Biology subjects

Montaudon, E.

Publications and source records attributed to Montaudon, E..

6 recordsLinked to original sources

bioRxiv2026

The SF3B1 inhibitor pladienolide B massively inhibits DNA damage signaling and repair and counteracts resistance to platinum salts in Non-Small Cell Lung Cancer

BackgroundLung cancer, including Non-Small Cell Lung Carcinoma (NSCLC), is the leading cause of cancer mortality worldwide. Platinum salts are the gold standard chemotherapy for NSCLC but many patients develop resistance leading to disease progression. Identifying new therapeutic strategies to counteract resistance is crucial. Pharmacological compounds targeting core components of the spliceosome machinery have emerged as promising anti-cancer agents. However, their mechanisms of action remain to be elucidated in NSCLC. MethodsVarious NSCLC cell lines were used in 2D and 3D cultures or clonogenic assays. NSCLC Patient-Derived Xenografts were also used. SF3B1 was silenced by siRNA. Flow cytometry was performed to analyze cell cycle distribution and apoptosis. Western-blot, immunofluorescence, SIRF analysis and DNA repair assays were done to assess globally the DNA damage response. RNA-Seq, RT-qPCR and RT-PCR studies were performed to identify gene and splicing events impacted by SF3B1 inhibition. Publicly available transcriptomic and proteomic data were analyzed. ResultsSF3B1 is a core component of the spliceosome machinery. We show that NSCLC cells with acquired resistance to platinum salts are vulnerable to pladienolide B, a SF3B1 inhibitor, or SF3B1 knock-down. Importantly, pladienolide B also slows down tumor growth of NSCLC Patient-Derived Xenografts (PDXs) poorly responsive to platinum salts. Mechanistically, we show that pladienolide B leads to genomic instability and apoptosis, that correlate with early transcription-dependent replication stress and DNA-PKcs activation, followed by the shutdown of ATR/DNA-PKcs-dependent signaling. In addition, pladienolide B profoundly regulates the expression and/or splicing, particularly exon skipping, of numerous genes involved in DNA repair, leading to decreased repair capacities of DNA double strand breaks. Although exon skipping events are mostly transient, skipping of exon 8 of MLH3, a gene involved in mismatch DNA repair, persisted along time. Finally, we show that pladienolide B counteracts resistance to platinum salts in NSCLC cells as well as PDXs, which correlates with enhanced MLH3 exon 8 skipping and decrease of ATR, DNA-PKCs and MLH3 protein levels. ConclusionsAs a whole, our data highlight the targeting of SF3B1 as a potential therapeutic strategy, alone or in combination, in NSCLC patients who escape platinum salts-based chemotherapy.

cancer biology↗

bioRxiv2025

Tumor-on-Chip as a Personalised Platform for Rapid Drug-Testing in Breast Cancer

Breast cancer (BC) remains one of the most common malignancies worldwide and continues to pose major therapeutic challenges, emphasizing the need for functional models that can inform fast treatment selection. Currently, patient-derived xenografts (PDXs) and organoids (PDOs) are valuable biological models for functional precision oncology; however, variable success rates of establishment and prolonged timelines limit their clinical application for real-time drug testing. To overcome this, we developed a Tumor-on-Chip (ToC) platform that enables functional drug sensitivity profiling within a clinically actionable 4-day timeframe. We compared ToC models with PDX results, and demonstrated high reproducibility and strong concordance with in vivo PDX responses. Drug sensitivity was correctly identified ex vivo in 88% of PDX-responsive cases, while resistance was detected in 91%, with no false positives at clinically relevant drug concentrations. To facilitate clinical translation, we engineered a custom microfluidic chip optimized for minimal breast cancer biopsy material, yielding results similar to those obtained from resection samples. We ultimately demonstrated the proof-of-concept for applying this platform to patient samples as a further tool for guiding clinical decision-making and discriminated between resistance and sensitive profiles among patients. These findings demonstrate the feasibility and translational potential of ToC models for personalized drug profiling in breast cancer, laying the groundwork for their integration into real-time clinical decision-making workflows.

