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1. Iron Mining for Erythropoiesis

Author

Correnti, M., Gammella, E., Cairo, G., and Recalcati, S.

Subjects
Settore MED/04 - Patologia Generale, hypoxia, Iron, Organic Chemistry, General Medicine, Catalysis, Mining, Computer Science Applications, Inorganic Chemistry, Hemoglobins, Hepcidins, erythroferrone, iron metabolism, Erythropoiesis, hepcidin, Physical and Theoretical Chemistry, erythropoiesis, Molecular Biology, Spectroscopy
Abstract

Iron is necessary for essential processes in every cell of the body, but the erythropoietic compartment is a privileged iron consumer. In fact, as a necessary component of hemoglobin and myoglobin, iron assures oxygen distribution; therefore, a considerable amount of iron is required daily for hemoglobin synthesis and erythroid cell proliferation. Therefore, a tight link exists between iron metabolism and erythropoiesis. The liver-derived hormone hepcidin, which controls iron homeostasis via its interaction with the iron exporter ferroportin, coordinates erythropoietic activity and iron homeostasis. When erythropoiesis is enhanced, iron availability to the erythron is mainly ensured by inhibiting hepcidin expression, thereby increasing ferroportin-mediated iron export from both duodenal absorptive cells and reticuloendothelial cells that process old and/or damaged red blood cells. Erythroferrone, a factor produced and secreted by erythroid precursors in response to erythropoietin, has been identified and characterized as a suppressor of hepcidin synthesis to allow iron mobilization and facilitate erythropoiesis.

Published
2022

3. The Gaia-ESO Public Spectroscopic Survey

Author

Gilmore, G., Randich, S., Asplund, M., Binney, J., Bonifacio, P., Drew, J., Feltzing, S., Ferguson, A., Jeffries, R., Micela, G., Negueruela, I., Prusti, T., Rix, H. -W, Vallenari, A., Alfaro, E., Allende-Prieto, C., Babusiaux, C., Bensby, T., Blomme, R., Bragaglia, A., Flaccomio, E., François, P., Irwin, M., Koposov, S., Korn, A., Lanzafame, A., Pancino, E., Paunzen, E., Recio-Blanco, A., Sacco, G., Smiljanic, R., Eck, S., Walton, N., Aden, D., Aerts, C., Affer, L., Alcala, J. -M, Altavilla, G., Alves, J., Antoja, T., Arenou, F., Costanza ARGIROFFI, Asensio Ramos, A., Bailer-Jones, C., Balaguer-Nunez, L., Bayo, A., Barbuy, B., Barisevicius, G., Barrado Y Navascues, D., Battistini, C., Bellas Velidis, I., Bellazzini, M., Belokurov, V., Bergemann, M., Bertelli, G., Biazzo, K., Bienayme, O., Bland-Hawthorn, J., Boeche, C., Bonito, S., Boudreault, S., Bouvier, J., Brandao, I., Brown, A., Bruijne, J., Burleigh, M., Caballero, J., Caffau, E., Calura, F., Capuzzo-Dolcetta, R., Caramazza, M., Carraro, G., Casagrande, L., Casewell, S., Chapman, S., Chiappini, C., Chorniy, Y., Christlieb, N., Cignoni, M., Cocozza, G., Colless, M., Collet, R., Collins, M., Correnti, M., Covino, E., Crnojevic, D., Cropper, M., Cunha, M., Damiani, F., David, M., Delgado, A., Duffau, S., Edvardsson, B., Eldridge, J., Enke, H., Eriksson, K., Evans, N. W., Eyer, L., Famaey, B., Fellhauer, M., Ferreras, I., Figueras, F., Fiorentino, G., Flynn, C., Folha, D., Franciosini, E., Frasca, A., Freeman, K., Fremat, Y., Friel, E., Gaensicke, B., Gameiro, J., Garzon, F., Geier, S., Geisler, D., Gerhard, O., Gibson, B., Gomboc, A., Gomez, A., Gonzalez-Fernandez, C., Gonzalez Hernandez, J., Gosset, E., Grebel, E., Greimel, R., Groenewegen, M., Grundahl, F., Guarcello, M., Gustafsson, B., Hadrava, P., Hatzidimitriou, D., Hambly, N., Hammersley, P., Hansen, C., Haywood, M., Heber, U., Heiter, U., Held, E., Helmi, A., Hensler, G., Herrero, A., Hill, V., Hodgkin, S., Huelamo, N., Huxor, A., Ibata, R., Jackson, R., Jong, R., Jonker, P., Jordan, S., Jordi, C., Jorissen, A., Katz, D., Kawata, D., Keller, S., Kharchenko, N., Klement, R., Klutsch, A., Knude, J., Koch, A., Kochukhov, O., Kontizas, M., Koubsky, P., Lallement, R., Laverny, P., Leeuwen, F., Lemasle, B., Lewis, G., Lind, K., Lindstrom, H. P. E., Lobel, A., Lopez Santiago, J., Lucas, P., Ludwig, H., Lueftinger, T., Magrini, L., Maiz Apellaniz, J., Maldonado, J., Marconi, G., Marino, A., Martayan, C., Martinez-Valpuesta, I., Matijevic, G., Mcmahon, R., Messina, S., Meyer, M., Miglio, A., Mikolaitis, S., Minchev, I., Minniti, D., Moitinho, A., Momany, Y., Monaco, L., Montalto, M., Monteiro, M. J., Monier, R., Montes, D., Mora, A., Moraux, E., Morel, T., Mowlavi, N., Mucciarelli, A., Munari, U., Napiwotzki, R., Nardetto, N., Naylor, T., Naze, Y., Nelemans, G., Okamoto, S., Ortolani, S., Pace, G., Palla, F., Palous, J., Parker, R., Penarrubia, J., Pillitteri, I., Piotto, G., Posbic, H., Prisinzano, L., Puzeras, E., Quirrenbach, A., Ragaini, S., Read, J., Read, M., Reyle, C., Ridder, J., Robichon, N., Robin, A., Roeser, S., Romano, D., Royer, F., Ruchti, G., Ruzicka, A., Ryan, S., Ryde, N., Santos, N., Sanz Forcada, J., Sarro Baro, L. M., Sbordone, L., Schilbach, E., Schmeja, S., Schnurr, O., Schoenrich, R., Scholz, R. -D, Seabroke, G., Sharma, S., Silva, G., Smith, M., Solano, E., Sordo, R., Soubiran, C., Sousa, S., Spagna, A., Steffen, M., Steinmetz, M., Stelzer, B., Stempels, E., Tabernero, H., Tautvaisiene, G., Thevenin, F., Torra, J., Tosi, M., Tolstoy, E., Turon, C., Walker, M., Wambsganss, J., Worley, C., Venn, K., Vink, J., Wyse, R., Zaggia, S., Zeilinger, W., Zoccali, M., Zorec, J., Zucker, D., Zwitter, T., Gaia-ESO Survey Team, Gilmore, G., Randich, S., Asplund, M., Binney, J., Bonifacio, P., Drew, J., Feltzing, S., Ferguson, A., Jeffries, R., Micela, G., Negueruela, I., Prusti, T., Rix, H.-W., Vallenari, A., Alfaro, E., Allende-Prieto, C., Babusiaux, C., Bensby, T., Blomme, R., Bragaglia, A., Flaccomio, E., François, P., Irwin, M., Koposov, S., Korn, A., Lanzafame, A., Pancino, E., Paunzen, E., Recio-Blanco, A., Sacco, G., Smiljanic, R., Van Eck, S., Walton, N., Aden, D., Aerts, C., Affer, L., Alcala, J.-M., Altavilla, G., Alves, J., Antoja, T., Arenou, F., Argiroffi, C., Asensio Ramos, A., Bailer-Jones, C., Balaguer-Nunez, L., Bayo, A., Barbuy, B., Barisevicius, G., Barrado y Navascues, D., Battistini, C., Bellas Velidis, I., Bellazzini, M., Belokurov, V., Bergemann, M., Bertelli, G., Biazzo, K., Bienayme, O., Bland-Hawthorn, J., Boeche, C., Bonito, S., Boudreault, S., Bouvier, J., Brandao, I., Brown, A., de Bruijne, J., Burleigh, M., Caballero, J., Caffau, E., Calura, F., Capuzzo-Dolcetta, R., Caramazza, M., Carraro, G., Casagrande, L., Casewell, S., Chapman, S., Chiappini, C., Chorniy, Y., Christlieb, N., Cignoni, M., Cocozza, G., Colless, M., Collet, R., Collins, M., Correnti, M., Covino, E., Crnojevic, D., Cropper, M., Cunha, M., Damiani, F., David, M., Delgado, A., Duffau, S., Edvardsson, B., Eldridge, J., Enke, H., Eriksson, K., Evans, N. W., Eyer, L., Famaey, B., Fellhauer, M., Ferreras, I., Figueras, F., Fiorentino, G., Flynn, C., Folha, D., Franciosini, E., Frasca, A., Freeman, K., Fremat, Y., Friel, E., Gaensicke, B., Gameiro, J., Garzon, F., Geier, S., Geisler, D., Gerhard, O., Gibson, B., Gomboc, A., Gomez, A., Gonzalez-Fernandez, C., Gonzalez Hernandez, J., Gosset, E., Grebel, E., Greimel, R., Groenewegen, M., Grundahl, F., Guarcello, M., Gustafsson, B., Hadrava, P., Hatzidimitriou, D., Hambly, N., Hammersley, P., Hansen, C., Haywood, M., Heber, U., Heiter, U., Held, E., Helmi, A., Hensler, G., Herrero, A., Hill, V., Hodgkin, S., Huelamo, N., Huxor, A., Ibata, R., Jackson, R., de Jong, R., Jonker, P., Jordan, S., Jordi, C., Jorissen, A., Katz, D., Kawata, D., Keller, S., Kharchenko, N., Klement, R., Klutsch, A., Knude, J., Koch, A., Kochukhov, O., Kontizas, M., Koubsky, P., Lallement, R., de Laverny, P., van Leeuwen, F., Lemasle, B., Lewis, G., Lind, K., Lindstrom, H. P. E., Lobel, A., Lopez Santiago, J., Lucas, P., Ludwig, H., Lueftinger, T., Magrini, L., Maiz Apellaniz, J., Maldonado, J., Marconi, G., Marino, A., Martayan, C., Martinez-Valpuesta, I., Matijevic, G., McMahon, R., Messina, S., Meyer, M., Miglio, A., Mikolaitis, S., Minchev, I., Minniti, D., Moitinho, A., Momany, Y., Monaco, L., Montalto, M., Monteiro, M. J., Monier, R., Montes, D., Mora, A., Moraux, E., Morel, T., Mowlavi, N., Mucciarelli, A., Munari, U., Napiwotzki, R., Nardetto, N., Naylor, T., Naze, Y., Nelemans, G., Okamoto, S., Ortolani, S., Pace, G., Palla, F., Palous, J., Parker, R., Penarrubia, J., Pillitteri, I., Piotto, G., Posbic, H., Prisinzano, L., Puzeras, E., Quirrenbach, A., Ragaini, S., Read, J., Read, M., Reyle, C., De Ridder, J., Robichon, N., Robin, A., Roeser, S., Romano, D., Royer, F., Ruchti, G., Ruzicka, A., Ryan, S., Ryde, N., Santos, N., Sanz Forcada, J., Sarro Baro, L. M., Sbordone, L., Schilbach, E., Schmeja, S., Schnurr, O., Schoenrich, R., Scholz, R.-D., Seabroke, G., Sharma, S., De Silva, G., Smith, M., Solano, E., Sordo, R., Soubiran, C., Sousa, S., Spagna, A., Steffen, M., Steinmetz, M., Stelzer, B., Stempels, E., Tabernero, H., Tautvaisiene, G., Thevenin, F., Torra, J., Tosi, M., Tolstoy, E., Turon, C., Walker, M., Wambsganss, J., Worley, C., Venn, K., Vink, J., Wyse, R., Zaggia, S., Zeilinger, W., Zoccali, M., Zorec, J., Zucker, D., and Zwitter, T.

