Biology subjects

Sadr, A. S.

Publications and source records attributed to Sadr, A. S..

3 recordsLinked to original sources

bioRxiv2025

KDM5-driven transcriptional noise fuels plasticity-led awakening and relapse in paediatric cancer

How drug-tolerant persister (DTP) cells escape quiescence to drive tumour relapse is a central unresolved question in cancer evolution. Here, we identify transcriptional noise (TN), defined as the stochastic variability in gene expression, as a latent property of paediatric cancer cells that becomes a driver of adaptive regrowth after treatment withdrawal. Using functional assays, lineage tracing, single-cell transcriptomics, and multiscale landscape modelling, we show that therapy enriches mesenchymal-like tolerant states in neuroblastoma without clonal selection, while post-treatment awakening is a stochastic process fuelled by noise-enabled plasticity in cell-identity programmes. The histone demethylase KDM5A relocates to noisy cell-state genes during awakening, promoting H3K4me3 removal and chromatin remodelling at these loci. KDM5 inhibition abrogates this process, and suppresses transcriptional noise, halts DTP exit, and prevents tumour recovery in both neuroblastoma and hepatoblastoma models. These results establish DTP as an exploitable evolutionary bottleneck, positioning KDM5-mediated transcriptional noise as an actionable therapeutic target to limit cancer adaptation and relapse GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=120 SRC="FIGDIR/small/682004v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@edba70org.highwire.dtl.DTLVardef@16b1bd9org.highwire.dtl.DTLVardef@f153acorg.highwire.dtl.DTLVardef@1ac5a4e_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2023

Dynamic Plasticity Systems Direct Early Adaptation to Treatment in Neuroblastoma

Neuroblastoma, like many aggressive cancers, exhibits phenotypic heterogeneity, contributing to therapy resistance and disease progression. However, direct evidence of how phenotypic plasticity influences tumour evolution remains limited. Using a multi-resolution quantitative approach, we define the principles, types, and dynamics of plasticity in neuroblastoma at unprecedented resolution. We demonstrate that intrinsic plasticity is a model-dependent process that enables the coexistence of drug-sensitive and drug-resistant states in environmentally stable conditions, positioning plasticity as a bet-hedging strategy that allows tumours to anticipate environmental changes. Additionally, we show plasticity varies across lineages and single-cell-derived clones, establishing that it is not merely an induced response but a heritable and selectable trait. By simultaneously mapping plasticity at and clonal dynamics in evolving neuroblastoma populations, we show plasticity is shaped by selective pressures, reinforcing its role as a fundamental driver of neuroblastoma evolution in a treatment- and genetic background-dependent manner. We define three distinct modes of plasticityled adaptation. In the selection of the plasticity model, strong selective pressure temporarily constrains phenotypic transitions, but they reemerge with greater dynamics once the stressor is removed, favouring the selection of highly plastic clones. In the adaptive plasticity model, phenotypic transitions actively reshape tumour heterogeneity, allowing for rapid adaptation to treatment while minimising the impact of clonal selection. Finally, in the plasticity equilibrium model, phenotypic transitions persist at baseline, maintaining a state of phenotypic fluidity, with clonal selection ultimately dictating tumour evolution. These findings highlight the diverse, context-dependent strategies that neuroblastoma populations employ to navigate selective pressures and therapy resistance, emphasizing the need for plasticity-targeting therapeutic approaches to disrupt tumour adaptation and improve treatment outcomes. TeaserNatural selection and phenotypic transitions shape adaptive evolution, guiding neuroblastoma survival under treatment pressure.

cancer biology↗

bioRxiv2020

Losartan promotes cell survival following SARS-CoV-2 infection in vitro

IntroductionCoronavirus disease 2019 (COVID-19) can be associated with mortality and high morbidity worldwide. There is an extensive effort to control infection and disease caused by SARS-CoV-2. This study addressed the hypothesis that angiotensin II type I receptor blocker, Losartan, may restrict pathogenesis caused by SARS-CoV-2 by decreasing viral-induced cytopathological changes by blocking angiotensin II type 1 receptor (AT1R), thus reducing the affinity of the virus for ACE2, and inhibiting papain-like protease of the virus. MethodLosartan inhibitory effect on deubiquitination and deISGylation properties of papain-like protease was investigated using a fluorescence method and gel shift analysis determining its inhibitory effects. The inhibitory effect of Losartan on SARS-CoV-2 cell replication was investigated both when losartan was added to the cell culture 1 hour before (pre-infection group) and 1 hour after (post-infection group) SARS-CoV-2 infection of Vero E6 cells. ResultsLosartan treatment of Vero E6 cells prior to and after SARS-CoV-2 infection reduced SARS-CoV-2 replication by 80% and 70% respectively. Losartan was not a strong deubiquitinase and deISGylase inhibitor of PLpro. ConclusionLosartan added pre- and post-infection to the Vero E6 cell culture significantly prevents cell destruction and replication by SARS-CoV2. Losartan has low side-effects, is readily available, and can be produced at high levels globally, all features of a promising drug in treatment of COVID-19 if validated by clinical trials.

pharmacology and toxicology↗