Biology subjects

Laverny, G.

Publications and source records attributed to Laverny, G..

3 recordsLinked to original sources

bioRxiv2025

Targeting Pre-existing Club-Like Cells in Prostate Cancer Potentiates Androgen Deprivation Therapy

A critical knowledge gap in prostate cancer research is understanding whether castration-tolerant progenitor-like cells that reside in treatment-naive tumors play a direct role in therapy resistance and tumor progression. Herein, we reveal that the castration tolerance of LSCmed (Lin-, Sca-1+, CD49fmed) progenitor cells, the mouse equivalent of human prostatic Club cells, arises not from intrinsic properties, but from significant transcriptional reprogramming. Utilizing single-cell RNA sequencing of LSCmed cells isolated from prostate-specific Pten-deficient (Ptenpc-/-) mice, we identify the emergence of castration-resistant LSCmed cells enriched in stem-like features, driven by the transcription factor FOSL1/AP-1. We demonstrate that cells exhibiting Ptenpc-/- LSCmed characteristics are prevalent in aggressive double-negative prostate cancer (DNPC) subtypes recently identified in human castration-resistant prostate cancer (CRPC). Furthermore, our findings show that the dual-targeting agents JQ-1 and CX-6258--focused on FOSL1/AP-1 and PIM kinases, respectively--effectively suppress both the progenitor properties and the growth of mouse and human DNPC surrogates in vitro and in vivo. Thus, early eradication of castration-tolerant Club-like cells presents a promising therapeutic strategy to mitigate prostate cancer progression toward CRPC.

cancer biology↗

bioRxiv2024

Experimental myositis: an optimised version of C-protein-induced myositis

IntroductionInflammatory myopathies (IM) are a group of severe autoimmune diseases, sharing some similarities, whose cause is unknown and treatment is empirical. While C-protein-induced myositis (CIM), the most currently used model of IM, has removed some roadblock to understand and improve the treatment of IM, it has only been partially characterised and its generation limited by reproducibility issues. This study aimed at optimising the generation and the characterisation of CIM. MethodsIn silico analysis was run to identify the top-3 specific and immunogenic regions of C-protein. The cognate polypeptides were synthetised and used to immunise C57BL/6N mice. Grip strength, walking ability, serum creatine-kinase levels and muscle pathology (histological and electron microscopic features) were assessed. Immune cell proportions and interferon signature in muscles were also determined. ResultsAmong the three C-protein polypeptides with the highest immunogenic score, amino acids 965-991 induced the most severe phenotype (i.e., 37% decrease in strength, 36% increase in hind base width, 45% increase in serum creatine-kinase level, 80% increase in histological inflammatory score) from day (D) 14 to at least D31 after immunisation [experimental myositis (EM)]. Optical and electron microscopy revealed mononuclear cell infiltrate, myofibre necrosis, atrophy, MHC-I expression as well as sarcolemmal, sarcomeric and mitochondrial abnormalities. Proinflammatory T-lymphocytes, macrophages, type-I and II interferon-stimulated transcripts were found within the muscle of EM mice. ConclusionEM recapitulates the common hallmarks of IM. This costless, high throughput, reproducible and stable model, generated in the most commonly used background for genetically engineered mice, may foster pre-clinical research in IM. Key messagesO_ST_ABSWhat is already known on this topicC_ST_ABSC-protein-induced myositis is currently the most used model of inflammatory myopathies but has been partially characterised and its generation is limited by reproducibility issues. What this study adds.Immunisation against the polypeptide encompassing C-protein amino acids 965-991 induces a costless, high throughput, reproducible and stable model of myositis (experimental myositis) that recapitulates the common hallmarks of inflammatory myopathies. How this study might affect research, practice or policyExperimental myositis, generated in the most used background for genetically engineered mice (C57BL/6N), might foster pre-clinical research in IM.

immunology↗

bioRxiv2017

PGC-1β prevents statin-associated myotoxicity in oxidative skeletal muscle

Statins are generally well-tolerated, but can induce myopathy. Statins are associated with impaired expression of PGC-1{beta} in human and rat skeletal muscle. The current study was performed to investigate the relation between PGC-1{beta} expression and function and statin-associated myopathy. In WT mice, atorvastatin impaired mitochondrial function in glycolytic, but not in oxidative muscle. In PGC-1{beta} KO mice, atorvastatin induced a shift from oxidative type IIA to glycolytic type IIB myofibers mainly in oxidative muscle and mitochondrial dysfunction was observed in both muscle types. In glycolytic muscle of WT and KO mice and in oxidative muscle of KO mice, atorvastatin suppressed mitochondrial proliferation and oxidative defense, leading to apoptosis. In contrast, mitochondrial function was maintained or improved and apoptosis decreased by atorvastatin in oxidative muscle of WT mice. In conclusion, PGC-1{beta} has an important role in preventing damage to oxidative muscle in the presence of a mitochondrial toxicant such as atorvastatin.

pharmacology and toxicology↗