Subjects
spectroscopy, stars, kinematics, abundances, Settore FIS/05 - Astronomia E Astrofisica, Astrophysics::Instrumentation and Methods for Astrophysics, Astrophysics::Solar and Stellar Astrophysics, Astrophysics::Earth and Planetary Astrophysics, Astrophysics::Cosmology and Extragalactic Astrophysics, Astrophysics::Galaxy Astrophysics
Abstract

The Gaia-ESO Public Spectroscopic Survey has begun and will obtain high quality spectroscopy of some 100000 Milky Way stars, in the field and in open clusters, down to magnitude 19, systematically covering all the major components of the Milky Way. This survey will provide the first homogeneous overview of the distributions of kinematics and chemical element abundances in the Galaxy. The motivation, organisation and implementation of the Gaia-ESO Survey are described, emphasising the complementarity with the ESA Gaia mission. Spectra from the very first observing run of the survey are presented.

4. NGC 5694: Another extra-galactic globular cluster

Author

Alessio Mucciarelli, Bellazzini, M., Catelan, M., Amigo, P., Correnti, M., Cortés, C., Dalessandro, E., and D Orazi, V.

Subjects
Astrophysics of Galaxies (astro-ph.GA), Astrophysics::Solar and Stellar Astrophysics, FOS: Physical sciences, Astrophysics::Earth and Planetary Astrophysics, Astrophysics::Cosmology and Extragalactic Astrophysics, Astrophysics - Astrophysics of Galaxies, Astrophysics::Galaxy Astrophysics
Abstract

We discuss the chemical composition of six giant stars of the outer Halo globular cluster NGC5694, through the analysis of UVES@FLAMES high-resolution spectra. The cluster has an average iron content [Fe/H]=--1.83+-0.01, solar-scaled [alpha/Fe] ratios and a very low Ba abundance ([Ba/Fe]=--0.71+-0.06). These anomalous abundance patterns are different from those observed in other Halo globular clusters but similar to those of the metal-poor stars in typical dwarf spheroidal galaxies. These findings suggest an extra-galactic origin for NGC5694, likely from a dwarf spheroidal galaxy., Comment: 4 pages, 3 figures, proceedings of the meeting "Reading the book of globular clusters with the lens of stellar evolution", Rome, Nov. 26-28, 2012, to be published in Memorie della Societa' Astronomica Italiana

5. Mitochondrial oxidative metabolism contributes to a cancer stem cell phenotype in cholangiocarcinoma

Author

Matteo Ramazzotti, Luca Viganò, Mirella Pastore, Maria Letizia Taddei, Monika Lewinska, Javier Cibella, Clelia Peano, Erica Pranzini, Luca Di Tommaso, Elena Sacco, Jessica Iorio, Paola Chiarugi, S. Madiai, Jesper B. Andersen, Chiara Raggi, Ivan Orlandi, B. Piombanti, Giovanni Di Maira, Margherita Correnti, N. Navari, Tiziano Lottini, Annarosa Arcangeli, Giulia Lori, Claudia Campani, Fabio Marra, Raggi, C, Taddei, M, Sacco, E, Navari, N, Correnti, M, Piombanti, B, Pastore, M, Campani, C, Pranzini, E, Iorio, J, Lori, G, Lottini, T, Peano, C, Cibella, J, Lewinska, M, Andersen, J, di Tommaso, L, Vigano, L, Di Maira, G, Madiai, S, Ramazzotti, M, Orlandi, I, Arcangeli, A, Chiarugi, P, and Marra, F

Subjects
Male, 0301 basic medicine, Indoles, Carcinogenesis, Propanols, PGC-1α, Mice, SCID, Mitochondrion, Oxidative Phosphorylation, Cholangiocarcinoma, Mice, Metformin/administration & dosage, 0302 clinical medicine, Mice, Inbred NOD, Signal Transduction/drug effects, SR-18292, CCLP1, Propanols/administration & dosage, Oxidative Phosphorylation/drug effects, Electron Transport Complex II, Indoles/administration & dosage, OXPHOS, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/antagonists & inhibitors, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Phenotype, Metformin, Progression-Free Survival, Mitochondria, Tumor Burden, Treatment Outcome, Neoplastic Stem Cells, 030211 gastroenterology & hepatology, Epithelial-Mesenchymal Transition/drug effects, Signal transduction, Electron Transport Complex II/metabolism, Tumor Burden/drug effects, Signal Transduction, Epithelial-Mesenchymal Transition, Oxidative phosphorylation, Biology, Transfection, 03 medical and health sciences, HUCCT1, Neoplastic Stem Cells/metabolism, Cancer stem cell, Cell Line, Tumor, Mitochondria/metabolism, Cholangiocarcinoma/drug therapy, Animals, Humans, Gene silencing, Gene Silencing, Hepatology, Bile Duct Neoplasms/drug therapy, Carcinogenesis/drug effects, Xenograft Model Antitumor Assays, Embryonic stem cell, 030104 developmental biology, Bile Duct Neoplasms, Mitochondrial biogenesis, Cancer research
Abstract

BACKGROUND & AIMS: Little is known about the metabolic regulation of cancer stem cells (CSCs) in cholangiocarcinoma (CCA). We analyzed whether mitochondrial-dependent metabolism and related signaling pathways contribute to stemness in CCA.METHODS: The stem-like subset was enriched by sphere culture (SPH) in human intrahepatic CCA cells (HUCCT1 and CCLP1) and compared to cells cultured in monolayer. Extracellular flux analysis was examined by Seahorse technology and high-resolution respirometry. In patients with CCA, expression of factors related to mitochondrial metabolism was analyzed for possible correlation with clinical parameters.RESULTS: Metabolic analyses revealed a more efficient respiratory phenotype in CCA-SPH than in monolayers, due to mitochondrial oxidative phosphorylation. CCA-SPH showed high mitochondrial membrane potential and elevated mitochondrial mass, and over-expressed peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α, a master regulator of mitochondrial biogenesis. Targeting mitochondrial complex I in CCA-SPH using metformin, or PGC-1α silencing or pharmacologic inhibition (SR-18292), impaired spherogenicity and expression of markers related to the CSC phenotype, pluripotency, and epithelial-mesenchymal transition. In mice with tumor xenografts generated by injection of CCA-SPH, administration of metformin or SR-18292 significantly reduced tumor growth and determined a phenotype more similar to tumors originated from cells grown in monolayer. In patients with CCA, expression of PGC-1α correlated with expression of mitochondrial complex II and of stem-like genes. Patients with higher PGC-1α expression by immunostaining had lower overall and progression-free survival, increased angioinvasion and faster recurrence. In GSEA analysis, patients with CCA and high levels of mitochondrial complex II had shorter overall survival and time to recurrence.CONCLUSIONS: The CCA stem-subset has a more efficient respiratory phenotype and depends on mitochondrial oxidative metabolism and PGC-1α to maintain CSC features.LAY SUMMARY: The growth of many cancers is sustained by a specific type of cells with more embryonic characteristics, termed 'cancer stem cells'. These cells have been described in cholangiocarcinoma, a type of liver cancer with poor prognosis and limited therapeutic approaches. We demonstrate that cancer stem cells in cholangiocarcinoma have different metabolic features, and use mitochondria, an organelle located within the cells, as the major source of energy. We also identify PGC-1α, a molecule which regulates the biology of mitochondria, as a possible new target to be explored for developing new treatments for cholangiocarcinoma.

