Biology subjects

Gaucherot, A.

Publications and source records attributed to Gaucherot, A..

3 recordsLinked to original sources

bioRxiv2025

Ribosome biogenesis is a therapeutic vulnerability in paediatric neuroblastoma

BackgroundNeuroblastoma is a heterogeneous malignant paediatric tumor with prognosis depending on patient age and disease stage. Current treatment strategies rely on four key diagnostic criteria: age, histological stage, MYCN gene status, and genomic profile. It has been reported that MYC oncogenic activity depends on ribosome biogenesis, whose hyperactivation in cancer cells supports their high proliferative capacity, and thus represent a potential therapeutic target. Methodswe utilized the well-established IMR-32 cell line along with a panel of patient-derived neuroblastoma cell lines with varying MYCN status, which we previously established. Additionally, we generated an IMR-32 cell line expressing an shRNA targeting the ribosome biogenesis factor fibrillarin (FBL). Cell growth, apoptosis markers, and cell cycle regulators were analyzed. Expression of ribosome biogenesis factors was assessed using publicly available datasets and RT-qPCR data from an in-house neuroblastoma cohort. ResultsWe explored whether ribosome biogenesis represents a vulnerability in neuroblastoma. Our findings demonstrate that inhibition of RNA polymerase I using CX-5461 and BMH-21 suppressed cell proliferation at nanomolar concentrations and induced ribosomal stress, leading to activation of apoptosis and the p21 pathway. Furthermore, we identified FBL as a marker of poor prognosis in neuroblastoma. Consistently, FBL knockdown reduced neuroblastoma cell proliferation, supporting its potential as a therapeutic target. ConclusionOur study reinforces the therapeutic potential of ribosome biogenesis inhibition in neuroblastoma and expands the list of potential targets to include rRNA maturation factors. These findings highlight the promise of targeting ribosome biogenesis as a novel approach for neuroblastoma treatment.

cancer biology↗

bioRxiv2025

Fibrillarin-mediated ribosomal RNA maturation is a novel therapeutic vulnerability in triple-negative breast cancer

Triple-negative breast cancer (TNBC) remains one of the most challenging breast cancer subtypes to treat due to the lack of effective therapeutic options. Ribosome biogenesis has recently emerged as a promising therapeutic target across various cancers. Despite the current targeting of ribosome biogenesis through RNA polymerase I (RNA Pol I) inhibition, we speculated that other factors essential for ribosome assembly, such as rRNA maturation factors, may also represent therapeutic targets in TNBC. Here, we demonstrate that ribosome biogenesis-related genes are notably overexpressed in TNBC compared to other breast cancer subtypes, highlighting its critical role in TNBC progression. Accordingly, we show that RNA Pol I inhibition exerts potent anti-proliferative effects in pre-clinical models of TNBC, both in vitro and in vivo. However, the DNA-damaging activity of RNA Pol I inhibitors raises safety concerns, highlighting the need for alternative strategies to inhibit ribosome biogenesis. To this end, we show that targeting a downstream rRNA maturation step, specifically pre-rRNA cleavage, by inhibiting the maturation factor Fibrillarin, also inhibits tumor growth in TNBC models. Notably, ribosome biogenesis inhibition, through either RNA Pol I or Fibrillarin targeting, induces cell cycle arrest without triggering significant cell death. These findings establish ribosome biogenesis as a therapeutic vulnerability in TNBC and identify rRNA maturation, and Fibrillarin in particular, as novel targets for potential therapeutic intervention. SignificanceTargeting ribosome biogenesis, through inhibition of either rRNA synthesis or maturation, induces anti-tumoral effects in TNBC, representing a novel therapeutic vulnerability with potential to improve patient outcomes.

cancer biology↗

bioRxiv2020

The RNA helicase DHX30 coordinates cytoplasmic translation and mitochondrial function contributing to cancer cell survival

DHX30 was recently implicated in the translation control of mRNAs involved in p53-dependent apoptosis. Here we show that DHX30 exhibits a more general function by integrating the activities of its cytoplasmic isoform and of the more abundant mitochondrial one. The depletion of both DHX30 isoforms in HCT116 cells leads to constitutive changes in polysome-associated mRNAs, enhancing the translation of mRNAs coding for cytoplasmic ribosomal proteins while reducing the translational efficiency of the nuclear-encoded mitoribosome mRNAs. Furthermore, depletion of both DHX30 isoforms exhibits higher global translation but slower proliferation, and reduced mitochondrial energy metabolism. Isoform-specific silencing established a role for cytoplasmic DHX30 in modulating global translation. The impact on global translation and proliferation were confirmed in U2OS and MCF7 cells, although the effect of DHX30 depletion on mitochondrial gene expression was observed only in MCF7 cells. Exploiting RIP, eCLIP, and gene expression data, we identified a gene signature comprising DHX30 and fourteen mitoribosome transcripts that we candidate as direct targets: this signature shows prognostic value in several TCGA cancer types, with higher expression associated with reduced overall survival. We propose that DHX30 contributes to cell homeostasis by coordinating ribosome biogenesis, global translation, and mitochondrial metabolism. Targeting DHX30 could, thus, expose a vulnerability in cancer cells. Author summaryTranslation occurs in the cell both through cytoplasmic and mitochondrial ribosomes, respectively translating mRNAs encoded by the nuclear and the mitochondrial genome. Here we found that DHX30, an RNA-binding protein implicated in p53-dependent apoptosis, enhances the translation of mRNAs coding for cytoplasmic ribosomal proteins while reducing that of the mitoribosome mRNAs when silenced. This coordination of the cytoplasmic and mitochondrial translation machineries affected both cell proliferation and energy metabolism, suggesting an important role for this mechanism in determining the fitness of cancer cells. Indeed, the analysis of publicly available cancer datasets led us to define a 15-genes signature that is able to affect the prognosis of a subset of cancer types. In this subset, we found that higher expression of the genes composing the signature is associated with a worse prognosis. We thus propose DHX30 as a potential vulnerability in cancer cells, that could be targeted to develop novel therapeutic strategies.

molecular biology↗