Associate Professor of Exp Pathology and senior researcher in Prof. Jiri Bartek group at MBB Dept, Sci Life Lab, Karolinska Institutet in Stockholm.
Cell phone: +46 (0) 709989566
MSc, Biomedicine, 1999, Karolinska Institutet, Stockholm, Sweden
PhD, Oncology-Experimental Oncology, 2004, Karolinska Institutet, Stockholm, Sweden
Docent, Experimental Pathology, 2012, Karolinska Institutet, Stockholm, Sweden
Our main goal is to understand the regulation of ribosome biogenesis in human cancer cells and how it is different from normal cells. The objectives of our studies are to identify and characterize proteins that are involved in ribosome biogenesis surveillance through the p53 tumor suppressor pathway, to better define and understand functions of the nucleolar histone chaperone NPM1, and finally to explore novel concepts related to the emerging "ribosome code" as it applies to cancer, especially glioma.
Cancer cells display several abnormal properties known as hallmarks including increased growth and proliferation. Better knowledge about cellular growth control will help to develop strategies for therapeutic intervention targeting aberrant cancer cell growth. How does a cell control its own growth - that is increase in biomass? Ribosomes are intracellular factories made up of large RNA species and around 80 ribosomal proteins and that synthesize proteins thus being essential for cell growth. The production of ribosomes, ribosome biogenesis, is one of the most energy-consuming processes in the cell and must be closely controlled. Ribosome biogenesis has been studied mainly in yeast and bacteria, but the mechanisms and control systems involved are still largely unexplored in mammalian cells. A deficiency in ribosome biogenesis triggers a cellular stress response that t least in part dependent on ribosomal protein L11 and L5 that signals to the tumor suppressor p53. One of our long-term goals is to further unravel the principles of ribosome biogenesis surveillance and to understand the dynamics and the finer details of the p53 pathway in sensing ribosome dysfunction. In fact, activation of the p53 anti-proliferative cellular response to ribosome loss could be used to our advantage in cancer therapy, and to this end, we are also evaluating novel combinations of small molecules that are inhibiting ribosome biogenesis. Cancer cells need a higher or altered protein synthesis in order to sustain their rapid growth. Changes in specific mRNA translation patterns may account for some of the changes seen in cancer cells but perhaps of equal importance are alterations in the ribosome itself. Are ribosomes made with a modification code in analogy with the histone code and that is in control of mRNA translation patterns?
The nucleolus is the site for ribosome biogenesis and if we want to understand the dynamics of ribosome production we should also study the nucleolus. The process of ribosome biogenesis in the nucleolus may be seen as a paradigm for understanding of how changes in chromatin are linked to a specific cell function. We are investigating how the structure and function of the nucleolus change during cell differentiation, cell stress and how it is different in cancer cells. We aim to understand how the structure of the surrounding nucleolar chromatin is adapting to changes in cellular growth demand and thereby control ribosome biogenesis and vice versa.
A key regulator of nucleolar structure is NPM1 (also known as nucleophosmin) a nucleolar histone chaperone and we are currently re-visiting the pleiotropic functions of NPM1 in genome stability, ribosome biogenesis, nucleolar structure and perinucleolar heterochromatin architecture.
For a complete list see Researchgate or use Pubmed string “Lindstrom MS”.
Role of ribosomal protein mutations in tumor development (Review).
Int. J. Oncol. 2016 Apr;48(4):1313-24
mTOR inhibitors blunt the p53 response to nucleolar stress by regulating RPL11 and MDM2 levels.
Cancer Biol. Ther. 2014 ;15(11):1499-514
Loss of nucleolar histone chaperone NPM1 triggers rearrangement of heterochromatin and synergizes with a deficiency in DNA methyltransferase DNMT3A to drive ribosomal DNA transcription.
J. Biol. Chem. 2014 Dec;289(50):34601-19
Targeting of MCL-1 kills MYC-driven mouse and human lymphomas even when they bear mutations in p53.
Genes Dev. 2014 Jan;28(1):58-70
Brain abnormalities and glioma-like lesions in mice overexpressing the long isoform of PDGF-A in astrocytic cells.
PLoS ONE 2011 Apr;6(4):e18303
An ARF-independent c-MYC-activated tumor suppression pathway mediated by ribosomal protein-Mdm2 Interaction.
Cancer Cell 2010 Sep;18(3):231-43
Ribosomal protein S9 is a novel B23/NPM-binding protein required for normal cell proliferation.
J. Biol. Chem. 2008 Jun;283(23):15568-76
Cancer-associated mutations in the MDM2 zinc finger domain disrupt ribosomal protein interaction and attenuate MDM2-induced p53 degradation.
Mol. Cell. Biol. 2007 Feb;27(3):1056-68
Myc and E2F1 induce p53 through p14ARF-independent mechanisms in human fibroblasts.
Oncogene 2003 Aug;22(32):4993-5005
p14ARF homozygous deletion or MDM2 overexpression in Burkitt lymphoma lines carrying wild type p53.
Oncogene 2001 Apr;20(17):2171-7