Published
2021

6. The Science Performance of JWST as Characterized in Commissioning

Author

Jane Rigby, Marshall Perrin, Michael McElwain, Randy Kimble, Scott Friedman, Matt Lallo, René Doyon, Lee Feinberg, Pierre Ferruit, Alistair Glasse, Marcia Rieke, George Rieke, Gillian Wright, Chris Willott, Knicole Colon, Stefanie Milam, Susan Neff, Christopher Stark, Jeff Valenti, Jim Abell, Faith Abney, Yasin Abul-Huda, D. Scott Acton, Evan Adams, David Adler, Jonathan Aguilar, Nasif Ahmed, Loïc Albert, Stacey Alberts, David Aldridge, Marsha Allen, Martin Altenburg, Javier Álvarez-Márquez, Catarina Alves de Oliveira, Greg Andersen, Harry Anderson, Sara Anderson, Ioannis Argyriou, Amber Armstrong, Santiago Arribas, Etienne Artigau, Amanda Arvai, Charles Atkinson, Gregory Bacon, Thomas Bair, Kimberly Banks, Jaclyn Barrientes, Bruce Barringer, Peter Bartosik, William Bast, Pierre Baudoz, Thomas Beatty, Katie Bechtold, Tracy Beck, Eddie Bergeron, Matthew Bergkoetter, Rachana Bhatawdekar, Stephan Birkmann, Ronald Blazek, Claire Blome, Anthony Boccaletti, Torsten Böker, John Boia, Nina Bonaventura, Nicholas Bond, Kari Bosley, Ray Boucarut, Matthew Bourque, Jeroen Bouwman, Gary Bower, Charles Bowers, Martha Boyer, Larry Bradley, Greg Brady, Hannah Braun, David Breda, Pamela Bresnahan, Stacey Bright, Christopher Britt, Asa Bromenschenkel, Brian Brooks, Keira Brooks, Bob Brown, Matthew Brown, Patricia Brown, Andy Bunker, Matthew Burger, Howard Bushouse, Steven Cale, Alex Cameron, Peter Cameron, Alicia Canipe, James Caplinger, Francis Caputo, Mihai Cara, Larkin Carey, Stefano Carniani, Maria Carrasquilla, Margaret Carruthers, Michael Case, Riggs Catherine, Don Chance, George Chapman, Stéphane Charlot, Brian Charlow, Pierre Chayer, Bin Chen, Brian Cherinka, Sarah Chichester, Zack Chilton, Taylor Chonis, Mark Clampin, Charles Clark, Kerry Clark, Dan Coe, Benee Coleman, Brian Comber, Tom Comeau, Dennis Connolly, James Cooper, Rachel Cooper, Eric Coppock, Matteo Correnti, Christophe Cossou, Alain Coulais, Laura Coyle, Misty Cracraft, Mirko Curti, Steven Cuturic, Katherine Davis, Michael Davis, Bruce Dean, Amy DeLisa, Wim deMeester, Nadia Dencheva, Nadezhda Dencheva, Joseph DePasquale, Jeremy Deschenes, Örs Hunor Detre, Rosa Diaz, Dan Dicken, Audrey DiFelice, Matthew Dillman, William Dixon, Jesse Doggett, Tom Donaldson, Rob Douglas, Kimberly DuPrie, Jean Dupuis, John Durning, Nilufar Easmin, Weston Eck, Chinwe Edeani, Eiichi Egami, Ralf Ehrenwinkler, Jonathan Eisenhamer, Michael Eisenhower, Michelle Elie, James Elliott, Kyle Elliott, Tracy Ellis, Michael Engesser, Nestor Espinoza, Odessa Etienne, Mireya Etxaluze, Patrick Falini, Matthew Feeney, Malcolm Ferry, Joseph Filippazzo, Brian Fincham, Mees Fix, Nicolas Flagey, Michael Florian, Jim Flynn, Erin Fontanella, Terrance Ford, Peter Forshay, Ori Fox, David Franz, Henry Fu, Alexander Fullerton, Sergey Galkin, Anthony Galyer, Macarena García Marín, Jonathan P. Gardner, Lisa Gardner, Dennis Garland, Bruce Garrett, Danny Gasman, Andras Gaspar, Daniel Gaudreau, Peter Gauthier, Vincent Geers, Paul Geithner, Mario Gennaro, Giovanna Giardino, Julien Girard, Mark Giuliano, Kirk Glassmire, Adrian Glauser, Stuart Glazer, John Godfrey, David Golimowski, David Gollnitz, Fan Gong, Shireen Gonzaga, Michael Gordon, Karl Gordon, Paul Goudfrooij, Thomas Greene, Matthew Greenhouse, Stefano Grimaldi, Andrew Groebner, Timothy Grundy, Pierre Guillard, Irvin Gutman, Kong Q. Ha, Peter Haderlein, Andria Hagedorn, Kevin Hainline, Craig Haley, Maryam Hami, Forrest Hamilton, Heidi Hammel, Carl Hansen, Tom Harkins, Michael Harr, Jessica Hart, Quyen Hart, George Hartig, Ryan Hashimoto, Sujee Haskins, William Hathaway, Keith Havey, Brian Hayden, Karen Hecht, Chris Heller-Boyer, Caroline Henriques, Alaina Henry, Karl Hermann, Scarlin Hernandez, Brigette Hesman, Brian Hicks, Bryan Hilbert, Dean Hines, Melissa Hoffman, Sherie Holfeltz, Bryan J. Holler, Jennifer Hoppa, Kyle Hott, Joseph M. Howard, Rick Howard, Alexander Hunter, David Hunter, Brendan Hurst, Bernd Husemann, Leah Hustak, Luminita Ilinca Ignat, Garth Illingworth, Sandra Irish, Wallace Jackson, Amir Jahromi, Peter Jakobsen, LeAndrea James, Bryan James, William Januszewski, Ann Jenkins, Hussein Jirdeh, Phillip Johnson, Timothy Johnson, Vicki Jones, Ron Jones, Danny Jones, Olivia Jones, Ian Jordan, Margaret Jordan, Sarah Jurczyk, Alden Jurling, Catherine Kaleida, Phillip Kalmanson, Jens Kammerer, Huijo Kang, Shaw-Hong Kao, Diane Karakla, Patrick Kavanagh, Doug Kelly, Sarah Kendrew, Herbert Kennedy, Deborah Kenny, Ritva Keski-kuha, Charles Keyes, Richard Kidwell, Wayne Kinzel, Jeff Kirk, Mark Kirkpatrick, Danielle Kirshenblat, Pamela Klaassen, Bryan Knapp, J. Scott Knight, Perry Knollenberg, Robert Koehler, Anton Koekemoer, Aiden Kovacs, Trey Kulp, Nimisha Kumari, Mark Kyprianou, Stephanie La Massa, Aurora Labador, Alvaro Labiano, Pierre-Olivier Lagage, Charles-Philippe Lajoie, Matthew Lallo, May Lam, Tracy Lamb, Scott Lambros, Richard Lampenfield, James Langston, Kirsten Larson, David Law, Jon Lawrence, David Lee, Jarron Leisenring, Kelly Lepo, Michael Leveille, Nancy Levenson, Marie Levine, Zena Levy, Dan Lewis, Hannah Lewis, Mattia Libralato, Paul Lightsey, Miranda Link, Lily Liu, Amy Lo, Alexandra Lockwood, Ryan Logue, Chris Long, Douglas Long, Charles Loomis, Marcos Lopez-Caniego, Jose Lorenzo Alvarez, Jennifer Love-Pruitt, Adrian Lucy, Nora Luetzgendorf, Peiman Maghami, Roberto Maiolino, Melissa Major, Sunita Malla, Eliot Malumuth, Elena Manjavacas, Crystal Mannfolk, Amanda Marrione, Anthony Marston, André Martel, Marc Maschmann, Gregory Masci, Michaela Masciarelli, Michael Maszkiewicz, John Mather, Kenny McKenzie, Brian McLean, Matthew McMaster, Katie Melbourne, Marcio Meléndez, Michael Menzel, Kaiya Merz, Michele Meyett, Luis Meza, Cherie Miskey, Karl Misselt, Christopher Moller, Jane Morrison, Ernie Morse, Harvey Moseley, Gary Mosier, Matt Mountain, Julio Mueckay, Michael Mueller, Susan Mullally, Jess Murphy, Katherine Murray, Claire Murray, David Mustelier, James Muzerolle, Matthew Mycroft, Richard Myers, Kaila Myrick, Shashvat Nanavati, Elizabeth Nance, Omnarayani Nayak, Bret Naylor, Edmund Nelan, Bryony Nickson, Alethea Nielson, Maria Nieto-Santisteban, Nikolay Nikolov, Alberto Noriega-Crespo, Brian O’Shaughnessy, Brian O’Sullivan, William Ochs, Patrick Ogle, Brenda Oleszczuk, Joseph Olmsted, Shannon Osborne, Richard Ottens, Beverly Owens, Camilla Pacifici, Alyssa Pagan, James Page, Sang Park, Keith Parrish, Polychronis Patapis, Lee Paul, Tyler Pauly, Cheryl Pavlovsky, Andrew Pedder, Matthew Peek, Maria Pena-Guerrero, Konstantin Penanen, Yesenia Perez, Michele Perna, Beth Perriello, Kevin Phillips, Martin Pietraszkiewicz, Jean-Paul Pinaud, Norbert Pirzkal, Joseph Pitman, Aidan Piwowar, Vera Platais, Danielle Player, Rachel Plesha, Joe Pollizi, Ethan Polster, Klaus Pontoppidan, Blair Porterfield, Charles Proffitt, Laurent Pueyo, Christine Pulliam, Brian Quirt, Irma Quispe Neira, Rafael Ramos Alarcon, Leah Ramsay, Greg Rapp, Robert Rapp, Bernard Rauscher, Swara Ravindranath, Timothy Rawle, Michael Regan, Timothy A. Reichard, Carl Reis, Michael E. Ressler, Armin Rest, Paul Reynolds, Timothy Rhue, Karen Richon, Emily Rickman, Michael Ridgaway, Christine Ritchie, Hans-Walter Rix, Massimo Robberto, Gregory Robinson, Michael Robinson, Orion Robinson, Frank Rock, David Rodriguez, Bruno Rodriguez Del Pino, Thomas Roellig, Scott Rohrbach, Anthony Roman, Fred Romelfanger, Perry Rose, Anthony Roteliuk, Marc Roth, Braden Rothwell, Neil Rowlands, Arpita Roy, Pierre Royer, Patricia Royle, Chunlei Rui, Peter Rumler, Joel Runnels, Melissa Russ, Zafar Rustamkulov, Grant Ryden, Holly Ryer, Modhumita Sabata, Derek Sabatke, Elena Sabbi, Bridget Samuelson, Benjamin Sapp, Bradley Sappington, B. Sargent, Arne Sauer, Silvia Scheithauer, Everett Schlawin, Joseph Schlitz, Tyler Schmitz, Analyn Schneider, Jürgen Schreiber, Vonessa Schulze, Ryan Schwab, John Scott, Kenneth Sembach, Clare Shanahan, Bryan Shaughnessy, Richard Shaw, Nanci Shawger, Christopher Shay, Evan Sheehan, Sharon Shen, Allan Sherman, Bernard Shiao, Hsin-Yi Shih, Irene Shivaei, Matthew Sienkiewicz, David Sing, Marco Sirianni, Anand Sivaramakrishnan, Joy Skipper, G. C. Sloan, Christine Slocum, Steven Slowinski, Erin Smith, Eric Smith, Denise Smith, Corbett Smith, Gregory Snyder, Warren Soh, Sangmo Tony Sohn, Christian Soto, Richard Spencer, Scott Stallcup, John Stansberry, Carl Starr, Elysia Starr, Alphonso Stewart, Massimo Stiavelli, Amber Straughn, David Strickland, Jeff Stys, Francis Summers, Fengwu Sun, Ben Sunnquist, Daryl Swade, Michael Swam, Robert Swaters, Robby Swoish, Joanna M. Taylor, Rolanda Taylor, Maurice Te Plate, Mason Tea, Kelly Teague, Randal Telfer, Tea Temim, Deepashri Thatte, Christopher Thompson, Linda Thompson, Shaun Thomson, Tuomo Tikkanen, William Tippet, Connor Todd, Sharon Toolan, Hien Tran, Edwin Trejo, Justin Truong, Chris