Dr Kristina Kirschner - Stem Cell Ageing & Cancer
Introduction
Age is the single biggest risk factor for many common diseases, including cancer. However, little is known about the changes associated with ageing that enable tumourigenesis. My lab studies the crosstalk of ageing and cancer on multiple levels.
Cellular senescence is a cell-intrinsic tumour suppressor mechanism and one of our main defences against cancer. Senescent cells that were involved in tumour suppression show similarities to old cells. We study how cellular senescence prevents cancer and why it fails in some patients that progress to cancer.
Stem cells are important in tissue homeostasis, with many stem cell properties changing with increased age. This is especially well characterised in blood stem cells, where ageing is associated with increased DNA damage, a bias in stem cell output towards the myeloid lineage and clonal haemopoiesis, the outgrowth of individual stem cell clones, a precursor to cancer.
Our research in understanding age-related changes in carcinogenesis uses state-of-the-art single cell technologies in patient samples combined with relevant in vivo models to understand how aberrant stem cells evolve with age and how the ageing microenvironment contributes to this process. Our ultimate goal is to provide biomarkers for early detection of age-associated cancer and novel treatment avenues.
Email
Biography
Education and qualifications
2007: PhD in Pathology, University of Edinburgh. Supervisor: Prof. D.W. Melton, Project. The role of DNA repair gene Ercc1 in the liver of progeria mice
2002: MSc (with integrated Bachelor) in Biomedical Sciences, University of Linköping, Sweden. MSc project Supervisor: Prof. O. Stål, Project: 17β-Hydroxysteroid dehydrogenase expression in
breast cancer.
Appointments
2018-present: John Goldman Research Fellow / Group leader and Lead for single-cell service, School of Cancer Sciences, University of Glasgow
2016-2018: Wellcome Trust ISSF Fellow, Institute of Cancer Sciences, University of Glasgow. Hosts: Prof T. L. Holyoake, Prof. P.W. Adams, Project: Single Cell Approaches in Haematological malignancies
2016-2012: Postdoctoral Fellow, Department of Haematology, University of Cambridge. Supervisor: Prof. A.R. Green, Project: Single Cell studies in myeloproliferative disease
2007-2012: Postdoctoral Fellow, CRUK Cambridge Institute, Cambridge. Supervisor: Prof. M. Narita, Project: Mechanisms of phenotype regulation by TP53
Recent Publications
2023
Edwards SC, Hedley A, Hoevenaar WHM, Wiesheu R, Glauner T, Kilbey A, Shaw R, Boufea K, Batada N, Hatano S, Yoshikai Y, Blyth K, Miller C, Kirschner K, Coffelt SB. PD-1 and TIM-3 differentially regulate subsets of mouse IL-17A-producing γδ T cells. J Exp Med. 2023;220.
Fetit R, White M, Mills ML, Cortes-Lavaud X, McLaren A, Falconer J, Gilroy K, Nixon C, Kirschner K, Jackstadt R, Campbell AD, Sansom OJ, Steele CW. Characterising neutrophil subtypes in cancer using human and murine single-cell RNA sequencing datasets. bioRxiv. 2023;Volume:2023.2007.2013.548820.
O'Sullivan ED, Mylonas KJ, Xin C, Baird DP, Carvalho C, Docherty MH, Campbell R, Matchett KP, Waddell SH, Walker AD, Gallagher KM, Jia S, Leung S, Laird A, Wilflingseder J, Willi M, Reck M, Finnie S, Pisco A, Gordon-Keylock S, Medvinsky A, Boulter L, Henderson NC, Kirschner K, Chandra T, Conway BR, Hughes J, Denby L, Bonventre JV, Ferenbach DA. Indian Hedgehog release from TNF-activated renal epithelia drives local and remote organ fibrosis. Sci Transl Med. 2023;15:eabn0736.
Pearson S, Blance R, Yan F, Hsieh YC, Geary B, Amaral FMR, Somervaille TCP, Kirschner K, Whetton AD, Pierce A. Identification of curaxin as a potential new therapeutic for JAK2 V617F mutant patients. PLoS One. 2023;18:e0286412.
Vande Voorde J, Steven RT, Najumudeen AK, Ford CA, Dexter A, Gonzalez-Fernandez A, Nikula CJ, Xiang Y, Ford L, Maneta Stavrakaki S, Gilroy K, Zeiger LB, Pennel K, Hatthakarnkul P, Elia EA, Nasif A, Murta T, Manoli E, Mason S, Gillespie M, Lannagan TRM, Vlahov N, Ridgway RA, Nixon C, Raven A, Mills M, Athineos D, Kanellos G, Nourse C, Gay DM, Hughes M, Burton A, Yan B, Sellers K, Wu V, De Ridder K, Shokry E, Huerta Uribe A, Clark W, Clark G, Kirschner K, Thienpont B, Li VSW, Maddocks ODK, Barry ST, Goodwin RJA, Kinross J, Edwards J, Yuneva MO, Sumpton D, Takats Z, Campbell AD, Bunch J, Sansom OJ. Metabolic profiling stratifies colorectal cancer and reveals adenosylhomocysteinase as a therapeutic target. Nature Metabolism. 2023;10.1038/s42255-023-00857-0.
