patrick C. Hermann, Laura Sánchez, Patricia Sancho, Miguel Ángel Fernández-Moreno, and Bruno Sainz

Subjects
Science
Abstract

Long-term cultures of pancreatic cancer stem cells (PaCSCs) are difficult to obtain. Here, the authors present a 2D culture method, based on the use of galactose, to establish cell cultures from pancreatic ductal adenocarcinoma xenotransplants enriched in PaCSCs.

Published
2020
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36. Gradual polyploid genome evolution revealed by pan-genomic analysis of Brachypodium hybridum and its diploid progenitors

Author

Sean P. Gordon, Bruno Contreras-Moreira, Joshua J. Levy, Armin Djamei, Angelika Czedik-Eysenberg, Virginia S. Tartaglio, Adam Session, Joel Martin, Amy Cartwright, Andrew Katz, Vasanth R. Singan, Eugene Goltsman, Kerrie Barry, Vinh Ha Dinh-Thi, Boulos Chalhoub, Antonio Diaz-Perez, Ruben Sancho, Joanna Lusinska, Elzbieta Wolny, Candida Nibau, John H. Doonan, Luis A. J. Mur, Chris Plott, Jerry Jenkins, Samuel P. Hazen, Scott J. Lee, Shengqiang Shu, David Goodstein, Daniel Rokhsar, Jeremy Schmutz, Robert Hasterok, Pilar Catalan, and John P. Vogel

Subjects
Science
Abstract

Existing plant pan-genomic studies usually report considerable intraspecific whole gene presence-absence variation. Here, the authors use pan-genomic approach to reveal gradual polyploid genome evolution by analyzing of Brachypodium hybridum and its diploid progenitors.

Published
2020
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37. ISG15 and ISGylation is required for pancreatic cancer stem cell mitophagy and metabolic plasticity

Author

Sonia Alcalá, Patricia Sancho, Paola Martinelli, Diego Navarro, Coral Pedrero, Laura Martín-Hijano, Sandra Valle, Julie Earl, Macarena Rodríguez-Serrano, Laura Ruiz-Cañas, Katerin Rojas, Alfredo Carrato, Laura García-Bermejo, Miguel Ángel Fernández-Moreno, Patrick C. Hermann, and Bruno Sainz

Subjects
Science
Abstract

The ubiquitin-like modifier ISG15 exerts post-translational protein regulation through ISGylation. Here, the authors show that ISGylation is necessary for pancreatic cancer stem cell self-renewal and tumourigenesis by supporting the recycling of non-functional mitochondria.

Published
2020
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38. mRNA display with library of even-distribution reveals cellular interactors of influenza virus NS1

Author

Yushen Du, Judd F. Hultquist, Quan Zhou, Anders Olson, Yenwen Tseng, Tian-hao Zhang, Mengying Hong, Kejun Tang, Liubo Chen, Xiangzhi Meng, Michael J. McGregor, Lei Dai, Danyang Gong, Laura Martin-Sancho, Sumit Chanda, Xinming Li, Steve Bensenger, Nevan J. Krogan, and Ren Sun

Subjects
Science
Abstract

Identification of low abundance proteins interacting with viral proteins can be challenging. Here, Du et al. develop an mRNA display approach with a library of even distribution, identify host proteins interacting with NS1 protein of influenza A virus, and show that one interactor provides a means to regulate cellular fatty acids synthesis.

Published
2020
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39. Cancer associated fibroblast FAK regulates malignant cell metabolism

Author

Fevzi Demircioglu, Jun Wang, Juliana Candido, Ana S. H. Costa, Pedro Casado, Beatriz de Luxan Delgado, Louise E. Reynolds, Jesus Gomez-Escudero, Emma Newport, Vinothini Rajeeve, Ann-Marie Baker, Marina Roy-Luzarraga, Trevor A. Graham, Julie Foster, Yu Wang, James J. Campbell, Rajinder Singh, Penglie Zhang, Thomas J. Schall, Frances R. Balkwill, Jane Sosabowski, Pedro R. Cutillas, Christian Frezza, Patricia Sancho, and Kairbaan Hodivala-Dilke

Subjects
Science
Abstract

Cancer associated fibroblasts (CAFs) have been suggested to regulate cancer cell metabolism, but the mechanisms are not completely elucidated. Here, the authors show that low FAK expression in stromal cells correlates with poor prognosis in breast and pancreatic cancer patients and that FAK-silencing in CAFs promotes tumourigenesis by the paracrine regulation of cancer cell metabolism.