Tsukamoto, Samuel Tustain, Harrison Tyra, Leonardo Ubeda, Kelli Underwood, Michael Uzzo, Julie Van Campen, Thomas Vandal, Bart Vandenbussche, Begoña Vila, Kevin Volk, Glenn Wahlgren, Mark Waldman, Chanda Walker, Michel Wander, Christine Warfield, Gerald Warner, Matthew Wasiak, Mitchell Watkins, Andrew Weaver, Mark Weilert, Nick Weiser, Ben Weiss, Sarah Weissman, Alan Welty, Garrett West, Lauren Wheate, Elizabeth Wheatley, Thomas Wheeler, Rick White, Kevin Whiteaker, Paul Whitehouse, Jennifer Whiteleather, William Whitman, Christina Williams, Christopher Willmer, Scott Willoughby, Andrew Wilson, Gregory Wirth, Emily Wislowski, Erin Wolf, David Wolfe, Schuyler Wolff, Bill Workman, Ray Wright, Carl Wu, Rai Wu, Kristen Wymer, Kayla Yates, Christopher Yeager, Jared Yeates, Ethan Yerger, Jinmi Yoon, Alice Young, Susan Yu, Dean Zak, Peter Zeidler, Julia Zhou, Thomas Zielinski, Cristian Zincke, Stephanie Zonak, Rigby, J., Perrin, M., Mcelwain, M., Kimble, R., Friedman, S., Lallo, M., Doyon, R., Feinberg, L., Ferruit, P., Glasse, A., Rieke, M., Rieke, G., Wright, G., Willott, C., Colon, K., Milam, S., Neff, S., Stark, C., Valenti, J., Abell, J., Abney, F., Abul-Huda, Y., Scott Acton, D., Adams, E., Adler, D., Aguilar, J., Ahmed, N., Albert, L., Alberts, S., Aldridge, D., Allen, M., Altenburg, M., Alvarez-Marquez, J., Alves de Oliveira, C., Andersen, G., Anderson, H., Anderson, S., Argyriou, I., Armstrong, A., Arribas, S., Artigau, E., Arvai, A., Atkinson, C., Bacon, G., Bair, T., Banks, K., Barrientes, J., Barringer, B., Bartosik, P., Bast, W., Baudoz, P., Beatty, T., Bechtold, K., Beck, T., Bergeron, E., Bergkoetter, M., Bhatawdekar, R., Birkmann, S., Blazek, R., Blome, C., Boccaletti, A., Boker, T., Boia, J., Bonaventura, N., Bond, N., Bosley, K., Boucarut, R., Bourque, M., Bouwman, J., Bower, G., Bowers, C., Boyer, M., Bradley, L., Brady, G., Braun, H., Breda, D., Bresnahan, P., Bright, S., Britt, C., Bromenschenkel, A., Brooks, B., Brooks, K., Brown, B., Brown, M., Brown, P., Bunker, A., Burger, M., Bushouse, H., Cale, S., Cameron, A., Cameron, P., Canipe, A., Caplinger, J., Caputo, F., Cara, M., Carey, L., Carniani, S., Carrasquilla, M., Carruthers, M., Case, M., Catherine, R., Chance, D., Chapman, G., Charlot, S., Charlow, B., Chayer, P., Chen, B., Cherinka, B., Chichester, S., Chilton, Z., Chonis, T., Clampin, M., Clark, C., Clark, K., Coe, D., Coleman, B., Comber, B., Comeau, T., Connolly, D., Cooper, J., Cooper, R., Coppock, E., Correnti, M., Cossou, C., Coulais, A., Coyle, L., Cracraft, M., Curti, M., Cuturic, S., Davis, K., Davis, M., Dean, B., Delisa, A., Demeester, W., Dencheva, N., Depasquale, J., Deschenes, J., Hunor Detre, I., Diaz, R., Dicken, D., Difelice, A., Dillman, M., Dixon, W., Doggett, J., Donaldson, T., Douglas, R., Duprie, K., Dupuis, J., Durning, J., Easmin, N., Eck, W., Edeani, C., Egami, E., Ehrenwinkler, R., Eisenhamer, J., Eisenhower, M., Elie, M., Elliott, J., Elliott, K., Ellis, T., Engesser, M., Espinoza, N., Etienne, O., Etxaluze, M., Falini, P., Feeney, M., Ferry, M., Filippazzo, J., Fincham, B., Fix, M., Flagey, N., Florian, M., Flynn, J., Fontanella, E., Ford, T., Forshay, P., Fox, O., Franz, D., Fu, H., Fullerton, A., Galkin, S., Galyer, A., Garcia Marin, M., Gardner, J. P., Gardner, L., Garland, D., Garrett, B., Gasman, D., Gaspar, A., Gaudreau, D., Gauthier, P., Geers, V., Geithner, P., Gennaro, M., Giardino, G., Girard, J., Giuliano, M., Glassmire, K., Glauser, A., Glazer, S., Godfrey, J., Golimowski, D., Gollnitz, D., Gong, F., Gonzaga, S., Gordon, M., Gordon, K., Goudfrooij, P., Greene, T., Greenhouse, M., Grimaldi, S., Groebner, A., Grundy, T., Guillard, P., Gutman, I., Ha, K. Q., Haderlein, P., Hagedorn, A., Hainline, K., Haley, C., Hami, M., Hamilton, F., Hammel, H., Hansen, C., Harkins, T., Harr, M., Hart, J., Hart, Q., Hartig, G., Hashimoto, R., Haskins, S., Hathaway, W., Havey, K., Hayden, B., Hecht, K., Heller-Boyer, C., Henriques, C., Henry, A., Hermann, K., Hernandez, S., Hesman, B., Hicks, B., Hilbert, B., Hines, D., Hoffman, M., Holfeltz, S., Holler, B. J., Hoppa, J., Hott, K., Howard, J. M., Howard, R., Hunter, A., Hunter, D., Hurst, B., Husemann, B., Hustak, L., Ilinca Ignat, L., Illingworth, G., Irish, S., Jackson, W., Jahromi, A., Jakobsen, P., James, L., James, B., Januszewski, W., Jenkins, A., Jirdeh, H., Johnson, P., Johnson, T., Jones, V., Jones, R., Jones, D., Jones, O., Jordan, I., Jordan, M., Jurczyk, S., Jurling, A., Kaleida, C., Kalmanson, P., Kammerer, J., Kang, H., Kao, S. -H., Karakla, D., Kavanagh, P., Kelly, D., Kendrew, S., Kennedy, H., Kenny, D., Keski-Kuha, R., Keyes, C., Kidwell, R., Kinzel, W., Kirk, J., Kirkpatrick, M., Kirshenblat, D., Klaassen, P., Knapp, B., Scott Knight, J., Knollenberg, P., Koehler, R., Koekemoer, A., Kovacs, A., Kulp, T., Kumari, N., Kyprianou, M., La Massa, S., Labador, A., Labiano, A., Lagage, P. -O., Lajoie, C. -P., Lam, M., Lamb, T., Lambros, S., Lampenfield, R., Langston, J., Larson, K., Law, D., Lawrence, J., Lee, D., Leisenring, J., Lepo, K., Leveille, M., Levenson, N., Levine, M., Levy, Z., Lewis, D., Lewis, H., Libralato, M., Lightsey, P., Link, M., Liu, L., Lo, A., Lockwood, A., Logue, R., Long, C., Long, D., Loomis, C., Lopez-Caniego, M., Lorenzo Alvarez, J., Love-Pruitt, J., Lucy, A., Luetzgendorf, N., Maghami, P., Maiolino, R., Major, M., Malla, S., Malumuth, E., Manjavacas, E., Mannfolk, C., Marrione, A., Marston, A., Martel, A., Maschmann, M., Masci, G., Masciarelli, M., Maszkiewicz, M., Mather, J., Mckenzie, K., Mclean, B., Mcmaster, M., Melbourne, K., Melendez, M., Menzel, M., Merz, K., Meyett, M., Meza, L., Miskey, C., Misselt, K., Moller, C., Morrison, J., Morse, E., Moseley, H., Mosier, G., Mountain, M., Mueckay, J., Mueller, M., Mullally, S., Murphy, J., Murray, K., Murray, C., Mustelier, D., Muzerolle, J., Mycroft, M., Myers, R., Myrick, K., Nanavati, S., Nance, E., Nayak, O., Naylor, B., Nelan, E., Nickson, B., Nielson, A., Nieto-Santisteban, M., Nikolov, N., Noriega-Crespo, A., O'Shaughnessy, B., O'Sullivan, B., Ochs, W., Ogle, P., Oleszczuk, B., Olmsted, J., Osborne, S., Ottens, R., Owens, B., Pacifici, C., Pagan, A., Page, J., Park, S., Parrish, K., Patapis, P., Paul, L., Pauly, T., Pavlovsky, C., Pedder, A., Peek, M., Pena-Guerrero, M., Penanen, K., Perez, Y., Perna, M., Perriello, B., Phillips, K., Pietraszkiewicz, M., Pinaud, J. -P., Pirzkal, N., Pitman, J., Piwowar, A., Platais, V., Player, D., Plesha, R., Pollizi, J., Polster, E., Pontoppidan, K., Porterfield, B., Proffitt, C., Pueyo, L., Pulliam, C., Quirt, B., Quispe Neira, I., Ramos Alarcon, R., Ramsay, L., Rapp, G., Rapp, R., Rauscher, B., Ravindranath, S., Rawle, T., Regan, M., Reichard, T. A., Reis, C., Ressler, M. E., Rest, A., Reynolds, P., Rhue, T., Richon, K., Rickman, E., Ridgaway, M., Ritchie, C., Rix, H. -W., Robberto, M., Robinson, G., Robinson, M., Robinson, O., Rock, F., Rodriguez, D., Rodriguez Del Pino, B., Roellig, T., Rohrbach, S., Roman, A., Romelfanger, F., Rose, P., Roteliuk, A., Roth, M., Rothwell, B., Rowlands, N., Roy, A., Royer, P., Royle, P., Rui, C., Rumler, P., Runnels, J., Russ, M., Rustamkulov, Z., Ryden, G., Ryer, H., Sabata, M., Sabatke, D., Sabbi, E., Samuelson, B., Sapp, B., Sappington, B., Sargent, B., Sauer, A., Scheithauer, S., Schlawin, E., Schlitz, J., Schmitz, T., Schneider, A., Schreiber, J., Schulze, V., Schwab, R., Scott, J., Sembach, K., Shanahan, C., Shaughnessy, B., Shaw, R., Shawger, N., Shay, C., Sheehan, E., Shen, S., Sherman, A., Shiao, B., Shih, H. -Y., Shivaei, I., Sienkiewicz, M., Sing, D., Sirianni, M., Sivaramakrishnan, A., Skipper, J., Sloan, G. C., Slocum, C., Slowinski, S., Smith, E., Smith, D., Smith, C., Snyder, G., Soh, W., Tony Sohn, S., Soto, C., Spencer, R., Stallcup, S., Stansberry, J., Starr, C., Starr, E., Stewart, A., Stiavelli, M., Straughn, A., Strickland, D., Stys, J., Summers, F., Sun, F., Sunnquist, B., Swade, D., Swam, M., Swaters, R., Swoish, R., Taylor, J. M., Taylor, R., Te Plate, M., Tea, M., Teague, K., Telfer, R., Temim, T., Thatte, D., Thompson, C., Thompson, L., Thomson, S., Tikkanen, T., Tippet, W., Todd, C., Toolan, S., Tran, H., Trejo, E., Truong, J., Tsukamoto, C., Tustain, S., Tyra, H., Ubeda, L., Underwood, K., Uzzo, M., Van Campen, J., Vandal, T., Vandenbussche, B., Vila, B., Volk, K., Wahlgren, G., Waldman, M., Walker, C., Wander, M., Warfield, C., Warner, G., Wasiak, M., Watkins, M., Weaver, A., Weilert, M., Weiser, N., Weiss, B., Weissman, S., Welty, A., West, G., Wheate, L., Wheatley, E., Wheeler, T., White, R., Whiteaker, K., Whitehouse, P., Whiteleather, J., Whitman, W., Williams, C., Willmer, C., Willoughby, S., Wilson, A., Wirth, G., Wislowski, E., Wolf, E., Wolfe, D., Wolff, S., Workman, B., Wright, R., Wu, C., Wu, R., Wymer, K., Yates, K., Yeager, C., Yeates, J., Yerger, E., Yoon, J., Young, A., Yu, S., Zak, D., Zeidler, P., Zhou, J., Zielinski, T., Zincke, C., Zonak, S., and bibliotheque, la.