Yang F, Nourse C, Helgason GV, Kirschner K. Unraveling Heterogeneity in the Aging Hematopoietic Stem Cell Compartment: An Insight From Single-cell Approaches. HemaSphere. 2023;7:e895.
2022
Jaber-Hijazi F, Swaminathan K, Gilroy K, Wenzel AT, Lagnado A, Kirschner K, Robertson N, Reid C, Fullarton N, Pawlikowski J, Blyth K, Mesirov JP, Rai TS, Passos JF, Machesky LM, Adams PD. Inactivation of histone chaperone HIRA unmasks a link between normal embryonic development of melanoblasts and maintenance of adult melanocyte stem cells. bioRxiv; 10.1101/2022.04.22.4891662022:2022.2004.2022.489166.
Kapeni C, Nitsche L, Kilpatrick AM, Wilson NK, Xia K, Mirshekar-Syahkal B, Chandrakanthan V, Malouf C, Pimanda JE, Gottgens B, Kirschner K, Tomlinson S, Ottersbach K. p57Kip2 regulates embryonic blood stem cells by controlling sympathoadrenal progenitor expansion. Blood. 2022; 140 (5): 464–477.
Kay EJ, Paterson K, Riero-Domingo C, Sumpton D, Däbritz JHM, Tardito S, Boldrini C, Hernandez-Fernaud JR, Athineos D, Dhayade S, Stepanova E, Gjerga E, Neilson LJ, Lilla S, Hedley A, Koulouras G, McGregor G, Jamieson C, Johson RM, Park M, Kirschner K, Miller C, Kamphorst JJ, Loayza-Puch F, Saez-Rodriguez J, Mazzone M, Blyth K, Zagoni M, Zanivan S. Cancer-associated fibroblasts require proline synthesis by PYCR1 for the deposition of pro-tumorigenic extracellular matrix. Nature Metabolism. 2022;4(6):693-710.
O’Sullivan ED, Mylonas KJ, Bell R, Carvalho C, Baird DP, Cairns C, Gallagher KM, Campbell R, Docherty M, Laird A, Henderson NC, Chandra T, Kirschner K, Conway B, Dihazi GH, Zeisberg M, Hughes J, Denby L, Dihazi H, Ferenbach DA. Single-cell analysis of senescent epithelia reveals targetable mechanisms promoting fibrosis. JCI Insight. 2022;7:e154124
Robertson NA, Latorre-Crespo E, Terradas-Terradas M, Lemos-Portela J, Purcell AC, Livesey BJ, Hillary RF, Murphy L, Fawkes A, MacGillivray L, Copland M, Marioni RE, Marsh JA, Harris SE, Cox SR, Deary IJ, Schumacher LJ, Kirschner K, Chandra T. Longitudinal dynamics of clonal hematopoiesis identifies gene-specific fitness effects. Nature Medicine. 2022;28:1439–1446
2021
Edwards SC, Hedley A, Hoevenaar WHM, Glauner T, Wiesheu R, Kilbey A, Shaw R, Boufea K, Batada N, Blyth K, Miller C, Kirschner K, Coffelt SB. Single-cell analysis uncovers differential regulation of lung γδ T cell subsets by the co-inhibitory molecules, PD-1 and TIM-3. bioRxiv. 2021.
Flanagan DJ, Pentinmikko N, Luopajärvi K, Willis NJ, Gilroy K, Raven AP, McGarry L, Englund JI, Webb AT, Scharaw S, Nasreddin N, Hodder MC, Ridgway RA, Minnee E, Sphyris N, Gilchrist E, Najumudeen AK, Romagnolo B, Perret C, Williams AC, Clevers H, Nummela P, Lähde M, Alitalo K, Hietakangas V, Hedley A, Clark W, Nixon C, Kirschner K, Jones EY, Ristimäki A, Leedham SJ, Fish PV, Vincent JP, Katajisto P, Sansom OJ. NOTUM from Apc-mutant cells biases clonal competition to initiate cancer. Nature. 2021;594(7863):430-435.
Latif AL, Newcombe A, Li S, Gilroy K, Robertson NA, Lei X, Stewart HJS, Cole J, Terradas MT, Rishi L, McGarry L, McKeeve C, Reid C, Clark W, Campos J, Kirschner K, Davis A, Lopez J, Sakamaki JI, Morton JP, Ryan KM, Tait SWG, Abraham SA, Holyoake T, Higgins B, Huang X, Blyth K, Copland M, Chevassut TJT, Keeshan K, Adams PD. BRD4-mediated repression of p53 is a target for combination therapy in AML. Nat Commun. 2021;12(1):241.
