Biology subjects

Lopes, F. J. P.

Publications and source records attributed to Lopes, F. J. P..

4 recordsLinked to original sources

bioRxiv2026

Phase-space distance between stationary states mudulates phenotypic plasticity in breast cancer

Phenotypic plasticity in breast cancer involves stochastic transitions between gene-expression states associated with clinically distinct subtypes, such as HER2+ and triple-negative breast cancer (TNBC). In non-conservative gene regulatory networks, however, the dynamical features controlling transition probabilities and timescales cannot be consistently reduced to potential-barrier depth, since potential functions are generally non-unique outside equilibrium. Here, by analyzing an NF-{kappa}B-centered regulatory network that supports HER2+ and TNBC attractors, we identify a geometric control principle: the phase-space distance between stationary states, together with the bifurcation structure organizing multistability, provides a robust determinant of transition probabilities, times, and variability. We show that multistability is necessary but not sufficient for transitions, whose accessibility is constrained by the global arrangement of basins and the intervening unstable state. Within this framework, we find a marked asymmetry in dynamical sensitivity: the HER2+ regime is robust to intrinsic parameter variations, whereas the TNBC regime strongly amplifies such variations, offering a dynamical explanation for the pronounced gene molecular and clinical variability observed in TNBC. Together, our results establish a general geometric perspective on phenotypic transitions in non-conservative regulatory networks.

systems biology↗

bioRxiv2025

In vivo effects of Cisplatin and titanium dioxide nanoparticles combined treatment

Cisplatin, the first metal-based chemotherapeutic drug, remains widely used despite its toxicity. Combining cisplatin with nanoparticles has been proposed to improve its therapeutic profile, although most studies rely on in vitro models. Using RNA-seq and bioinformatic analyses, we investigated the in vivo transcriptional effects of cisplatin (50 g/ml) and titanium dioxide nanoparticles (TiO2 NPs; 50 g/ml), alone and in combination, in Drosophila melanogaster. Flies exposed to cisplatin or TiO2 NPs alone exhibited modulation of genes associated with xenobiotic metabolism and detoxification. In contrast, combined exposure resulted in a markedly reduced number of upregulated differentially expressed genes (DEGs):CG10013, aqz, CG5568, and CG3213, which are related to cell division and DNA/RNA metabolism, likely due to a synergistic effect of the cisplatin and TiO2 administered simultaneously. We also observed that combined exposure promotes downregulation of genes involved in xenobiotic metabolism, detoxification, innate immune collapse, and reproduction and fertility. Although mortality rates were not significantly affected in any group, flies from the CIS/NPTIO2 group exhibited impaired climbing performance. These results suggest that co-exposure to cisplatin and TiO2 nanoparticles induces transcriptional suppression, potentially impairing essential cellular processes.

pharmacology and toxicology↗

bioRxiv2024

NF-κB Epigenetic Attractor Landscape Drives Breast Cancer Heterogeneity

Heterogeneity in breast cancer (BC) subtypes contributes to therapy resistance and recurrence. Subtype heterogeneity arises from stochastic genetic and epigenetic changes, phenotypic plasticity, and microenvironment-driven selection during tumor evolution. Here, we investigate how NF-{kappa}B epigenetic variability contributes to HER2+ BC progression. Using RNA-seq, we quantified NF-{kappa}B, TWIST1, SIP1, and SLUG expression in two BC cell lines: HCC-1954 (HER2+) and MDA-MB-231 (TNBC). Next, we built and calibrated a gene regulatory network model reproducing transcriptional interactions among these genes. The models epigenetic landscape displays two attractor basins that reproduce the HER2+ and TNBC expression profiles. Validation was performed using DHMEQ-treated cells, published patient and in vitro data. Stochastic fluctuations in NF-{kappa}B levels induce spontaneous, irreversible transitions from HER2+ to TNBC states at variable times, contributing to heterogeneity. These transitions are mediated by an unstable intermediate state that provides a noise-sensitive route. Mutations or drugs altering NF-{kappa}B availability reshape basin sizes, altering basin sizes and transition probabilities. Our work refines the attractor landscape framework, linking NF-{kappa}B dynamics to BC heterogeneity, supporting more accurate classification, prognosis, and treatment strategies.

systems biology↗

bioRxiv2020

A Reaction-Diffusion Network model predicts a dual role of Cactus/IκB to regulate Dorsal/NFκB nuclear translocation in Drosophila

Dorsal-ventral patterning of the Drosophila embryo depends on the NF{kappa}B superfamily transcription factor Dorsal (Dl). Toll receptor activation signals for degradation of the I{kappa}B inhibitor Cactus (Cact), leading to a ventral-to-dorsal nuclear Dl gradient. Cact is critical for Dl nuclear import, as it binds to and prevents Dl from entering the nuclei. Quantitative analysis of cact mutants revealed an additional Cact function to promote Dl nuclear translocation in ventral regions of the embryo. To investigate this dual Cact role, we developed a predictive model based on a reaction-diffusion regulatory network. This network considers non-uniform Toll activation as well as Toll-dependent Dl nuclear import and Cact degradation. In addition, it incorporates translational control of Cact levels by Dl, a Toll-independent pathway for Cact regulation and reversible nuclear-cytoplasmic Dl flow. Our model successfully reproduces wild-type data and emulates the Dl nuclear gradient in mutant dl and cact allelic combinations. Our results indicate that the dual role of Cact depends on targeting distinct Dl complexes along the dorsal-ventral axis: In the absence of Toll activation, free Dl-Cact trimers inhibit direct Dl nuclear entry; upon ventral-lateral Toll activation, Dl-Cact trimers are recruited into predominant signaling complexes and promote active Dl nuclear translocation. Simulations suggest that Toll-independent regulatory mechanisms that target Cact are fundamental to reproduce the full assortment of Cact effects. Considering the high evolutionary conservation of these pathways, our analysis should contribute to understand NF{kappa}B/c-Rel activation in other contexts such as in the vertebrate immune system and disease.

developmental biology↗