Subjects
Science & Technology, Observatories, Infrared astronomy, Astronomical instrumentation, INFRARED SPECTROGRAPH NIRSPEC, FOS: Physical sciences, Astronomy and Astrophysics, Astronomy & Astrophysics, Settore FIS/05 - Astronomia e Astrofisica, Space and Planetary Science, Physical Sciences, Astrophysics - Instrumentation and Methods for Astrophysics, [PHYS.ASTR] Physics [physics]/Astrophysics [astro-ph], Instrumentation and Methods for Astrophysics (astro-ph.IM)
Abstract

This paper characterizes the actual science performance of the James Webb Space Telescope (JWST), as determined from the six month commissioning period. We summarize the performance of the spacecraft, telescope, science instruments, and ground system, with an emphasis on differences from pre-launch expectations. Commissioning has made clear that JWST is fully capable of achieving the discoveries for which it was built. Moreover, almost across the board, the science performance of JWST is better than expected; in most cases, JWST will go deeper faster than expected. The telescope and instrument suite have demonstrated the sensitivity, stability, image quality, and spectral range that are necessary to transform our understanding of the cosmos through observations spanning from near-earth asteroids to the most distant galaxies., Comment: 5th version as accepted to PASP; 31 pages, 18 figures; https://iopscience.iop.org/article/10.1088/1538-3873/acb293

Published
2022
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7. The protease-inhibitor SerpinB3 as a critical modulator of the stem-like subset in human cholangiocarcinoma

Author

Matteo Parri, Cédric Coulouarn, Stefania Recalcati, Giuliana Cavalloni, Matteo Fassan, Claudia Campani, Luca Di Tommaso, Guido Torzilli, Andrea Cappon, Alessandra Biasiolo, Fabio Marra, Jesper B. Andersen, Chiara Raggi, B. Piombanti, Matteo Ramazzotti, Giulia Lori, Patricia Munoz-Garrido, Pietro Invernizzi, Laurent Sulpice, Santina Quarta, M. Correnti, Patrizia Pontisso, Caterina Peraldo Neia, Mirella Pastore, Monika Lewinska, Douglas Vnp Oliveira, Correnti, M, Cappon, A, Pastore, M, Piombanti, B, Lori, G, Oliveira, D, Munoz-Garrido, P, Lewinska, M, Andersen, J, Coulouarn, C, Sulpice, L, Peraldo Neia, C, Cavalloni, G, Quarta, S, Biasiolo, A, Fassan, M, Ramazzotti, M, Parri, M, Recalcati, S, di Tommaso, L, Campani, C, Invernizzi, P, Torzilli, G, Marra, F, Pontisso, P, Raggi, C, Humanitas Clinical and Research Center [Rozzano, Milan, Italy], Università degli Studi di Milano = University of Milan (UNIMI), Università degli Studi di Padova = University of Padua (Unipd), Università degli Studi di Firenze = University of Florence (UniFI), University of Copenhagen = Københavns Universitet (UCPH), CHU Pontchaillou [Rennes], Oncogenesis, Stress, Signaling (OSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Eugène Marquis (CRLCC), Nutrition, Métabolismes et Cancer (NuMeCan), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Cancer Genomics Laboratory, Fondazione 'Edo ed Elvo Tempia Valenta', Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo Cancer Institute [Candiolo, Italie], Università degli studi di Torino = University of Turin (UNITO), Humanitas University [Milan] (Hunimed), Università degli Studi di Milano-Bicocca = University of Milano-Bicocca (UNIMIB), San Gerardo Hospital [Monza, Italy] (SGH), and Funding for this work was partially provided by the Italian Foundation of Cancer Research award (MFGA17588, IG23117) to Dr Raggi and (IG17786) to Prof. Marra, and in part by the University of Padua (Project: CPDA110795) to Prof. Pontisso. Dr Coulouarn was supported by Inserm, University of Rennes 1, and ITMO Cancer AVIESAN dans le cadre du Plan cancer (Non-coding RNA in cancerology: fundamental to translational). Dr Andersen, Dr Coulouarn, Dr Sulpice, Prof. Recalcati, Prof. Invernizzi and Dr Raggi are members of the European Network for the Study of Cholangiocarcinoma (ENSCCA) and participate in the initiative COST Action EURO-CHOLANGIO-NET granted by the COST Association (CA18122). Prof. Invernizzi is a member of the European Reference Network on Hepatological Diseases (ERN RARE LIVER). This study was partly supported by Italian Ministry of Health grants (PE-2016-02363915 and GR-2018-12367794). The authors thank AMAF Monza ONLUS and AIRCS for the unrestricted research funding.

