Translating the ribosome code of pediatric cancers

Wider research context This project tackles an unexplored mechanism of gene regulation that could redefine our understanding of how genes are translated into proteins. Prompted by recent evidence that ribosomes are not monolithic machines but dynamic, heterogeneous complexes with regulatory functions, we aim to chart the ribosome code of pediatric cancers. With millions of ribosomes in a human cell, we hypothesize that there is a plethora of ribosomes with specialized functions and a ribosome code that regulates translation from mRNA to protein in a cell-type and cell-state specific manner. Pediatric cancers provide a genetically trackable (and medically relevant) model for studying mechanisms of post-transcriptional gene regulation, given that they harbor few genetic aberrations. Importantly, in the absence of targeted drugs for many of these cancers, fresh ideas are urgently needed to address their unmet medical need. Pioneering aspects of research Scope. Ribosomes as an unexplored regulatory layer in pediatric oncology, which contributes not only to the understanding of fundamental biology but also opens new opportunities in biomedical research. Scale and Ambition. Crack the ribosome code across the spectrum of pediatric cancer types. Deep functional characterization of ribosome heterogeneity enabling new discoveries. Transformative potential. Establish translational control by the ribosomes as the third major regulator of cellular identity, oncogenesis and drug resistance, joining the ranks of transcriptional and post-translational control. Identify novel drug targets for pediatric cancers. Hypotheses, research questions, objectives We hypothesize that there is a diverse spectrum of specialized ribosomes inside human cells that provides an underappreciated layer of regulatory control and is hijacked in pediatric cancers. Our research question is: What is the composition of ribosomes in various pediatric cancers and how does it contribute to the characteristic cell states observed in pediatric cancers? We will tackle this research question by pursuing three complementary objectives: (i) map the ribosome landscape of pediatric cancers; (ii) connect ribosome composition to cellular phenotypes; (iii) establish ribosomal regulation as a cause of drug resistance. Approach, methods We will employ ribosome footprinting, mass spectrometry, long-read sequencing and cryo-EM to build a reference atlas of ribosome composition (WP1). We will link ribosome composition to cellular phenotypes using functional screens (WP2). We will dissect mechanisms of drug resistance driven by cell plasticity attributed to the dynamic composition of heterogeneous ribosomes (WP3). Primary researchers involved This project brings together four institutes and six PIs with a research background in pediatric cancers, structural biology, and protein biogenesis; and technical expertise in functional screening, in vivo modelling, proteomics, cryo-EM and sequencing.

FWF - excellent = austria - Emerging Fields - 2. Ausschreibungsrunde

Universität Wien
Funktion: Projektleitung
St. Anna Kinderkrebsforschung GmbH
Funktion: Partner