San Raffaele Telethon Institute for Gene Therapy
Senescence in stem cell aging, differentiation and cancer
Group research activity is interested in dissecting the mechanisms that regulate cellular senescence during aging, differentiation and cancer. Gene transcription, chromatin conformation and DNA damage orchestrate the tightly controlled program of cellular senescence. However, very little is known on how the identity of senescence cells is established and how it contributes to fundamental biological processes such as aging, cellular differentiation and cancer. By combining cell and molecular biology approaches, together with next generation sequencing and clinically relevant human samples, the unit is elucidating the functional role of senescence-associated pathways and regulators in the hematopoietic stem cell compartment (HSPCs).
Research activity
The aim is to identify molecular determinants of human aged and stressed hematopoiesis, focusing on both cell intrinsic and cell extrinsic mechanisms of stem cell aging. The group employs artificial nucleases to study the interplay between DNA damage response (DDR) and chromatin and senescence establishment in ex-vivo gene targeting strategies in HSPCs.
Therapy-induced senescence is a relatively unexplored area in hematological tumors because cancer cells often undergo a mixture of apoptosis and senescence following chemotherapy. In the lab, researchers are developing in vitro models of senescence induction upon DNA damaging agents and characterizing the functional role of therapy-induced senescent cells (TIS cells) on tumor survival and chemo-resistance.
As part of a collaborative project with the laboratory of Dr. Luca Vago, the unit is studying the transcriptional and epigenetic alterations responsible of leukemia immune evasion in paired AML patient samples. Thecomprehensive analysis involves DNA methylation studies, mapping of post-translational modifications on histone tails, a low input proteomic approach for modified histones and a functional screening platform to delay or revert cancer immuno-editing.
Therapy-induced senescence is a relatively unexplored area in hematological tumors because cancer cells often undergo a mixture of apoptosis and senescence following chemotherapy. In the lab, researchers are developing in vitro models of senescence induction upon DNA damaging agents and characterizing the functional role of therapy-induced senescent cells (TIS cells) on tumor survival and chemo-resistance.
As part of a collaborative project with the laboratory of Dr. Luca Vago, the unit is studying the transcriptional and epigenetic alterations responsible of leukemia immune evasion in paired AML patient samples. Thecomprehensive analysis involves DNA methylation studies, mapping of post-translational modifications on histone tails, a low input proteomic approach for modified histones and a functional screening platform to delay or revert cancer immuno-editing.
Gambacorta V, Gnani D, Vago L, Di Micco R. Epigenetic Therapies for Acute Myeloid Leukemia and Their Immune-Related Effects Front Cell Dev Biol. 2019 Oct 11;7:207. eCollection 2019. Review.
Schiroli G, Conti A, Ferrari S, Della Volpe L, Jacob A, Albano L, Beretta S, Calabria A, Vavassori V, Gasparini P, Salataj E, Ndiaye-Lobry D, Brombin C, Chaumeil J, Montini E, Merelli I, Genovese P, Naldini L, Di Micco R. Precise Gene Editing Preserves Hematopoietic Stem Cell Function following Transient p53-Mediated DNA Damage Response. Cell Stem Cell. 2019 Apr 4;24(4):551-565.e8.
Gnani D, Crippa S, Della Volpe L, Rossella V, Conti A, Lettera E, Rivis S, Ometti M, Fraschini G, Bernardo ME, Di Micco R. An early-senescence state in aged mesenchymal stromal cells contributes to hematopoietic stem and progenitor cell clonogenic impairment through the activation of a pro-inflammatory program, Aging Cell. 2019 Jun;18(3):e12933.
Conti A, Di Micco R. p53 activation: a checkpoint for precision genome editing?Genome Med. 2018 Aug 17;10(1):66.
Di Micco R, Montini E. De(bar)coding aged hematopoiesis in primates. Blood. 2018 Mar 15;131(11):1157-1159.