Published
2020
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40. Author Correction: Defective HNF4alpha-dependent gene expression as a driver of hepatocellular failure in alcoholic hepatitis

Author

Josepmaria Argemi, Maria U. Latasa, Stephen R. Atkinson, Ilya O. Blokhin, Veronica Massey, Joel P. Gue, Joaquin Cabezas, Juan J. Lozano, Derek Van Booven, Aaron Bell, Sheng Cao, Lawrence A. Vernetti, Juan P. Arab, Meritxell Ventura-Cots, Lia R. Edmunds, Constantino Fondevila, Peter Stärkel, Laurent Dubuquoy, Alexandre Louvet, Gemma Odena, Juan L. Gomez, Tomas Aragon, Jose Altamirano, Juan Caballeria, Michael J. Jurczak, D. Lansing Taylor, Carmen Berasain, Claes Wahlestedt, Satdarshan P. Monga, Marsha Y. Morgan, Pau Sancho-Bru, Philippe Mathurin, Shinji Furuya, Carolin Lackner, Ivan Rusyn, Vijay H. Shah, Mark R. Thursz, Jelena Mann, Matias A. Avila, and Ramon Bataller

Subjects
Science
Published
2023
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41. An Abl-FBP17 mechanosensing system couples local plasma membrane curvature and stress fiber remodeling during mechanoadaptation

Author

Asier Echarri, Dácil M. Pavón, Sara Sánchez, María García-García, Enrique Calvo, Carla Huerta-López, Diana Velázquez-Carreras, Christine Viaris de Lesegno, Nicholas Ariotti, Ana Lázaro-Carrillo, Raffaele Strippoli, David De Sancho, Jorge Alegre-Cebollada, Christophe Lamaze, Robert G. Parton, and Miguel A. Del Pozo

Subjects
Science
Abstract

Mechanical forces are sensed by cells and can alter plasma membrane properties, but biochemical changes underlying this are not clear. Here the authors show tension is sensed by c-Abl and FBP17, which couples changes in mechanical tension to remodelling of the plasma membrane and actin cytoskeleton.

Published
2019
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42. Defective HNF4alpha-dependent gene expression as a driver of hepatocellular failure in alcoholic hepatitis

Author

Josepmaria Argemi, Maria U. Latasa, Stephen R. Atkinson, Ilya O. Blokhin, Veronica Massey, Joel P. Gue, Joaquin Cabezas, Juan J. Lozano, Derek Van Booven, Aaron Bell, Sheng Cao, Lawrence A. Vernetti, Juan P. Arab, Meritxell Ventura-Cots, Lia R. Edmunds, Constantino Fondevila, Peter Stärkel, Laurent Dubuquoy, Alexandre Louvet, Gemma Odena, Juan L. Gomez, Tomas Aragon, Jose Altamirano, Juan Caballeria, Michael J. Jurczak, D. Lansing Taylor, Carmen Berasain, Claes Wahlestedt, Satdarshan P. Monga, Marsha Y. Morgan, Pau Sancho-Bru, Philippe Mathurin, Shinji Furuya, Carolin Lackner, Ivan Rusyn, Vijay H. Shah, Mark R. Thursz, Jelena Mann, Matias A. Avila, and Ramon Bataller

Subjects
Science
Abstract

Alcoholic hepatitis, a common cause of liver failure, lacks effective treatment. Here, the authors show altered hepatic HNF4a isoform expression and hypermethylation of its target genes in patients. HNF4a dysregulation is improved in vitro by TGFb or PPARg modulation suggesting potential therapeutic avenues.

Published
2019
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43. Single cell analysis of human foetal liver captures the transcriptional profile of hepatobiliary hybrid progenitors

Author

Joe M. Segal, Deniz Kent, Daniel J. Wesche, Soon Seng Ng, Maria Serra, Bénédicte Oulès, Gozde Kar, Guy Emerton, Samuel J. I. Blackford, Spyros Darmanis, Rosa Miquel, Tu Vinh Luong, Ryo Yamamoto, Andrew Bonham, Wayel Jassem, Nigel Heaton, Alessandra Vigilante, Aileen King, Rocio Sancho, Sarah Teichmann, Stephen R. Quake, Hiromitsu Nakauchi, and S. Tamir Rashid

Subjects
Science
Abstract

The liver parenchyma consists of several cell types, but the origin of this tissue in humans is unclear. Here, the authors perform single cell RNA sequencing of human fetal and adult liver to identify a hepatobiliary hybrid progenitor population of cells, which have a similar gene signature to mouse oval cells.

Published
2019
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44. Highly emissive excitons with reduced exchange energy in thermally activated delayed fluorescent molecules

Author

Anton Pershin, David Hall, Vincent Lemaur, Juan-Carlos Sancho-Garcia, Luca Muccioli, Eli Zysman-Colman, David Beljonne, and Yoann Olivier

Subjects
Science
Abstract

Thermally activated delayed fluorescence is a mechanism for enhancing the efficiency of organic light emitting diodes by harvesting triplet excitons, but there is still a need to design more efficient materials. Here, the authors rationally design and characterize a series of π-extended boron- and nitrogen-doped nanographenes as promising candidates.

