A pre-rRNA positive feedback loop drives malignant ribosome biogenesis

Prof Faraz Mardakheh; University of Oxford

Faraz studied Biochemistry as an undergraduate at the University of Birmingham, where he also undertook his PhD in the laboratory of Professor John Heath, studying feedback regulation of RTK signalling. He then joined the laboratory of the late Professor Chris Marshall at the Institute of Cancer Research as a postdoctoral fellow in 2010, in order to study signalling regulation of cancer invasion and metastasis. An unexpected discovery steered his focus towards RNA Binding Proteins (RBPs) and their role in cancer invasion. This led to receiving an MRC Career Development Award fellowship in 2017 to establish his own research group at the Barts Cancer Institute, Queen Mary University of London, focusing on studying the wider roles played by RBPs in promoting cancer development and progression. In 2024, Faraz moved his laboratory to the Department of Biochemistry, University of Oxford, where his team continues to research RBPs and their roles in cancer.

Altered nucleoli are a well-established hallmark of cancer1, but how oncogenic signalling remodels the nucleolus remains poorly understood. Here we used an inducible mouse model of pancreatic ductal adenocarcinoma (PDAC)2 to generate spatially resolved proteomic and phosphoproteomic maps of the nucleolus upon RAS oncogene activation. We identify a phosphorylation programme initiated by translocation of the Casein Kinase 2 (CK2) holoenzyme to the nucleolus. This programme amplifies rRNA synthesis and malignant ribosome biogenesis by phosphorylating factors that control RNA polymerase I transcription and early ribosomal RNA (rRNA)processing. Preventing the nucleolar activity of CK2 inhibits oncogene-induced rRNA production, while constitutive nucleolar trapping ofCK2 is sufficient to activate rRNA synthesis in the absence of RAS oncogene. Mechanistically, CK2 accumulation in the nucleolus is mediated by direct binding to the 3’ External Transcribed Sequence (3’ETS) of nascent precursor rRNA, creating an RNA-dependent self-amplifying feedback loop. Nucleolar CK2 accumulation is conserved across diverse human cancers, and its disruption synergises with inhibition of oncogenic RAS signalling to suppress anchorage-independent growth and tumourigenesis. Our study reveals 3’ETS as a CK2 signalling scaffold that amplifies oncogenic ribosome biogenesis, and defines a druggable nucleolar vulnerability that can be exploited by targeting this process.