Biology subjects

Tollis, S.

Publications and source records attributed to Tollis, S..

7 recordsLinked to original sources

bioRxiv2025

Functionalist Oncology to Model the Contextuality of Dynamics and Treatment in Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a disease with a high degree of intra- and interpatient heterogeneity. Current treatments almost uniformly employ the standardized 7+3 regimen, which is based on cytarabine combined with an anthracycline, with long-term survival rates below 30%. Our work specifically focuses on the cytarabine component of this regimen. Functionalist oncology utilizes edge-weighted digraphs as a representational tool to model the mathematical functional interdependencies of disease factors. This methodology enables a conceptual and mechanistic analysis of key factors influencing therapeutic success, providing a framework that can be parameterized to explore patient-specific treatment responses when suitable data are available. It incorporates the oligoclonal nature of AML to perform, in principle, comprehensive cost-benefit analyses regarding the addition of individual drugs to existing treatment regimens and the number and type of chemotherapy courses to be given. Extrapolating from experimental data, we investigate the therapeutic potential and risks of SAMHD1 inhibitors in AML treatment as a proof-of-concept. We also provide a web-based interactive application to visualize hypothetical AML treatment scenarios, which can be combined with ex vivo single-cell phenotypic (gene expression), genotypic (somatic mutations), and functional (drug responses) analyses. Functionalist oncology can thus be used to generate testable hypotheses that might contribute to improving oncological decision-making, e.g., by identifying the optimal number, nature and sequence of chemotherapy blocks, including both existing AML-directed blocks and additional drugs, such as SAMHD1 inhibitors.

systems biology↗

bioRxiv2025

Hematopoietic proliferation is orchestrated by the sequential and lineage-specific activation of Cyclin D, Cyclin E and CDKN sub-modules within the G1/S network

Commitment to the cell division cycle constrains other fate choices at the single cell level. Hence the molecular network controlling the G1/S transition must be coordinated with developmental phases. Healthy hematopoiesis relies on shifts in cell cycle dynamics that balance proliferation and differentiation of hematopoietic stem cells (HSCs) and lineage progenitors, offering an ideal model system to study the coordination of cell division with development. The G1/S network orchestrates this process by regulating the activites of the master G1/S transcription factors (E2F), and cyclin dependent kinases whose activities drive the progression to S phase. By using single cell transcriptomics profiles of human bone marrow cells and mathematical modeling, we demonstrate that variations in the expression of cyclin D- and cyclin E-centered sub-modules of the G1/S network carve out distinct trajectories from G1 to S, explaining the distinct proliferation properties of hematopoietic cell types evolving in the same microenvironment, and biasing cell fate decisions towards certain lineages. We map 68 hematopoietic cell types to specific model parameters, and identify their individual route through G1/S, using our model. This improved mechanistic understanding of the G1/S transition across cell types could enhance the design of more nuanced pharmacological strategies, enabling more personalized treatment recommendations for current cell cycle-targeted cancer therapies.

systems biology↗

bioRxiv2023

Swi4-dependent SWI4 transcription couples cell size to cell cycle commitment

Growth-dependent accumulation of the limiting SBF transcription factor, composed of Swi4 and Swi6, occurs in G1 phase in budding yeast and is limiting for commitment to division, termed Start. Here we measure size-dependence of Swi4 protein copy number under different genetic contexts using the scanning number and brightness technique. Mutation of SBF binding sites in the SWI4 promoter or disruption of SBF activation resulted in [~]33-50% decrease in Swi4 accumulation rate and concordantly increased cell size at Start. Ectopic inducible expression of Swi4 in G1 phase cells increased production of Swi4 from the endogenous promoter, upregulated transcription of the G1/S regulon, and accelerated Start. Despite the potential for Swi4 positive feedback, G1 phase Swi4 accumulation was linear unless the Whi5 transcriptional repressor was inactivated. A threshold model in which Swi4 titrates SBF binding sites in G1/S promoters predicted the effects of nutrients, ploidy, and G1/S regulatory mutations on cell size. These results exemplify how transcription factor auto-production can contribute to a cell state transition.

cell biology↗

bioRxiv2023

Estradiol propionate reduction of nuclear size in prostate cancer lines lacking DHRS7suggests DHRS7 absence as a biomarker for the effectiveness of estrogen therapy

Increased nuclear size correlates with lower survival rates for prostate cancer and is a hallmark of late-stage androgen-insensitive tumors. The short-chain dehydrogenase/reductase (SDR) family member DHRS7 was suggested as a marker for prostate cancer grading because it is lost in late-stage androgen-insensitive tumors. Here we find that loss of DHRS7 from the early-stage LNCaP prostate cancer cell line increases nuclear size, potentially explaining the nuclear size increase observed in higher-grade prostate tumors. Exogenous expression of DHRS7 in the late-stage PC3 prostate cancer cell line correspondingly decreases nuclear size. We separately tested 80 compounds from the Microsource Spectrum library for their ability to restore normal nuclear size to PC3 cells, finding estradiol propionate had the same effect as re-expression of DHRS7 in the PC3 cells. However, the drug had no effect on LNCaP cells or PC3 cells re-expressing DHRS7. We speculate that reported beneficial effects of estrogens in late-stage prostate cancer may target a pathway which is only active in cells lacking DHRS7 that have increased nuclear size and propose DHRS7 as a potential biomarker for the likely effectiveness of estrogen-based treatments.