Subjects
Homeobox protein NANOG, cancer stem cells, cancer stem cell, Epithelial-Mesenchymal Transition, [SDV.CAN]Life Sciences [q-bio]/Cancer, Mice, SCID, Cholangiocarcinoma, Mice, SOX2, Cancer stem cell, Antigens, Neoplasm, Mice, Inbred NOD, Cell Line, Tumor, Animals, Humans, Protease Inhibitors, Progenitor cell, Serpins, Hepatology, biology, SerpinB3, CD44, Liver Neoplasms, Membrane Proteins, Transfection, invasion, ADAM Proteins, Bile Ducts, Intrahepatic, Bile Duct Neoplasms, KLF4, Cell culture, Cancer research, biology.protein, Neoplastic Stem Cells, cholangiocarcinoma, Peptide Hydrolases
Abstract

Background and aims: Cholangiocarcinoma (CCA) is a form of primary liver cancer with limited therapeutic options. Recently, cancer stem cells (CSCs) have been proposed as a driving force of tumour initiation and dissemination, thus representing a crucial therapeutic target. The protease inhibitor SerpinB3 (SB3) has been identified in several malignancies including hepatocellular carcinoma. SB3 has been involved in the early events of hepatocarcinogenesis and is highly expressed in hepatic progenitor cells and in a mouse model of liver progenitor cell activation. However, only limited information on the possible role of SB3 in CCA stem-like compartment is available. Methods: Enrichment of CCA stem-like subset was performed by sphere culture (SPH) in CCA cell lines (CCLP1, HUCCT1, MTCHC01 and SG231). Quantitative RT-PCR and Western blotting were used to detect SB3 in both SPH and parental monolayer (MON) cells. Acquired CSC-like features were analysed using an endogenous and a paracrine in vitro model, with transfection of SB3 gene or addition of recombinant SB3 to cell medium respectively. SB3 tumorigenic role was explored in an in vivo mouse model of CCA by subcutaneous injection of SB3-transfected MON (MONSB3+) cells in immune-deficient NOD-SCID/IL2Rgnull (NSG) mice. SB3 expression in human CCA sections was investigated by immunohistochemistry. Overall survival (OS) and time to recurrence (TTR) analyses were carried out from a transcriptome database of 104 CCA patients. Results: SB3, barely detected in parental MON cells, was overexpressed in the same CCA cells grown as 3D SPH. Notably, MONSB3+ showed significant overexpression of genes associated with stemness (CD24, CD44, CD133), pluripotency (c-MYC, NOTCH1, STAT3, YAP, NANOG, BMI1, KLF4, OCT4, SOX2), epithelial mesenchymal transition (β-catenin, SLUG) and extracellular matrix remodelling (MMP1, MMP7, MMP9, ADAM9, ADAM10, ADAM17, ITGB3). SB3-overexpressing cells showed superior spherogenic capacity and invasion ability compared to control. Importantly, MONSB3+ exhibited activation of MAP kinases (ERK1/2, p38, JNK) as well as phosphorylation of NFκB (p65) in addition to up-regulation of the proto-oncogene β-catenin. All these effects were reversed after transient silencing of SB3. According to the in vitro finding, MONSB3+ cells retained high tumorigenic potential in NSG mice. SB3 overexpression was observed in human CCA tissues and analysis of OS as well as TTR indicated a worse prognosis in SB3+ CCA patients. Conclusion: These findings indicate a SB3 role in mediating malignant phenotype of CCA and identify a new therapeutic target.

Published
2021

8. CXCR7 contributes to the aggressive phenotype of cholangiocarcinoma cells

Author

Matteo Donadon, Krista Rombouts, Massimo Pinzani, Luca Di Tommaso, N. Navari, Margherita Correnti, Sabina Di Matteo, Fabio Marra, Elisabetta Rovida, Domenico Alvaro, Giulia Lori, Carlotta Raschioni, Pietro Invernizzi, Chiara Raggi, Jesus M. Banales, Pedro M. Rodrigues, Alessandra Caligiuri, A. Gentilini, Gentilini, A, Caligiuri, A, Raggi, C, Rombouts, K, Pinzani, M, Lori, G, Correnti, M, Invernizzi, P, Rovida, E, Navari, N, Di Matteo, S, Alvaro, D, Banales, J, Rodrigues, P, Raschioni, C, Donadon, M, Di Tommaso, L, and Marra, F

Subjects
Male, 0301 basic medicine, Chemokine, Stromal cell, Cell Survival, CXCR4, Cholangiocarcinoma, 03 medical and health sciences, 0302 clinical medicine, Cell Movement, Tumor Cells, Cultured, Humans, Cell migration, Liver stromal cell, RNA, Small Interfering, Receptor, Molecular Biology, Receptors, CXCR, Gene knockdown, biology, Chemistry, Cancer stem cell, β-Arrestin 2, Adhesion, beta-Arrestin 2, Chemokine CXCL12, Cell biology, Phenotype, 030104 developmental biology, Bile Duct Neoplasms, Liver, Cell culture, 030220 oncology & carcinogenesis, biology.protein, Molecular Medicine, Female, RNA Interference, Cancer stem cells, Cell migration, Chemokines, Liver stromal cells, β-Arrestin 2
Abstract

Development of cholangiocarcinoma (CCA) is dependent on a cross-talk with stromal cells, which release different chemokines including CXCL12, that interacts with two different receptors, CXCR4 and CXCR7. The aim of the present study was to investigate the role of CXCR7 in CCA cells. CXCR7 is overexpressed by different CCA cell lines and in human CCA specimens. Knock-down of CXCR7 in HuCCT-1 cells reduced migration, invasion, and CXCL12-induced adhesion to collagen I. Survival of CCA was also reduced in CXCR7-silenced cells. The ability of CXCL12 to induce cell migration and survival was also blocked by CCX733, a CXCR7 antagonist. Similar effects of CXCR7 activation were observed in CCLP-1 cells and in primary iCCA cells. Enrichment of tumor stem-like cells by a 3D culture system resulted in increased CXCR7 expression compared to cells grown in monolayers, and genetic knockdown of CXCR7 robustly reduced sphere formation both in HuCCT-1 and in CCLP-1 cells. In HuCCT-1 cells CXCR7 was found to interact with β-arrestin 2, which was necessary to mediate CXCL12-induced migration, but not survival. In conclusion, CXCR7 is widely expressed in CCA, and contributes to the aggressive phenotype of CCA cells, inducing cell migration, invasion, adhesion, survival, growth and stem cell-like features. Cell migration induced by CXCR7 requires interaction with β-arrestin 2.

Published
2019

9. A very dark stellar system lost in Virgo: kinematics and metallicity of SECCO 1 with MUSE

Author

Filippo Fraternali, Bernd Husemann, Michele Bellazzini, Lodovico Coccato, M. Correnti, Vincenzo Testa, Giovanni Cresci, S. Perina, Giuseppina Battaglia, Rodrigo A. Ibata, P. T. de Zeeuw, Laura Magrini, Giacomo Beccari, Nicolas F. Martin, Observatoire astronomique de Strasbourg (ObAS), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS), Astronomy, Beccari, G., Bellazzini, M., Magrini, L., Coccato, L., Cresci, G., Fraternali, F., de Zeeuw, P. T., Husemann, B., Ibata, R., Battaglia, G., Martin, N., Testa, V., Perina, S., and Correnti, M.

Subjects
Stellar kinematics, DWARF GALAXIES, 010504 meteorology & atmospheric sciences, Stellar mass, Metallicity, FOS: Physical sciences, POPULATION SYNTHESIS, Astrophysics::Cosmology and Extragalactic Astrophysics, Astrophysics, 01 natural sciences, star formation, H-II REGIONS, H II regions, 0103 physical sciences, PHOTOMETRY, Astrophysics::Solar and Stellar Astrophysics, H II regions -galaxies, HIGH-VELOCITY CLOUDS, 010303 astronomy & astrophysics, Astrophysics::Galaxy Astrophysics, 0105 earth and related environmental sciences, Dwarf galaxy, Physics, Star formation, Local Group, Astronomy, CLUSTER, Astronomy and Astrophysics, galaxies: dwarf, Astrophysics - Astrophysics of Galaxies, Virgo Cluster, Galaxy, dwarf -galaxies, [SDU]Sciences of the Universe [physics], Space and Planetary Science, Astrophysics of Galaxies (astro-ph.GA), galaxies: star formation, EVOLUTION DATABASE, Astrophysics::Earth and Planetary Astrophysics, H II regions – galaxies: dwarf – galaxies: star formation, HIGH-REDSHIFT, EMISSION, LOCAL GROUP
Abstract

We present the results of VLT-MUSE integral field spectroscopy of SECCO1, a faint, star-forming stellar system recently discovered as the stellar counterpart of an Ultra Compact High Velocity Cloud (HVC274.68+74.0), very likely residing within a substructure of the Virgo cluster of galaxies. We have obtained the radial velocity of a total of 38 individual compact sources identified as HII regions in the main and secondary body of the system, and derived the metallicity for 18 of them. We provide the first direct demonstration that the two stellar bodies of SECCO1 are physically associated and that their velocities match the HI velocities. The metallicity is quite uniform over the whole system, with a dispersion sigma_12+log(O/H/)=0.08, lower than the uncertainty on individual metallicity estimates. The mean abundance, 12+log(O/H)=8.44, is much higher than the typical values for local dwarf galaxies of similar stellar mass. This strongly suggests that the SECCO~1 stars were born from a pre-enriched gas cloud, possibly stripped from a larger galaxy. Using archival HST images we derive a total stellar mass of ~1.6 X 10^5 M_sun for SECCO1, confirming that it has a very high HI to stellar mass ratio for a dwarf galaxy, M_HI/M_*~ 100. The star formation rate, derived from the H_alpha flux is a factor of more than 10 higher than in typical dwarf galaxies of similar luminosity., Accepted for publication by MNRAS. pdfLaTeX. 10 pages, 4 figures, 4 tables

Published
2016

10. Iron Metabolism in Liver Cancer Stem Cells

Author

Stefania Recalcati, Margherita Correnti, Elena Gammella, Chiara Raggi, Pietro Invernizzi, Gaetano Cairo, Recalcati, S, Correnti, M, Gammella, E, Raggi, C, Invernizzi, P, and Cairo, G

Subjects
cancer stem cells, 0301 basic medicine, Cancer Research, Review, lcsh:RC254-282, liver cancer, 03 medical and health sciences, iron, 0302 clinical medicine, Cancer stem cell, Medicine, business.industry, Ferroptosis, Cancer, Metabolism, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, ferroptosis, Cancer stem cells, Chelators, Ferroptosis, Iron, Liver cancer, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Cancer cell, Cancer research, chelators, Stem cell, business, Liver cancer, Adult stem cell
Abstract

Cancer stem cells (CSC) which have been identified in several tumors, including liver cancer, represent a particular subpopulation of tumor cells characterized by properties similar to those of adult stem cells. Importantly, CSC are resistant to standard therapies, thereby leading to metastatic dissemination and tumor relapse. Given the increasing evidence that iron homeostasis is deregulated in cancer, here we describe the iron homeostasis alterations in cancer cells, particularly in liver CSC. We also discuss two paradoxically opposite iron manipulation-strategies for tumor therapy based either on iron chelation or iron overload-mediated oxidant production leading to ferroptosis. A better understanding of iron metabolism modifications occurring in hepatic tumors and particularly in liver CSC cells may offer new therapeutic options for this cancer, which is characterized by increasing incidence and unfavorable prognosis.

