Prof Laura Greaves - Mitochondrial Genetics in Cancer
Introduction
Mitochondria are essential intracellular metabolic hubs, performing numerous crucial roles in bioenergetics and cellular biosynthesis. Alterations in mitochondrial metabolism are well-established hallmarks of both ageing and cancer. Age remains the greatest risk factor for many cancer types, prompting important questions about whether age-associated mitochondrial dysfunction directly influences cancer development. Our work investigates this link, particularly through somatic mutations in the mitochondrial DNA (mtDNA), a feature commonly observed in both ageing tissues and cancer cells.
We focus on the role of mtDNA mutations in colorectal cancer pathogenesis. These mutations are prevalent in both normal human colonocytes and colorectal tumours and can lead to altered mitochondrial function. This suggests that mtDNA mutations and consequent metabolic changes may act as early modulators of colorectal cancer development and progression. To interrogate these mechanisms, we employ state-of-the-art preclinical models combining key oncogenic nuclear drivers with relevant mtDNA mutations. This approach enables us to interrogate the molecular mechanisms by which mitochondrial dysfunction influences colorectal cancer progression, metastasis, and response to therapy.
Cell scientist to watch - Laura Greaves | Journal of Cell Science | The Company of Biologists
Email
Lab Report
Key Publications
*Corresponding author
Kelly G, Kataura Y, Ma G, Panek J, Salmonowicz H, Davis A, Kendall H, Brookes C, Moscoh D, Tora A, Banks P, Nelson G, Dobby L, Pitrez P, Booth L, Costello L, Richardson GD, Lovat P, Przyborski S, Lino Ferreira, Greaves L, Szczepanowska K, von Zglinicki T, Miwa S, Brown M, Flagle M, Oblong JE, Bascom CC, Carroll B, Reynisson J, Korolchuk VI. Suppressed basal mitophagy drives cellular ageing phenotypes, Dev Cell. 2024; 2024 Aug 5;59(15):1924-1939.e7
Victorelli S, Salmonowicz, H, Chapman J, Martini H, Vizioli MG, Riley JS, Cloix C, Hall-Younger E, Espindola-Netto JM, Jurk D, Lagnado AB, Gomez LS, Farr JN, Saul D, Reed R, Kelly G, Eppard M, Greaves LC, Dou Z, Pirius N, Szczepanowska S, Porritt RA, Huang H, Huang TY, Mann DA, Masuda CA, Khosla S, Dai H, Kaufmann SJ, Zacharioudakis E, Gavathiotis E, LeBrasseur N, Lei X, Sainz AG, Korolchuk VI, Adams PD, Shadel GS, Tait SWG, Passos JF. Apoptotic stress causes mtDNA release during senescence and drives the SASP. Nature. 2023;622(7983):627-636
Pickett SJ, Hudson G, Greaves LC*. Single-cell multiomic analyses sheds light on mitochondrial mutational selection. Nat Genet. 2023;55(7):1083-1085
Smith A, Whitehall JC, Greaves LC*. Mitochondrial DNA mutations in aging and cancer. Mol Oncol. 2022;16(18):3276-3294.
Yu X, Arden C, Berlinguer-Palmini R, Chen C, Bradshaw C, Smith AL, Whitehall J, White M, Anderson S, Kattner N, Shaw J, Turnbull D, Greaves LC*, Walker M. Mitochondrial complex I subunit deficiency promotes pancreatic α-cell proliferation. Mol Metab. 2022;60:101489.
Stamp C, Whitehall JC, Smith ALM, Houghton D, Bradshaw C, Stoll EA, Blain AP, Turnbull DM, Greaves LC*. Age-associated mitochondrial complex I deficiency is linked to increased stem cell proliferation rates in the mouse colon. Aging Cell. 2021;20(3):e13321.