Published
2019
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45. Mechanical architecture and folding of E. coli type 1 pilus domains

Author

Alvaro Alonso-Caballero, Jörg Schönfelder, Simon Poly, Fabiano Corsetti, David De Sancho, Emilio Artacho, and Raul Perez-Jimenez

Subjects
Science
Abstract

The pilus type 1 of uropathogenic E. coli must resist mechanical forces to remain attached to the epithelium. Here the authors use single-molecule force spectroscopy to demonstrate a hierarchy of mechanical stability among the pilus domains and show that the oxidoreductase DsbA also acts as a folding chaperone on the domains.

Published
2018
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46. P53 and mTOR signalling determine fitness selection through cell competition during early mouse embryonic development

Author

Sarah Bowling, Aida Di Gregorio, Margarida Sancho, Sara Pozzi, Marieke Aarts, Massimo Signore, Michael D. Schneider, Juan Pedro Martinez-Barbera, Jesús Gil, and Tristan A. Rodríguez

Subjects
Science
Abstract

During embryo development, cell fitness determines survival but how this is regulated is unclear. Here, the authors show that in early embryonic development and stem cells exiting the naive state, cells sense the fitness of their neighbours and trigger p53 to repress mTOR to eliminate a third of cells.

Published
2018
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47. Forest productivity in southwestern Europe is controlled by coupled North Atlantic and Atlantic Multidecadal Oscillations

Author

Jaime Madrigal-González, Juan A. Ballesteros-Cánovas, Asier Herrero, Paloma Ruiz-Benito, Markus Stoffel, Manuel E. Lucas-Borja, Enrique Andivia, Cesar Sancho-García, and Miguel A. Zavala

Subjects
Science
Abstract

The North Atlantic Oscillation (NAO) drives biological responses in terrestrial ecosystems through oscillatory modes of climatic variability. Here, the authors show how landscape scale productivity responses to NAO are contingent upon the Atlantic Multidecadal Oscillation in southwestern Europe.

Published
2017
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48. Enhanced anti-tumour immunity requires the interplay between resident and circulating memory CD8+ T cells

Author

Michel Enamorado, Salvador Iborra, Elena Priego, Francisco J. Cueto, Juan A. Quintana, Sarai Martínez-Cano, Ernesto Mejías-Pérez, Mariano Esteban, Ignacio Melero, Andrés Hidalgo, and David Sancho

Subjects
Science
Abstract

Circulating memory cells include central memory T cells retaining the ability to enter the lymph nodes whereas tissue resident memory cells are confined to the parenchymal tissues. Here the authors explore the interplay between the two T-cell types and show that both cooperate in anti-tumour immunity.

Published
2017
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49. Dynamic clonal equilibrium and predetermined cancer risk in Barrett’s oesophagus

Author

Pierre Martinez, Margriet R. Timmer, Chiu T. Lau, Silvia Calpe, Maria del Carmen Sancho-Serra, Danielle Straub, Ann-Marie Baker, Sybren L. Meijer, Fiebo J. W. ten Kate, Rosalie C. Mallant-Hent, Anton H. J. Naber, Arnoud H. A. M. van Oijen, Lubbertus C. Baak, Pieter Scholten, Clarisse J. M. Böhmer, Paul Fockens, Jacques J. G. H. M. Bergman, Carlo C. Maley, Trevor A. Graham, and Kausilia K Krishnadath

Subjects
Science
Abstract

Barrett’s oesophagus is thought to be a precursor lesion for oesophageal cancer, and predicting the benign lesions that progress to cancer is clinically important. Here, the authors use FISH to study the clonal evolution of Barrett’s oesophagus and show that genetic diversity and somatic mutations are present early in the benign disease.

Published
2016
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50. Structural basis for selective recognition of acyl chains by the membrane-associated acyltransferase PatA

Author

David Albesa-Jové, Zuzana Svetlíková, Montse Tersa, Enea Sancho-Vaello, Ana Carreras-González, Pascal Bonnet, Pedro Arrasate, Ander Eguskiza, Shiva K. Angala, Javier O. Cifuente, Jana Korduláková, Mary Jackson, Katarína Mikušová, and Marcelo E. Guerin

Subjects
Science
Abstract

PatA is a membrane-associated acyltransferase that is essential for the biosynthesis of mycobacterial glycolipids. Here, Albesa-Jovéet al. describe structures of PatA from Mycobacterium smegmatisin complex with acyl donors and show that catalysis occurs by an unusual charge-relay mechanism.

Published
2016
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