Ola Larsson's Group

Gene expression is regulated post-transcriptionally at multiple levels including mRNA-splicing, -transport, -stability and -translation. Regulation of translation enables quick alterations in gene expression in response to internal and external signals; and highly controlled expression of genes with potentially detrimental functions (e.g. oncogenes). In many cases, mRNA translation is regulated at the level of initiation and therefore involves a shift in the number of ribosomes synthesizing proteins from each mRNA. In addition, we and other research groups have shown that key oncogenic pathways modulate translation by tuning translation elongation. This has expanded the repertoire of mechanisms controlling mRNA translation in health and disease.

Translational can be a regulated globally, by targeting translation of mRNA transcribed from most genes in a similar fashion, or selectively, by targeting subsets of mRNAs. The specificity for regulation depends on features in the mRNA molecule, often found in the untranslated region (UTR) but also in the coding region when regulation occurs at the level of elongation. Regulation of translation depends on interactions between these RNA-features and e.g. translation factors and RNA-binding proteins. A broader understanding of how mRNA translation is regulated and dysregulated in diseases is lacking.

The goal of our research program is to generate knowledge about the organization, specificity and mechanisms acting to control translation at a transcriptome-wide level, and how these mechanisms are affected in e.g. breast cancer. In particular, we aim to understand whether translation defines molecular subtypes of cancer and identify mechanisms that are potential targets for their treatment. This may guide us towards new therapeutic targets for treatment of poor prognosis breast cancers.

Selected publications

Stress-induced perturbations in intracellular amino acids reprogram mRNA translation in osmoadaptation independently of the ISR.
Krokowski D, Jobava R, Szkop KJ, Chen CW, Fu X, Venus S, Guan BJ, Wu J, Gao Z, Banaszuk W, Tchorzewski M, Mu T, Ropelewski P, Merrick WC, Mao Y, Sevval AI, Miranda H, Qian SB, Manifava M, Ktistakis NT, Vourekas A, Jankowsky E, Topisirovic I, Larsson O, Hatzoglou M
Cell Rep 2022 Jul;40(3):111092

Translational offsetting as a mode of estrogen receptor α-dependent regulation of gene expression.
Lorent J, Kusnadi EP, van Hoef V, Rebello RJ, Leibovitch M, Ristau J, Chen S, Lawrence MG, Szkop KJ, Samreen B, Balanathan P, Rapino F, Close P, Bukczynska P, Scharmann K, Takizawa I, Risbridger GP, Selth LA, Leidel SA, Lin Q, Topisirovic I, Larsson O, Furic L
EMBO J 2019 Dec;38(23):e101323

Distinct Cancer-Promoting Stromal Gene Expression Depending on Lung Function.
Sandri BJ, Masvidal L, Murie C, Bartish M, Avdulov S, Higgins L, Markowski T, Peterson M, Bergh J, Yang P, Rolny C, Limper AH, Griffin TJ, Bitterman PB, Wendt CH, Larsson O
Am J Respir Crit Care Med 2019 Aug;200(3):348-358

Generally applicable transcriptome-wide analysis of translation using anota2seq.
Oertlin C, Lorent J, Murie C, Furic L, Topisirovic I, Larsson O
Nucleic Acids Res 2019 Jul;47(12):e70

Polysome-profiling in small tissue samples.
Liang S, Bellato HM, Lorent J, Lupinacci FCS, Oertlin C, van Hoef V, Andrade VP, Roffé M, Masvidal L, Hajj GNM, Larsson O
Nucleic Acids Res 2018 Jan;46(1):e3

A Unique ISR Program Determines Cellular Responses to Chronic Stress.
Guan BJ, van Hoef V, Jobava R, Elroy-Stein O, Valasek LS, Cargnello M, Gao XH, Krokowski D, Merrick WC, Kimball SR, Komar AA, Koromilas AE, Wynshaw-Boris A, Topisirovic I, Larsson O, Hatzoglou M
Mol Cell 2017 Dec;68(5):885-900.e6

nanoCAGE reveals 5' UTR features that define specific modes of translation of functionally related MTOR-sensitive mRNAs.
Gandin V, Masvidal L, Hulea L, Gravel SP, Cargnello M, McLaughlan S, Cai Y, Balanathan P, Morita M, Rajakumar A, Furic L, Pollak M, Porco JA, St-Pierre J, Pelletier J, Larsson O, Topisirovic I
Genome Res 2016 May;26(5):636-48

Distinct perturbation of the translatome by the antidiabetic drug metformin.
Larsson O, Morita M, Topisirovic I, Alain T, Blouin M, Pollak M, et al
Proc. Natl. Acad. Sci. U.S.A. 2012 Jun;109(23):8977-82

Identification of differential translation in genome wide studies.
Larsson O, Sonenberg N, Nadon R
Proc. Natl. Acad. Sci. U.S.A. 2010 Dec;107(50):21487-92

Eukaryotic translation initiation factor 4E induced progression of primary human mammary epithelial cells along the cancer pathway is associated with targeted translational deregulation of oncogenic drivers and inhibitors.
Larsson O, Li S, Issaenko OA, Avdulov S, Peterson M, Smith K, Bitterman PB, Polunovsky VA
Cancer Res 2007 Jul;67(14):6814-24

Developed software

anota (https://www.bioconductor.org/packages/release/bioc/html/anota.html)

anota2seq (https://bioconductor.org/packages/release/bioc/html/anota2seq.html)

NOMAD (https://github.com/carlmurie/NOMAD)

Group members

Ola Larsson, Group leader
Sherwin Chan, Assistant professor
Kathleen Watt, post-doc
Solenne Bleuse, post-doc
Krzyszof Szkop, post-doc
Arash Rostami, PhD-student
Inci Aksoylu, PhD-student
Kiana Hosseinpour Moghaddam, PhD-student

Funding

• Swedish Cancer Society
• Swedish Research Council
• Knut and Alice Wallenberg Foundation
• Cancer Research Funds of Radiumhemmet
• Swedish Brain Foundation