Smith ALM, Whitehall JC, Gay D, Bradshaw C, Robertson F, Blain AP, Houghton D, Hunt M, Sampson JN, Stamp C, Baker A, Russell OM, Johnson R, Richardson CA, Gupta B, McCallum I, Kelly S, Mathers JC, Heer R, Taylor RW, Perkins ND, Turnbull DM, Sansom OJ, Greaves LC*. Age-associated mitochondrial DNA mutations cause metabolic remodelling that contributes to accelerated intestinal tumorigenesis. Nat Cancer. 2020;1, 976–989
Dobson PF, Hipps D, Reeve AK, Laude A, Stamp C, Smith ALM, Deehan DJ, Turnbull DM, Greaves LC*. Mitochondrial dysfunction impairs in vitro osteogenesis, osteoclast function and accelerates age-related bone loss. Sci Rep. 2020;10(1):11643.
Lawless C, Greaves LC, Reeve AK, Turnbull DM, Vincent AE. The rise and rise of mitochondrial DNA mutations. Open Biol. 2020;10(5):200061.
Whitehall JC and Greaves LC*. Aberrant mitochondrial function in ageing and cancer. Biogerontology. 2020;21(4):445-459.
Su T, Grady JP, Afshar S, McDonald SA, Taylor RW, Turnbull DM, Greaves LC*. Inherited pathogenic mitochondrial DNA mutations and gastrointestinal stem cell populations. J Pathol. 2018;246(4):427-432.
Stamp C, Zupanic A, Sachdeva A, Stoll EA, Shanley DP, Mathers JC, Kirkwood TBL, Heer R, Simons BD, Turnbull DM, Greaves LC*. Predominant Asymmetrical Stem Cell Fate Outcome Limits the Rate of Niche Succession in Human Colonic Crypts. EBioMedicine. 2018;31:166-173.
Simard ML, Mourier A, Greaves LC, Taylor RW, Stewart JB. A novel histochemistry assay to assess and quantify focal cytochrome c oxidase deficiency. J Pathol. 2018;245(3):311-323.
Su T, Turnbull DM, Greaves LC*. Roles of Mitochondrial DNA Mutations in Stem Cell Ageing. Genes (Basel). 2018;9(4).
Houghton D, Stewart CJ, Stamp C, Nelson A, Aj Ami NJ, Petrosino JF, Wipat A, Trenell MI, Turnbull DM, Greaves LC*. Impact of Age-Related Mitochondrial Dysfunction and Exercise on Intestinal Microbiota Composition. J Gerontol A Biol Sci Med Sci. 2018;73(5):571-578.
Moad M, Hannezo E, Buczacki SJ, Wilson L, El-Sherif A, Sims D, Pickard R, Wright NA, Williamson SC, Turnbull DM, Taylor RW, Greaves LC, Robson CN, Simons BD, Heer R. Multipotent Basal Stem Cells, Maintained in Localized Proximal Niches, Support Directed Long-Ranging Epithelial Flows in Human Prostates. Cell Rep. 2017;20(7):1609-1622.
Dobson P, Rocha M, Grady J, Chrysostomou A, Hipps D, Watson S, Greaves LC, Deehan DJ, Turnbull DM. Unique quadruple immunofluorescence assay demonstrates mitochondrial respiratory chain dysfunction in osteoblasts of aged and PolgA-/- mice. Sci Rep. 2016;6:31907.
Correia-Melo C, Marques FD, Anderson R, Hewitt G, Hewitt R, Cole J, Carroll BM, Miwa S, Birch J, Merz A, Rushton MD, Charles M, Jurk D, Tait SW, Czapiewski R, Greaves LC, Nelson G, Bohlooly-Y M, Rodriguez-Cuenca S, Vidal-Puig A, Mann D, Saretzki G, Quarato G, Green DR, Adams PD, von Zglinicki T, Korolchuk VI, Passos JF. Mitochondria are required for pro-ageing features of the senescent phenotype. EMBO J. 2016;35(7):724-42.
Kauppila JHK, Baines HL, Bratic A, Simard ML, Freyer C, Mourier A, Stamp C, Filograna R, Larsson NG, Greaves LC, Stewart JB. A phenotype-driven approach to generate mouse models with pathogenic mtDNA mutations causing mitochondrial disease. Cell Reports. 2016;16(11):2980-2990.
