Biology subjects

RIVALS, E.

Publications and source records attributed to RIVALS, E..

5 recordsLinked to original sources

bioRxiv2026

A Novel miR-4745-KLC2 Axis Regulates Cancer Stem Cell Traits in Colorectal Cancer

Advanced colorectal cancer (CRC) treatments often fail due to chemoresistance and tumor recurrence, primarily driven by cancer stem cells (CSCs), which play a significant role in therapy ineffectiveness. MicroRNAs (miRNAs) play a pivotal role in regulating numerous biological functions within CSCs. Through a gain-of-function miRNA screening, we identified miRNAs that regulate the ALDEFLUOR-positive CSC population in colon cancer, with miR-4745 emerging as a promising inhibitor. Overexpression of miR-4745 reduced CSC self-renewal, diminished chemoresistance, and prevented CSC enrichment after chemotherapy in patient-derived CRC models. Mechanistically, miR-4745 directly targets the 3UTR of kinesin-light chain 2 (KLC2) mRNA, a member of the kinesin superfamily associated with poor clinical outcomes across various cancers. siRNA-mediated KLC2 downregulation reduced ALDH-positive CSCs and suppressed sphere formation, while KLC2 overexpression promoted CSC traits. Additionally, we observed an inverse correlation between KLC2 and miR-4745 mRNA levels in different colon cancer cell culture settings. Notably, KLC2 mRNA levels increased with local CRC progression and were correlated with poor overall survival in a cohort of over 1 000 stage I to IV colorectal cancer patients. Our study uncovers a novel miR-4745-KLC2 axis that regulates CSC properties and chemoresistance in CRC, offering a promising strategy to prevent relapse and improve clinical outcomes for patients.

cancer biology↗

bioRxiv2024

Translational control of cell plasticity drives 5-FU tolerance

All routine clinical treatments for colorectal cancer include 5-fluorouracil (5-FU), which cannot counteract recurrence and metastases formation. As the pyrimidine analog 5-FU can impact multiple pathways including both DNA and RNA metabolism, studying its mode of actions could lead to improved therapies. Using a dedicated reporter system for lineage-tracing and deep translatome profiling we demonstrate that 5-FU causes some colorectal cancer cells to tolerate the drug, due to a durable translational reprogramming that sustains cell plasticity. This period of drug tolerance coincides with specific translational activation of genes coding for proteins with major pro-tumoral functions. We unravel a major unexpected translational overexpression of the pro-inflammatory and pro-tumoral IL-8 cytokine, alongside other anti-apoptotic, senescence-associated secretory phenotype and cancer-related senescence phenotype genes. Given the adverse prognostic implications of elevated IL-8 levels across various cancers, our findings suggest IL-8 targeting could counteract 5-FU resistance.

cancer biology↗

bioRxiv2022

dipwmsearch: a python package for searching di-PWM motifs

MotivationSeeking probabilistic motifs in a sequence is a common task to annotate putative transcription factor binding sites (TFBS). Useful motif representations include Position Weight Matrices (PWMs), dinucleotidic PWMs (di-PWMs), and Hidden Markov Models (HMMs). Dinucleotidic PWMs combine the simplicity of PWMs - a matrix form and a cumulative scoring function -, but also incoporate dependency between adjacent positions in the motif (unlike PWMs which disregard any dependency). For instance, to represent binding sites, the HOCOMOCO database provides di-PWM motifs derived from experimental data. Currently, two programs, SPRy-SARUS and MOODS, can search for di-PWMs in sequences. ResultsWe propose a Python package, dipwmsearch, which provides an original and efficient algorithm for this task (it first enumerates matching words for the di-PWM, and then search them at once in the sequence even if it contains IUPAC codes). The user benefits from an easy installation via Pypi or conda, a documented Python interface, and reusable example scripts that smooth the use of di-PWMs. Availability and Implementationdipwmsearch is available at https://pypi.org/project/dipwmsearch/ and https://gite.lirmm.fr/rivals/dipwmsearch/ under Cecill license.

bioinformatics↗

bioRxiv2021

RNA-Ribo Explorer: interactive mining and visualisation of Ribosome profiling data

RNA translation has long been thought as a stable and uniform process by which a ribosome produces a protein encoded by the main Open Reading Frame (ORF) of an mRNA. Recently, growing evidence support incomplete correlation between RNA and protein abundance levels, the existence of alternative ORFs in numerous mammalian RNAs, and the involvement of ribosomes in gene expression regulation, thereby challenging previous views of translation. Ribosome profiling (aka Ribo-seq) has renewed the study of translation by enabling the mapping of translating ribosomes on the whole transcriptome using deep-sequencing. Despite increasing use of Ribo-seq, recent review articles conclude that flexible, interactive tools for mining such data are missing. As Ribo-seq protocols still evolve, flexibility is highly desirable for the end-user. Here we describe RNA-Ribo-Explorer (RRE) a stand-alone tool that fills this gap. With RRE, one can explore read-count profiles of RNAs obtained after mapping, compare them between conditions, and visualize the profiles of individual RNAs. Importantly, the user can mine the data by defining queries that combine several criteria to detect interesting subsets of RNAs. For instance, one can ask RRE to find all RNAs whose translation of UTR region compared to that of the main ORF has changed between two conditions. This feature seems useful for finding candidate RNAs whose translation status or processing has changed across conditions. RRE is a platform independent software and is freely available at https://gite.lirmm.fr/rivals/RRE/-/releases.

bioinformatics↗

bioRxiv2020

FTO-mediated cytoplasmic m6Am demethylation adjusts stem-like properties in colorectal cancer cell

Cancer stem cells (CSCs) are a small but critical cell population for cancer biology since they display inherent resistance to standard therapies and give rise to metastases. Despite accruing evidence establishing a link between deregulation of epitranscriptome-related players and tumorigenic process, the role of messenger RNA (mRNA) modifications dynamic in the regulation of CSC properties remains poorly understood. Here, we show that the cytoplasmic pool of fat mass and obesity-associated protein (FTO) impedes CSC abilities in colorectal cancer through its m6Am (N6,2-O-dimethyladenosine) demethylase activity. While m6Am is strategically located next to the m7G-mRNA cap, its biological function is not well understood and has not been addressed in cancer. Low FTO expression in patient-derived cell lines elevates m6Am level in mRNA which results in enhanced in vivo tumorigenicity and chemoresistance. Inhibition of the nuclear m6Am methyltransferase, PCIF1/CAPAM, partially reverses this phenotype. FTO-mediated regulation of m6Am marking constitutes a novel, reversible pathway controlling CSC abilities that does not involve transcriptome remodeling, but could fine-tune translation efficiency of selected m6Am marked transcripts. Altogether, our findings bring to light the first biological function of the m6Am modification and its potential adverse consequences for colorectal cancer management.

cancer biology↗