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Ribosome defects in cancer

Objective

"Cancer cells are defective in vital cell functions such as cell cycle control and response to growth signals. We found that cancer cells acquire defects in yet another vital function: translation of mRNA into proteins. We saw that 9.8% of children with T-cell leukemia (T-ALL) harbor acquired mutations in the ribosome, the cellular protein translation factory. We found mutations in RPL10, RPL5 and RPL22, 3 proteins of the large 60S ribosomal subunit. Strikingly, 6.5% of T-ALL patients had the same RPL10 R98S missense mutation. Although congenital ribosome defects were previously linked to higher cancer risk, the concept that defects in the ribosome are acquired during life and are selected for in cancer is novel. In addition, it is currently not understood by what mechanism ribosome defects are carcinogenic.
Patients with inherited ribosome defects are predisposed to all types of cancer. Therefore, other cancers than T-ALL may show acquired defects in the ribosome and I want to explore the prevalence of acquired ribosome defects in various cancer types. Second, I want to explore by which mechanism ribosome mutations promote cancer. Initially, I will focus on the RPL10 R98S mutation, the most frequent acquired ribosome defect we found so far. We will test the effect of RPL10 R98S on cell behavior parameters such as self-renewal capacity and resistance to apoptosis. I hypothesize that altered translation of a subset of cellular mRNAs, including mRNAs coding major tumor suppressors or oncogenes, may explain the oncogenic action of RPL10 R98S. Therefore, we will identify all mRNAs with altered translation efficiency or fidelity in RPL10 R98S cells. In addition, we will test if RPL10 R98S promotes cancer by altering extra-ribosomal roles of RPL10 or by driving inactivation of the TP53 pathway. Finally, acquired ribosome defects may represent a novel target for cancer therapy and we will test if ribosome defective cancer cells are hypersensitive to translation inhibitors."

Field of science

  • /natural sciences/biological sciences/genetics and heredity/mutation
  • /natural sciences/biological sciences/biochemistry/biomolecules/proteins
  • /medical and health sciences/clinical medicine/oncology/cancer
  • /medical and health sciences/clinical medicine/oncology/leukemia

Call for proposal

ERC-2013-StG
See other projects for this call

Funding Scheme

ERC-SG - ERC Starting Grant

Host institution

KATHOLIEKE UNIVERSITEIT LEUVEN
Address
Oude Markt 13
3000 Leuven
Belgium
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 1 159 958,75
Principal investigator
Kim Diana Lea De Keersmaecker (Dr.)
Administrative Contact
Stijn Delauré (Mr.)

Beneficiaries (2)

KATHOLIEKE UNIVERSITEIT LEUVEN
Belgium
EU contribution
€ 1 159 958,75
Address
Oude Markt 13
3000 Leuven
Activity type
Higher or Secondary Education Establishments
Principal investigator
Kim Diana Lea De Keersmaecker (Dr.)
Administrative Contact
Stijn Delauré (Mr.)
VIB VZW

Participation ended

Belgium
EU contribution
€ 337 079,25
Address
Rijvisschestraat 120
9052 Zwijnaarde - Gent
Activity type
Research Organisations
Administrative Contact
Rik Audenaert (Mr.)