Biography
Education and qualifications
2006: PhD Newcastle University
2002: BSc (Hons) Pharmacology, Newcastle University
Appointments
2024-present: Professor of Molecular Biology, Newcastle University
2022-2024: Senior Lecturer: Newcastle University
2022-2022: Lecturer, Newcastle University
2016-2022: Newcastle University Research Fellow, Newcastle University
2014-2015: Senior Research Associate, Centre for Ageing and Vitality (Co-director), Newcastle University
2012-2014: Research Associate, Centre for Brain Ageing and Vitality, Newcastle University
2010-2012: Faculty Research Fellow, Institute for Ageing and Health, Newcastle University (3 month placement at Harvard University, USA)
2009-2010: Research Associate, Centre for Brain Ageing and Vitality, Newcastle University
2005-2008: Research Associate, Mitochondrial Research Group, Newcastle University. (1 month placement at Harvard University, USA)
Other Appointments
Faculty Research Theme Lead - Mitochondria and Neuromuscular Diseases
Curriculum Chair, Faculty of Medical Sciences MRes Programme
MRC National Mouse Genetics Network Executive Board
NC3Rs Panel Member
Awards and Prizes
British Society for Cell Biology, Women in Cell Biology Early Career Medal (2022)
Recent Publications
*Corresponding author
2024
Kelly G, Kataura Y, Ma G, Panek J, Salmonowicz H, Davis A, Kendall H, Brookes C, Moscoh D, Tora A, Banks P, Nelson G, Dobby L, Pitrez P, Booth L, Costello L, Richardson GD, Lovat P, Przyborski S, Lino Ferreira, Greaves L, Szczepanowska K, von Zglinicki T, Miwa S, Brown M, Flagle M, Oblong JE, Bascom CC, Carroll B, Reynisson J, Korolchuk VI. Suppressed basal mitophagy drives cellular ageing phenotypes, Dev Cell. 2024; 2024 Aug 5;59(15):1924-1939.e7
2023
Victorelli S, Salmonowicz, H, Chapman J, Martini H, Vizioli MG, Riley JS, Cloix C, Hall-Younger E, Espindola-Netto JM, Jurk D, Lagnado AB, Gomez LS, Farr JN, Saul D, Reed R, Kelly G, Eppard M, Greaves LC, Dou Z, Pirius N, Szczepanowska S, Porritt RA, Huang H, Huang TY, Mann DA, Masuda CA, Khosla S, Dai H, Kaufmann SJ, Zacharioudakis E, Gavathiotis E, LeBrasseur N, Lei X, Sainz AG, Korolchuk VI, Adams PD, Shadel GS, Tait SWG, Passos JF. Apoptotic stress causes mtDNA release during senescence and drives the SASP. Nature. 2023;622(7983):627-636
Pickett SJ, Hudson G, Greaves LC*. Single-cell multiomic analyses sheds light on mitochondrial mutational selection. Nat Genet. 2023;55(7):1083-1085
2022
Sachdeva A, Hart CA, Carey CD, Vincent AE, Greaves LC, Heer R, Oliveira P, Brown MD, Clarke NW, Turnbull DM. Automated quantitative high-throughput multiplex immunofluorescence pipeline to evaluate OXPHOS defects in formalin-fixed human prostate tissue. Sci Rep. 2022;12(1):6660.
Smith A, Whitehall JC, Greaves LC*. Mitochondrial DNA mutations in aging and cancer. Mol Oncol. 2022;16(18):3276-3294.
Yu X, Arden C, Berlinguer-Palmini R, Chen C, Bradshaw C, Smith AL, Whitehall J, White M, Anderson S, Kattner N, Shaw J, Turnbull D, Greaves LC*, Walker M. Mitochondrial complex I subunit deficiency promotes pancreatic α-cell proliferation. Mol Metab. 2022;60:101489.
2021
Fuller A, Okwose N, Scragg J, Eggett C, Luke P, Bandali A, Velicki R, Greaves L, MacGowan GA, Jakovljevic DG. The effect of age on mechanisms of exercise tolerance: Reduced arteriovenous oxygen difference causes lower oxygen consumption in older people. Exp Gerontol. 2021;149:111340.
Stamp C, Whitehall JC, Smith ALM, Houghton D, Bradshaw C, Stoll EA, Blain AP, Turnbull DM, Greaves LC*. Age-associated mitochondrial complex I deficiency is linked to increased stem cell proliferation rates in the mouse colon. Aging Cell. 2021;20(3):e13321.
