The role of snoRNAs and RNA modifications in non-small cell lung cancer (NSLSC)

• Applicant: Professor Dr. Carsten Müller-Tidow
• Subject Area: Pneumology, Thoracic Surgery
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 571154436

Lung cancer remains the leading cause of cancer death worldwide with an estimated 1.8 million deaths each year. Non-small cell lung cancer (NSCLC) is the dominant form of lung cancer which accounts for 85% of all cases. Cure of NSCLC is possible in patients with resectable disease but despite complete resection of stage I and stage II NSCLC, up to half of these patients ultimately die, most frequently from development of distant metastasis. Thus, an improved understanding of how metastasis develop during cancer pathogenesis is urgently needed and novel metastasis prevention approaches are required to increase the cure rate. Recently, the epitranscriptome, i.e. biochemical modifications of RNA species, has been shown to be an important player in regulating many physiological and pathological processes including cancer. 2′-O-methylation of the ribose nucleotide backbone is the most common modification found in ribosomal RNA (rRNA), which is guided by small nuclelar RNAs (snoRNAs) acting as part of multicomponent protein complexes, the small nucleolar ribonucleoprotein (snoRNP) complexes. Several studies demonstrated that snoRNAs are frequently altered in solid tumors including lung cancer and hematological disorders. 2´-O-me patterns of rRNA can shape ribosomal heterogeneity and may enhance cellular plasticity by adapting mRNA translation to specific cellular needs. High 2´-O-me levels of single rRNA sites were shown to be required for clonogenic growth and proliferation of Acute Myeloid Leukemia cells. How 2´-O-me profiles contribute to ribosomal heterogeneity in lung cancer tumorigenesis and development of metastasis is currently unknown. In preparatory work for this project proposal, we discovered a prognostic 2ʹ-O-Me signature in lung adenocarcinoma patients. This epitranscriptomic pro-metastatic signature (EPROMET) predicted a high risk of metastasis and worse overall survival. In this project we aim to identify how changes in rRNA modifications lead to an altered translation to induce a pro-metastatic phenotype and to treat the pro-metastatic phenotype by inhibiting 2´-O-methylation. Using RiboMethSeq and Mass Spec we are going to analyze plasticity of the rRNA modification levels in cell lines with overexpression of EPROMET snoRNAs as well as in primary NSCLC samples with high and low metastatic potential. Further, we are going to study the mechanistic changes in ribosome composition upon altered 2’-O-me and analyze alter ribosome composition, protein translation and secretion. Finally, we will evaluate the anti-metastatic potential of targeting EPROMET-snoRNAs using xenograft mouse models. Taken together, this project will reveal how changes in rRNA modifications induce a pro-metastatic phenotype and whether the pro-metastatic phenotype can be reverted by inhibiting 2´-O-methylation.

• DFG Programme: Research Grants