Published
2019

11. Cancer stem cells and tumor-associated macrophages: a roadmap for multitargeting strategies

Author

Pietro Invernizzi, Antonio Sica, Hani S Mousa, Margherita Correnti, Chiara Raggi, Raggi, C, Mousa, H, Correnti, M, Sica, A, and Invernizzi, P

Subjects
0301 basic medicine, Cancer Research, Cell type, Macrophage, Tumor initiation, Biology, Malignancy, 03 medical and health sciences, Genetic, MED/12 - GASTROENTEROLOGIA, Cancer stem cell, Neoplasms, Biological property, Tumor Microenvironment, Genetics, medicine, Animals, Humans, Molecular Targeted Therapy, Stem Cell Niche, Molecular Biology, Tumor microenvironment, Animal, Macrophages, Cancer, medicine.disease, 030104 developmental biology, Cancer cell, Immunology, Neoplastic Stem Cells, Cancer research, Neoplasm, Neoplastic Stem Cell, Human
Abstract

The idea that tumor initiation and progression are driven by a subset of cells endowed with stem-like properties was first described by Rudolf Virchow in 1855. 'Cancer stem cells', as they were termed more than a century later, represent a subset of tumor cells that are able to generate all tumorigenic and nontumorigenic cell types within the malignancy. Although their existence was hypothesized >150 years ago, it was only recently that stem-like cells started to be isolated from different neoplastic malignancies. Interestingly, Virchow, in suggesting a correlation between cancer and the inflammatory microenvironment, also paved the way for the 'Seed and Soil' theory proposed by Paget a few years later. Despite the time that has passed since these two important concepts were suggested, the relationships between Virchow's 'stem-like cells' and Paget's 'soil' are far from being fully understood. One emerging topic is the importance of a stem-like niche in modulating the biological properties of stem-like cancer cells and thus in affecting the response of the tumor to drugs. This review aims to summarize the recent molecular data concerning the multilayered relationship between cancer stem cells and tumor-associated macrophages that form a key component of the tumor microenvironment. We also discuss the therapeutic implications of targeting this synergistic interplay.

Published
2015

12. Kinematics of a globular cluster with an extended profile: NGC5694

Author

P. Amigo, Alessio Mucciarelli, Valentina D'Orazi, Michele Bellazzini, Márcio Catelan, Antonio Sollima, Emanuele Dalessandro, M. Correnti, Cristián E. Cortés, Bellazzini, M., Mucciarelli, A., Sollima, A., Catelan, M., Dalessandro, E., Correnti, M., D'Orazi, V., Cortés, C., Amigo, P., ITA, and CHL

Subjects
Physics, Metallicity, Velocity dispersion, Astronomy, FOS: Physical sciences, Astronomy and Astrophysics, Astrophysics, Astrophysics::Cosmology and Extragalactic Astrophysics, Horizontal branch, Blue straggler, Radial velocity, Red-giant branch, Astrophysics - Solar and Stellar Astrophysics, Space and Planetary Science, Globular cluster, Astrophysics::Solar and Stellar Astrophysics, Astrophysics::Earth and Planetary Astrophysics, stars: abundances, globular clusters: individual: NGC 5694, Astrophysics::Galaxy Astrophysics, Solar and Stellar Astrophysics (astro-ph.SR), Open cluster
Abstract

We present a study of the kinematics of the remote globular cluster NGC5694 based on GIRAFFE@VLT medium resolution spectra. A sample of 165 individual stars selected to lie on the Red Giant Branch in the cluster Color Magnitude Diagram was considered. Using radial velocity and metallicity from Calcium triplet, we were able to select 83 bona-fide cluster members. The addition of six previously known members leads to a total sample of 89 cluster giants with typical uncertainties, Accepted for publication by MNRAS. Pdflatex, 10 pages, 10 figures

Published
2014
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13. The non-peculiar velocity dispersion profile of the stellar system omega Centauri

Author

M. Bellazzini, M. Correnti, E. Pancino, Donatella Romano, Richard L. Smart, F. R. Ferraro, Antonio Sollima, Sollima A., Bellazzini M., Smart R. L., Correnti M., Pancino E., Ferraro F. R., and Romano D.

Subjects
Physics, Milky Way, Velocity dispersion, FOS: Physical sciences, Astronomy and Astrophysics, Astrophysics, Astrophysics::Cosmology and Extragalactic Astrophysics, Astrophysics - Astrophysics of Galaxies, Stars, Star cluster, Astrophysics - Solar and Stellar Astrophysics, Space and Planetary Science, Astrophysics of Galaxies (astro-ph.GA), Peculiar velocity, Astrophysics::Solar and Stellar Astrophysics, Omega Centauri, Surface brightness, Astrophysics::Earth and Planetary Astrophysics, Galaxy rotation curve, Astrophysics::Galaxy Astrophysics, Solar and Stellar Astrophysics (astro-ph.SR)
Abstract

We present the results of a survey of radial velocities over a wide region extending from r~10 arcmin out to r~80 arcmin (~1.5 tidal radii) within the massive star cluster omega Centauri. The survey was performed with FLAMES@VLT, to study the velocity dispersion profile in the outer regions of this stellar system. We derived accurate radial velocities for a sample of 2557 newly observed stars, identifying 318 bona-fide cluster red giants. Merging our data with those provided by Pancino et al. (2007), we assembled a final homogeneous sample of 946 cluster members that allowed us to trace the velocity dispersion profile from the center out to r~32 arcmin. The velocity dispersion appears to decrease monotonically over this range, from a central value of sigma_{v}~17.2 Km/s down to a minimum value of sigma_{v}~5.2 Km/s. The observed surface brightness profile, rotation curve, velocity dispersion profile and ellipticity profile are simultaneously well reproduced by a simple dynamical model in which mass follows light, within the classical Newtonian theory of gravitation. The comparison with an N-body model of the evolution of a system mimicking omega Cen during the last 10 orbits into the Galactic potential suggests that (a) the rotation of stars lying in the inner ~20 arcmin of the clusters is not due to the effects of the tidal field of the Milky Way, as hypothized by other authors, and (b) the overall observational scenario is still compatible with the possibility that the outer regions of the cluster are subject to some tidal stirring., Comment: 12 pages, 12 figures, accepted for publication by MNRAS

Published
2009
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14. H ii REGIONS WITHIN A COMPACT HIGH VELOCITY CLOUD. A NEARLY STARLESS DWARF GALAXY?

Author

A. Marchetti, Nicolas F. Martin, Filippo Fraternali, Alessio Mucciarelli, Rodrigo A. Ibata, Giuseppina Battaglia, Michele Bellazzini, Laura Magrini, M. Correnti, M. Fumana, Giacomo Beccari, Vincenzo Testa, Kapteyn Astronomical Institute, Bellazzini, M., Magrini, L., Mucciarelli, A., Beccari, G., Ibata, R., Battaglia, G., Martin, N., Testa, V., Fumana, M., Marchetti, A., Correnti, M., and Fraternali, F.

Subjects
Physics, Local Group, Astronomy and Astrophysics, Large Binocular Telescope, Astrophysics::Cosmology and Extragalactic Astrophysics, galaxies: dwarf, Astrophysics, Virgo Cluster, Galaxy, High-velocity cloud, Radial velocity, H ii regions, Space and Planetary Science, galaxies: star formation, HII region, Astrophysics::Galaxy Astrophysics, Galaxy cluster, Dwarf galaxy
Abstract

Within the SECCO survey we identified a candidate stellar counterpart to the Ultra Compact High Velocity Cloud (UCHVC) HVC274.68+74.70-123 that was suggested by Adams et al. to be a possible mini halo within the Local Group of galaxies. The spectroscopic follow-up of the brightest sources within the candidate reveals the presence of two H ii regions whose radial velocity is compatible with a physical association with the UVHVC. The available data do not allow us to give a definite answer on the nature of the newly identified system. A few alternative hypotheses are discussed. However, the most likely possibility is that we have found a new faint dwarf galaxy residing in the Virgo cluster of galaxies, which we name SECCO 1. Independently of its actual distance, SECCO 1 displays a ratio of neutral hydrogen mass to V luminosity of {{M}H I}/{{L}V}≳ 20, by far the largest among local dwarfs. Hence, it appears to be a nearly starless galaxy and it may be an example of the missing links between normal dwarfs and the dark mini halos that are predicted to exist in large numbers according to the currently accepted cosmological model. Based on data acquired using the Large Binocular Telescope (LBT). The LBT is an international collaboration among institutions in the United States, Italy, and Germany. LBT Corporation partners are The University of Arizona on behalf of the Arizona university system; Istituto Nazionale di Astrofisica, Italy; LBT Beteiligungsgesellschaft, Germany, representing the Max-Planck Society, the Astrophysical Institute Potsdam, and Heidelberg University; The Ohio State University; and The Research Corporation, on behalf of The University of Notre Dame, University of Minnesota, and University of Virginia.

Published
2015

15. Detection of a population gradient in the Sagittarius Stream

Author

Michele Bellazzini, M. Correnti, Francesco R. Ferraro, Lorenzo Monaco, Heidi Jo Newberg, Bellazzini M., Newberg H. J., Correnti M., Ferraro F. R., and Monaco L.