2020
Smith ALM, Whitehall JC, Gay D, Bradshaw C, Robertson F, Blain AP, Houghton D, Hunt M, Sampson JN, Stamp C, Baker A, Russell OM, Johnson R, Richardson CA, Gupta B, McCallum I, Kelly S, Mathers JC, Heer R, Taylor RW, Perkins ND, Turnbull DM, Sansom OJ, Greaves LC*. Age-associated mitochondrial DNA mutations cause metabolic remodelling that contributes to accelerated intestinal tumorigenesis. Nat Cancer. 2020;1, 976–989
Dobson PF, Hipps D, Reeve AK, Laude A, Stamp C, Smith ALM, Deehan DJ, Turnbull DM, Greaves LC*. Mitochondrial dysfunction impairs in vitro osteogenesis, osteoclast function and accelerates age-related bone loss. Sci Rep. 2020;10(1):11643.
Lawless C, Greaves LC, Reeve AK, Turnbull DM, Vincent AE. The rise and rise of mitochondrial DNA mutations. Open Biol. 2020;10(5):200061.
Whitehall JC and Greaves LC*. Aberrant mitochondrial function in ageing and cancer. Biogerontology. 2020;21(4):445-459.
2019
Anderson R, Lagnado A, Maggiorani D, Walaszczyk A, Dookun E, Chapman J, Birch J, Salmonowicz H, Ogrodnik M, Jurk D, Proctor C, Correia-Melo C, Victorelli S, Fielder E, Berlinguer-Palmini R, Owens A, Greaves LC, Kolsky KL, Parini A, Douin-Echinard V, LeBrasseur NK, Arthur HM, Tual-Chalot S, Schafer MJ, Roos CM, Miller JD, Robertson N, Mann J, Adams PD, Tchkonia T, Kirkland JL, Mialet-Perez J, Richardson GD, Passos JF. Length-independent telomere damage drives post-mitotic cardiomyocyte senescence. EMBO J. 2019;38(5):e100492.
Breininger SP, Malcomson FC, Afshar S, Turnbull DM, Greaves L, Mathers JC. Effects of obesity and weight loss on mitochondrial structure and function and implications for colorectal cancer risk. Proc Nutr Soc. 2019;78(3):426-437.
Malcomson FC, Breininger SP, ElGendy K, Joel A, Ranathunga T, Hill T, Bradburn DM, Turnbull DM, Greaves LC, Mathers JC. Design and Baseline Characteristics of the BORICC Follow-Up (BFU) Study: a 12+ years follow-up of the Biomarkers Of Risk of Colorectal Cancer Study. Nutr Health. 2019;25(3):231-238.
Paish HL, Reed LH, Brown H, Bryan MC, Govaere O, Leslie J, Barksby BS, Garcia Macia M, Watson A, Xu X, Zaki MYW, Greaves L, Whitehall J, French J, White SA, Manas DM, Robinson SM, Spoletini G, Griffiths C, Mann DA, Borthwick LA, Drinnan MJ, Mann J, Oakley F. A novel bioreactor technology for modelling fibrosis in human and rodent precision-cut liver slices. Hepatology. 2019;70(4):1377-1391.
2018
Simard ML, Mourier A, Greaves LC, Taylor RW, Stewart JB. A novel histochemistry assay to assess and quantify focal cytochrome c oxidase deficiency. J Pathol. 2018;245(3):311-323.
Stamp C, Zupanic A, Sachdeva A, Stoll EA, Shanley DP, Mathers JC, Kirkwood TBL, Heer R, Simons BD, Turnbull DM, Greaves LC*. Predominant Asymmetrical Stem Cell Fate Outcome Limits the Rate of Niche Succession in Human Colonic Crypts. EBioMedicine. 2018;31:166-173.
Su T, Grady JP, Afshar S, McDonald SA, Taylor RW, Turnbull DM, Greaves LC*. Inherited pathogenic mitochondrial DNA mutations and gastrointestinal stem cell populations. J Pathol. 2018;246(4):427-432.
Su T, Turnbull DM, Greaves LC*. Roles of Mitochondrial DNA Mutations in Stem Cell Ageing. Genes (Basel). 2018;9(4).