bioengineering↗

bioRxiv2025

Spatiotemporal dynamics of tumor microenvironment remodelling

During tumorigenesis, interactions between tumor and stromal cells progressively remodel the tumor microenvironment (TME) towards pro-tumoral functions. Understanding early TME remodeling dynamics is therefore crucial for developing interceptive therapies. However, clinical samples typically provide isolated, late tumorigenesis snapshots. To overcome this limitation, we generated triple-negative breast cancer mice that develop multifocal, asynchronous tumors along a continuous luminal-to-basal transdifferentiation trajectory. Ordering spatial transcriptomes from 100+ ducts along this trajectory reveals the spatiotemporal dynamics of TME remodeling and underlying molecular mechanisms. Cancer-associated myofibroblasts (myCAFs) emerge as key players in advanced tumors, where they orchestrate pro-invasive remodeling of the tumor-stromal interface. myCAFs are conserved in patient-derived xenograft models and steer tumor trajectories towards invasive phenotypes when co-injected with tumor cells in syngeneic mice. Our study shows that temporal ordering of spatially-resolved disease snapshots unravels some of the molecular "forces" that, starting from the cell-of-origin, propel cells/microenvironments along a disease trajectory.

cancer biology↗

bioRxiv2025

Identification of a shared persistence program in triple-negative breast cancer across treatments and patients

Acquisition of resistance to anti-cancer therapies is a multistep process, which initiates with the survival of drug persister cells. Understanding the mechanisms driving the emergence of persister cells remains challenging, primarily because of their limited accessibility in patients. Here, using mouse models to isolate persister cells from patient tumors, we determine the identity features of persister cells from eight patients with triple-negative breast cancer (TNBC). Combining over 80 transcriptome studies, we reveal hallmarks of the persister state across patient models and treatment modalities: high expression of basal keratins together with activation of a stress response and inflammation pathways. Patient-derived persister cells are transcriptionally plastic and return to a common treatment-naive like state upon relapse, regardless of the treatment they have been exposed to. Leveraging gene regulatory networks, we identify AP-1, NFKB and IRF/STAT as the key drivers of this hallmark persister state. As a proof of concept, we show that FOSL1 - an AP-1 member - is sufficient to drive cells to the persister state by binding enhancers and reprogramming the transcriptome of cancer cells. On the contrary, cancer cells without FOSL1 have a decreased ability to reach the persister state. By defining hallmarks of drug persistence to multiple therapies of the standard of care, our study provides a resource to design novel combination therapeutic strategies to limit resistance.

cancer biology↗

bioRxiv2022

Ants act as olfactory bio-detectors of tumour in patient-derived xenograft mice

Early detection of cancer is critical in medical sciences, as the sooner a cancer is diagnosed, the higher the chances of recovery. Tumour cells are characterized by specific volatile organic compounds (VOCs) that can be used as cancer biomarkers. Through olfactory associative learning, animals can be trained to detect these VOCs. Insects, such as ants, have a refined sense of smell and can be easily and rapidly trained with olfactory conditioning. Using urine from patient-derived xenograft mice as stimulus, we demonstrate that individual ants can learn to discriminate the odour of healthy mice from that of tumour bearing mice, and do so after only three conditioning trials. Chemical analyses confirmed that the presence of the tumour changed the urine odour, supporting the behavioural results. Our study demonstrates that ants reliably detect tumour cues in mice urine and have the potential to act as efficient and inexpensive cancer bio detectors.

animal behavior and cognition↗

bioRxiv2021

mTOR repression in response to amino acid starvation promotes ECM degradation through MT1-MMP endocytosis arrest

Under conditions of starvation, normal and tumor epithelial cells can rewire their metabolism towards the consumption of extracellular matrix-derived components as nutrient sources. The mechanism of pericellular matrix degradation by starved cells has been largely overlooked. Here we show that matrix degradation by breast and pancreatic tumor cells and patient-derived xenograft explants increases by one order of magnitude upon amino acid and growth factor deprivation. In addition, we found that collagenolysis requires the invadopodia components, TKS5 and the transmembrane metalloproteinase, MT1-MMP, which are key to the tumor invasion program. Increased collagenolysis is controlled by mTOR repression upon nutrient depletion or pharmacological inhibition by rapamycin. Our results reveal that starvation hampers clathrin-mediated endocytosis, resulting in MT1-MMP accumulation in arrested clathrin-coated pits. Our study uncovers a new mechanism whereby mTOR repression in starved cells leads to the repurposing of abundant plasma membrane clathrin-coated pits into robust ECM-degradative assemblies.

cancer biology↗