Subjects
Physics, education.field_of_study, Astrophysics::High Energy Astrophysical Phenomena, Population, Astrophysics (astro-ph), FOS: Physical sciences, Astronomy and Astrophysics, Astrophysics, Sagittarius Stream, Astrophysics::Cosmology and Extragalactic Astrophysics, Horizontal branch, Galaxy, Dwarf spheroidal galaxy, Stars, Space and Planetary Science, Astrophysics::Solar and Stellar Astrophysics, education, Red clump, Sagittarius, Astrophysics::Galaxy Astrophysics
Abstract

We present a quantitative comparison between the Horizontal Branch morphology in the core of the Sagittarius dwarf spheroidal galaxy (Sgr) and in a wide field sampling a portion of its tidal stream (Sgr Stream), located tens of kpc away from the center of the parent galaxy. We find that the Blue Horizontal Branch (BHB) stars in that part of the Stream are five times more abundant than in the Sgr core, relative to Red Clump stars. The difference in the ratio of BHB to RC stars between the two fields is significant at the 4.8 sigma level. This indicates that the old and metal-poor population of Sgr was preferentially stripped from the galaxy in past peri-Galactic passages with respect to the intermediate-age metal rich population that presently dominates the bound core of Sgr, probably due to a strong radial gradient that was settled within the galaxy before its disruption. The technique adopted in the present study allows to trace population gradients along the whole extension of the Stream., Comment: 4 pages, 3 .ps figures (fig. 1 at low resolution); Accepted for publication by A&A Letters

Published
2006
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16. An optical and H i study of the dwarf Local Group galaxy VV124 = UGC4879

Author

Michele Cignoni, Michele Bellazzini, Filippo Fraternali, Tom Oosterloo, S. Galleti, M. Correnti, Vincenzo Testa, Giacomo Beccari, A. Sollima, Lucio Mayer, Stefano Gallozzi, Astronomy, University of Zurich, Bellazzini, M, Bellazzini M., Beccari G., Oosterloo T. A., Galleti S., Sollima A., Correnti M., Testa V., Mayer L., Cignoni M., Fraternali F., and Gallozzi S.

Subjects
Cosmology and Nongalactic Astrophysics (astro-ph.CO), 530 Physics, STRUCTURAL-PROPERTIES, METALLICITY DISTRIBUTION, Metallicity, galaxies: individual: UGC4879, FOS: Physical sciences, Astrophysics::Cosmology and Extragalactic Astrophysics, Astrophysics, Star count, STAR-FORMATION, Luminosity, ABUNDANCES, 1912 Space and Planetary Science, GALACTIC GLOBULAR-CLUSTERS, Astrophysics::Solar and Stellar Astrophysics, content, Surface brightness, Astrophysics::Galaxy Astrophysics, Dwarf galaxy, Physics, CHEMICAL, Local Group, Astronomy and Astrophysics, galaxies: dwarf, CHEMICAL ABUNDANCES, galaxies: structure, galaxies: stellar, galaxies: ISM, DIGITAL SKY SURVEY, RED GIANT BRANCH, NEUTRAL INTERSTELLAR-MEDIUM, SPHEROIDAL GALAXIES, MILKY-WAY, Galaxy, Interstellar medium, Space and Planetary Science, 10231 Institute for Computational Science, galaxies: stellar content, 3103 Astronomy and Astrophysics, Astrophysics::Earth and Planetary Astrophysics, Astrophysics - Cosmology and Nongalactic Astrophysics
Abstract

We present a detailed study of the dwarf galaxy VV124, recently recognized as a isolated member of the Local Group. We have obtained deep (r=26.5) wide-field g,r photometry of individual stars with the LBT under sub-arcsec seeing conditions. The Color-Magnitude Diagram suggests that the stellar content of the galaxy is dominated by an old, metal-poor population, with a significant metallicity spread. A very clean detection of the RGB tip allows us to derive an accurate distance of D=1.3 +/- 0.1 Mpc. Combining surface photometry with star counts, we are able to trace the surface brightness profile of VV124 out to ~ 5' = 1.9 kpc radius (where mu_r=30 mag/arcsec^2), showing that it is much more extended than previously believed. Moreover, the surface density map reveals the presence of two symmetric flattened wings emanating from the central elongated spheroid and aligned with its major axis, resembling a stellar disk seen nearly edge-on. We also present HI observations obtained with the WSRT, the first ever of this object. A total amount of 10^6 M_sun of HI gas is detected in VV124. Compared to the total luminosity, this gives a value of M_HI/L_V=0.11, which is particularly low for isolated Local Group dwarfs. The spatial distribution of the gas does not correlate with the observed stellar wings. The systemic velocity of the HI in the region superposed to the stellar main body of the galaxy is V_h=-25 km/s. The velocity field shows substructures typical of galaxies of this size but no sign of rotation. The HI spectra indicates the presence of a two-phase interstellar medium, again typical of many dwarf galaxies., Comment: Accepted for publication in A&A. 19 pages, 20 reduced-resolution figures, pdflatex, A&A style. The full resolution pdf file can be be downloaded from http://www.bo.astro.it/SGR/

Published
2011

17. Cholangiocarcinoma Stem-like Subset Shapes Tumor-initiating Niche by Educating Associated Macrophages

Author

Jesper B. Andersen, Cédric Coulouarn, Massimo Roncalli, Elisa Forti, Annarita Destro, Margherita Correnti, Chiara Raggi, Luca Di Tommaso, Giovanna Chiorino, Jesus M. Banales, Francesca Sozio, Vincenzo Cardinale, Domenico Alvaro, Antonio Sica, Guido Torzilli, Shannon Glaser, Gianfranco Alpini, Luis Bujanda, Pietro Invernizzi, Istituto Clinico Humanitas [Milan] (IRCCS Milan), Humanitas University [Milan] (Hunimed), University of Copenhagen = Københavns Universitet (UCPH), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Cancer Genomics Laboratory, Fondazione 'Edo ed Elvo Tempia Valenta', Texas AandM Health Science Center, Hospital Donostia. CIBERehd, Foie, métabolismes et cancer, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Università degli Studi di Milano-Bicocca = University of Milano-Bicocca (UNIMIB), The study was supported partly by the Italian Foundation of Cancer Research award (MFGA17588) to Dr. Raggi, partly by the Dr. Nicholas C. Hightower Centennial Chair of Gastroenterology from Scott & White, a VA Research Career Scientist Award, VA Merit award (5I01BX000574) to Dr. Alpini and a VA Merit award (5I01BX002192) to Dr. Glaser. Dr. Raggi was supported by U. Veronesi Foundation Post-Doctoral fellowship., University of Copenhagen = Københavns Universitet (KU), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Università degli Studi di Milano-Bicocca [Milano] (UNIMIB), Raggi, C, Correnti, M, Sica, A, Andersen, J, Cardinale, V, Alvaro, D, Chiorino, G, Forti, E, Glaser, S, Alpini, G, Destro, A, Sozio, F, Di Tommaso, L, Roncalli, M, Banales, J, Coulouarn, C, Bujanda, L, Torzilli, G, and Invernizzi, P

Subjects
0301 basic medicine, Stromal cell, Carcinogenesis, CD14, information science, [SDV.CAN]Life Sciences [q-bio]/Cancer, Tumor initiation, Biology, medicine.disease_cause, Article, Cholangiocarcinoma, 03 medical and health sciences, Mice, Tumor-associated macrophage, Cancer stem cell, Antigens, CD, parasitic diseases, medicine, Animals, Humans, cardiovascular diseases, Innate immune system, Membrane Glycoproteins, Hepatology, Cluster of differentiation, Cancer stem cells, Tumor-associated macrophages, Interleukins, Macrophages, fungi, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Embryonic stem cell, 3. Good health, 030104 developmental biology, Bile Duct Neoplasms, Immunology, Cancer research, cardiovascular system, Carcinogens, Neoplastic Stem Cells
Abstract

Background & Aims A therapeutically challenging subset of cells, termed cancer stem cells (CSCs) are responsible for cholangiocarcinoma (CCA) clinical severity. Presence of tumor-associated macrophages (TAMs) has prognostic significance in CCA and other malignancies. Thus, we hypothesized that CSCs may actively shape their tumor-supportive immune niche. Methods CCA cells were cultured in 3D conditions to generate spheres. CCA sphere analysis of in vivo tumorigenic-engraftment in immune-deficient mice and molecular characterization was performed. The in vitro and in vivo effect of CCA spheres on macrophage precursors was tested after culturing healthy donor cluster of differentiation (CD)14 + with CCA-sphere conditioned medium. Results CCA spheres engrafted in 100% of transplanted mice and revealed a significant 20.3-fold increase in tumor-initiating fraction ( p =0.0011) and a sustained tumorigenic potential through diverse xenograft-generations. Moreover, CCA spheres were highly enriched for CSC, liver cancer and embryonic stem cell markers both at gene and protein levels. Next, fluorescence-activated cell sorting analysis showed that in the presence of CCA sphere conditioned medium, CD14 + macrophages expressed key markers (CD68, CD115, human leukocyte antigen-D related, CD206) indicating that CCA sphere conditioned medium was a strong macrophage-activator. Gene expression profile of CCA sphere activated macrophages revealed unique molecular TAM-like features confirmed by high invasion capacity. Also, freshly isolated macrophages from CCA resections recapitulated a similar molecular phenotype of in vitro -educated macrophages. Consistent with invasive features, the largest CD163 + set was found in the tumor front of human CCA specimens (n=23) and correlated with a high level of serum cancer antigen 19.9 (n=17). Among mediators released by CCA spheres, only interleukin (IL)13, IL34 and osteoactivin were detected and further confirmed in CCA patient sera (n=12). Surprisingly, a significant association of IL13, IL34 and osteoactivin with sphere stem-like genes was provided by a CCA database (n=104). In vitro combination of IL13, IL34, osteoactivin was responsible for macrophage-differentiation and invasion, as well as for in vivo tumor-promoting effect. Conclusion CCA-CSCs molded a specific subset of stem-like associated macrophages thus providing a rationale for a synergistic therapeutic strategy for CCA-disease. Lay summary Immune plasticity represents an important hallmark of tumor outcome. Since cancer stem cells are able to manipulate stromal cells to their needs, a better definition of the key dysregulated immune subtypes responsible for cooperating in supporting tumor initiation may facilitate the development of new therapeutic approaches. Considering that human cholangiocarcinoma represents a clinical emergency, it is essential to move to predictive models in order to understand the adaptive process of macrophage component (imprinting, polarization and maintenance) engaged by tumor stem-like compartment.

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