Fontanals-Cirera B, Hasson D, Vardabasso C, Di Micco R, Agrawal P, Chowdhury A, Gantz M, de Pablos-Aragoneses A, Morgenstern A, Wu P, Filipescu D, Valle-Garcia D, Darvishian F, Roe JS, Davies MA, Vakoc CR, Hernando E, Bernstein E. Harnessing BET Inhibitor Sensitivity Reveals AMIGO2 as a Melanoma Survival Gene, Molecular Cell 2017, Nov 16;68(4):731-744.e9
Di Micco R*, Fontanals-Cirera B, Low V, Ntziachristos P, Yuen S, Lovell C, Dolgalev I, Yonekubo Y, Zhang G, Rusinova E, Gerona-Navarro G, Canamero M, Ohlmeyer M, Aifantis I, Zhou MM, Tsirigos A*, Hernando E*. Control of embryonic stem cell identity by BRD4-dependent transcriptional elongation of super-enhancer-associated pluripotency genes. Cell Reports 2014 Oct 9;9(1):234-47. (*corresponding author)
Ogrunc M, Di Micco R, Liontos M, Bombardelli L, Mione M, Fumagalli M, Gorgoulis VG, d’Adda di Fagagna F. Oncogene-induced reactive oxygen species fuel hyper-proliferation and DNA damage response activation. Cell Death and Differentiation 2014 Jun; 21(6): 998–1012.
Sulli G, Di Micco R, d’Adda di Fagagna F. Crasstalk between chromatin state and DNA damage response in senescence and cancer. Nat Rev Cancer. 2012 Oct;12(10):709-20.
Suram A, Kaplunov J, Patel PL, Ruan H, Cerutti A, Boccardi V, Fumagalli M, Di Micco R, Mirani N, Gurung RL, Hande MP, d'Adda di Fagagna F, Herbig U. Oncogene-induced telomere dysfunction enforces cellular senescence in human cancer precursor lesions. EMBO J. 2012 Jun 29;31(13):2839-51.
Gaziel-Sovran A, Segura MF, Di Micco R, Collins MK, Hanniford D, Vega-Saenz de Miera E,Rakus JF, Dankert JF, Shang S, Kerbel RS, Bhardwaj N, Shao Y, Darvishian F, Zavadil J, Erlebacher A, Mahal LK, Osman I, Hernando E. miR- 30b/30d regulation of GalNAc transferases enhances invasion and immunosuppression during metastasis. Cancer Cell 2011 Jul 12;20(1):104-18.
Di Micco R, Sulli G, Dobreva M, Liontos M, Botrugno OA, Gargiulo G, dal Zuffo R, Matti V, d’Ario G, Montani E, Mercurio C, Hahn WC, Gorgoulis VG, Minucci S, d'Adda di Fagagna F. Interplay between oncogene-induced DNA damage response and heterochromatin in senescence and cancer. Nature Cell Biology 2011 Mar;13(3):292-302.
Di Micco R, Cicalese A, Fumagalli M, Dobreva M, Verrecchia A, Pelicci PG, d'Adda di Fagagna F. DNA damage response activation in mouse embryonic fibroblasts undergoing replicative senescence and following spontaneous immortalization. Cell Cycle 2008 Nov 15;7(22):3601-6.
Di Micco R., Fumagalli M. and d’Adda di Fagagna F. Breaking news: high speed run away ends in arrest. How oncogenes induce senescence. Trends in Cell Biology, 2007 2007 Nov;17(11):529-36.
Di Micco R, Fumagalli M, Cicalese A, Piccinin S, Gasparini P, Luise C, Schurra C, Garrè M, Nuciforo P, Bensimon A, Maestro R, Pelicci PG, d'Adda di Fagagna F. Oncogene-induced senescence is a DNA-damage checkpoint response triggered by DNA hyper-replication. Nature 2006 Nov 30;444(7119):638-42.