Robertson NA, Latorre-Crespo E, Terrada-Terradas M, Purcell AC, Livesey BJ, Marsh JA, Murphy L, Fawkes A, MacGillvray L, Copland M, Marioni RE, Harris SE, Cox SR, Deary IJ, Schumacher LJ, Kirschner K, Chandra T. Longitudinal dynamics of clonal hematopoiesis identifies gene-specific fitness effects. bioRxiv. 2021
Hsieh YC, Kirschner K, Copland M. Improving outcomes in chronic myeloid leukemia through harnessing the immunological landscape. Leukemia. 2021; ed2021.
Mooney L, Goodyear CS, Chandra T, Kirschner K, Copland M, Petrie MC, Lang NN. Clonal haematopoiesis of indeterminate potential: intersections between inflammation, vascular disease and heart failure. Clin Sci (Lond). 2021;135(7):991-1007.
Rattanavirotkul N, Kirschner K, Chandra T. Induction and transmission of oncogene-induced senescence. Cell Mol Life Sci. 2021;78(3):843-852.
2020
Alivernini S, MacDonald L, Elmesmari A, Finlay S, Tolusso B, Gigante MR, Petricca L, Di Mario C, Bui L, Perniola S, Attar M, Gessi M, Fedele AL, Chilaka S, Somma D, Sansom SN, Filer A, McSharry C, Millar NL, Kirschner K, Nerviani A, Lewis MJ, Pitzalis C, Clark AR, Ferraccioli G, Udalova I, Buckley CD, Gremese E, McInnes IB, Otto TD, Kurowska-Stolarska M. Distinct synovial tissue macrophage subsets regulate inflammation and remission in rheumatoid arthritis. Nat Med. 2020;26(8):1295-1306.
Crosse EI, Gordon-Keylock S, Rybtsov S, Binagui-Casas A, Felchle H, Nnadi NC, Kirschner K, Chandra T, Tamagno S, Webb DJ, Rossi F, Anderson RA, Medvinsky A. Multi-layered Spatial Transcriptomics Identify Secretory Factors Promoting Human Hematopoietic Stem Cell Development. Cell Stem Cell. 2020;27(5):822-839.e828.
Kirschner K, Rattanavirotkul N, Quince MF, Chandra T. Functional heterogeneity in senescence. Biochem Soc Trans. 2020;48(3):765-773.
Terradas-Terradas M, Robertson NA, Chandra T, Kirschner K. Clonality in haematopoietic stem cell ageing. Mech Ageing Dev. 2020;189:111279.
2019
Burt R, Dey A, Aref S, Aguiar M, Akarca A, Bailey K, Day W, Hooper S, Kirkwood A, Kirschner K, Lee SW, Lo Celso C, Manji J, Mansour MR, Marafioti T, Mitchell RJ, Muirhead RC, Cheuk Yan Ng K, Pospori C, Puccio I, Zuborne-Alapi K, Sahai E, Fielding AK. Activated stromal cells transfer mitochondria to rescue acute lymphoblastic leukemia cells from oxidative stress. Blood. 2019;134:1415-1429.
Robertson NA, Hillary RF, McCartney DL, Terradas-Terradas M, Higham J, Sproul D, Deary IJ, Kirschner K, Marioni RE, Chandra T. Age-related clonal haemopoiesis is associated with increased epigenetic age. Curr Biol. 2019;29:R786-r787.
Teo YV, Rattanavirotkul N, Olova N, Salzano A, Quintanilla A, Tarrats N, Kiourtis C, Müller M, Green AR, Adams PD, Acosta JC, Bird TG, Kirschner K, Neretti N, Chandra T. Notch Signaling Mediates Secondary Senescence. Cell Rep. 2019;27:997-1007.e1005.
2018
Baran-Gale J, Chandra T, Kirschner K. Experimental design for single-cell RNA sequencing. Brief Funct Genomics. 2018;17:233-239.
2017
Kirschner K, Chandra T, Kiselev V, Flores-Santa Cruz D, Macaulay IC, Park HJ, Li J, Kent DG, Kumar R, Pask DC, Hamilton TL, Hemberg M, Reik W, Green AR. Proliferation Drives Aging-Related Functional Decline in a Subpopulation of the Hematopoietic Stem Cell Compartment. Cell Rep. 2017;19:1503-1511.
Kiselev VY, Kirschner K, Schaub MT, Andrews T, Yiu A, Chandra T, Natarajan KN, Reik W, Barahona M, Green AR, Hemberg M. SC3: consensus clustering of single-cell RNA-seq data. Nat Methods. 2017;14:483-486.