cancer biology↗

bioRxiv2020

Nsr1, a nitrogen source-regulated microprotein, confers an alternative mechanism of G1/S transcriptional activation in budding yeast

Commitment to cell division at the end of G1 phase, termed Start in the budding yeast Saccharomyces cerevisiae, is strongly influenced by nutrient availability. To identify new dominant activators of Start that might operate under different nutrient conditions, we screened a genome-wide ORF overexpression library for genes that bypass a Start arrest caused by absence of the G1 cyclin Cln3 and the transcriptional activator Bck2. We recovered a hypothetical gene YLR053c, renamed NRS1 for Nitrogen-Responsive Start regulator 1, which encodes a poorly characterized 108 amino acid microprotein. Endogenous Nrs1 was nuclear-localized, restricted to poor nitrogen conditions, induced upon mTORCl inhibition, and cell cycle-regulated with a peak at Start. NRS1 interacted genetically with SWI4 and SWI6, which encode subunits of the main G1/S transcription factor complex SBF. Correspondingly, Nrs1 physically interacted with Swi4 and Swi6 and was localized to G1/S promoter DNA. Nrs1 exhibited inherent transactivation activity and fusion of Nrs1 to the SBF inhibitor Whi5 was sufficient to suppress other Start defects. Nrs1 appears to be a recently evolved microprotein that rewires the G1/S transcriptional machinery under poor nitrogeny conditions. Author SummarUnicellular microorganisms must adapt to ever-changing nutrient conditions and hence must adjust cell growth and proliferation to maximize fitness. In the budding yeast Saccharomyces cerevisiae, commitment to cell division, termed Start, is heavily influenced by nutrient availability. Our understanding of how Start is activated is based mainly on experiments carried out under rich nutrient conditions. To identify potential new Start regulators specific to poor nutrient environments, we screened for genes able to bypass a genetic Start arrest caused by loss of the G1 cyclin Cln3 and the transcriptional activator Bck2. This screen uncovered YLR053c, which we renamed NRS1 for Nitrogen-Responsive Start regulator. Sequence analysis across yeast species indicated that Nrs1 is a recently-evolved microprotein. We showed that NRS1 is nutrient- and cell cycle-regulated, and directly binds the main G1/S transcription factor complex SBF. We demonstrated that Nrs1 has an intrinsic trans-activation activity and provided genetic evidence to suggest that Nrs1 can bypass the requirement for normal Cln3-dependent activation of G1/S transcription. These results uncover a new mechanism of Start activation and illustrate how microproteins can rapidly emerge to rewire fundamental cellular processes.

cell biology↗

bioRxiv2020

Chemical-Genetic Interrogation of Nuclear Size Control Reveals Cancer-Specific Effects on Cell Migration and Invasion

Lower survival rates for many cancer types correlate with increases or decreases in nuclear size/scaling in a tumor-type/tissue-specific manner. Postulating that nuclear size changes confer a fitness advantage on tumor cells, we screened for FDA/EMA-approved compounds that reverse tumor nuclear size changes in cell lines from three such tumor types: prostate adenocarcinoma, colonic adenocarcinoma, and small-cell squamous lung cancer. We found distinct, largely non-overlapping sets of compounds that either rectify or exacerbate nuclear size changes for each tumor type. Nuclear size phenotypes across cell lines clustered particular classes of compounds including serotonin uptake inhibitors, cyclo-oxygenase inhibitors, beta-adrenergic receptor agonists, monoamine oxidase inhibitors, and Na+/K+ ATPase inhibitors. Nearly all compounds selected for further investigation inhibited cell migration and/or invasion, suggesting that targeting nuclear size control pathways in chemotherapy regimens could improve patient survival.

cancer biology↗

bioRxiv2019

G1/S transcription factors assemble in discrete clusters that increase in number as cells grow

The spatio-temporal organization of transcription factor (TF)-promoter interactions is critical for the coordination of transcriptional programs. In budding yeast, the main G1/S transcription factors, SBF and MBF, are limiting with respect to target promoters in small G1 phase cells and accumulate as cells grow, raising the question of how SBF/MBF are dynamically distributed across the G1/S regulon. Super-resolution Photo-Activatable Localization Microscopy (PALM) mapping of the static positions of SBF/MBF subunits revealed that 85% were organized into discrete clusters containing [~]8 copies regardless of cell size, while the number of clusters increased with growth. Stochastic simulations with a mathematical model based on co-localization of promoters in clusters recapitulated observed cluster behavior. A prediction of the model that SBF/MBF should exhibit both fast and slow dynamics was confirmed in PALM experiments on live cells. This spatio-temporal organization of the TFs that activate the G1/S regulon may help coordinate commitment to division.

cell biology↗