RiboHetMet (101165750)

  https://cordis.europa.eu/project/id/101165750

  Horizon Europe (2021-2027)

  Unraveling Ribosome Heterogeneity: Implications for Metastasis and Beyond

  ERC STARTING GRANTS (ERC-2024-STG)

  oncology  ·  RNA

  2025-01-01 Start Date (YY-MM-DD)

  2029-12-31 End Date (YY-MM-DD)

  € 1,500,000 Total Cost

  Description

Protein translation, considered a mere reflection of transcription, emerges as a regulatory hub, shaping proteomes and directing cellular outcomes. This is due to existence of heterogeneous ribosome populations, yielding specialized ribosomes that drive context-dependent translation. While technological advances enable mapping of ribosomal diversity, questions remain as to the prevalence of the phenomenon and the mechanisms by which specialized ribosomes confer specific functions. Studies propose the presence of onco-ribosomes promoting oncogenic translational programs and regulating disease-related functions. Metastasis, the deadly spread of cancer cells to remote organs, is a key process that relies on rewiring of gene expression networks. Accordingly, our work shows that changes in the expression of coding and non-coding genes affect metastatic potential and correlates with patient prognosis. We further show that environmentally-regulated RNA modifications add to ribosomal heterogeneity. Yet, the involvement of specialized ribosomes in metastasis development is mostly unknown. Here, I propose to map ribosomal heterogeneity in metastatic cancers and decipher the 'ribosomal code' empowering specialized ribosomes to promote oncogenic translational programs and drive metastasis. Using cell lines, animal models and patient-derived samples, we will chart metastatic patterns of rRNA and ribosomal proteins (RPs), as well as of snoRNAs and rRNA modifications they guide. Employing in vivo and in vitro assays, we will uncover individual RPs and snoRNAs influencing ribosomal functions and metastasis formation and investigate their mechanisms of action. These genes and their metastatic patterns along with metastasis-specific rRNA compositions may serve as cancer biomarkers and targets for therapy. This research will advance our understanding of molecular mechanisms underlying ribosome heterogeneity and elucidate involvement of specialized ribosomes in cancer progression.

  Complicit Organisations

1 Israeli organisation participates in RiboHetMet.