Biology subjects

Pfeuty, B.

Publications and source records attributed to Pfeuty, B..

3 recordsLinked to original sources

bioRxiv2024

Spatial self-organization of cancer stem cell niches revealed by live single-cell imaging

Phenotypic plasticity is a major factor of tumor heterogeneity and treatment resistance. In particular, cancer stem cells (CSCs) represent a small subpopulation within tumors with self-renewal and tumor-forming capabilities. Understanding reprogramming, maintenance, and lineage properties of CSCs requires dedicated tools to disentangle the respective influences of phenotypic inheritance and cell-cell interactions. Here we set up ultra-wide field microscopy of breast cancer cell lines expressing a stemness fluorescent reporter for several days. The fluorescent reporter distinguishes three phenotypes: cancer stem cells (CSCs), cancer differentiated cells (CDCs) and intermediate/transiting cancer cells (iCCs). Spatial statistics indicate significant zonation, aka phenotypic niches, with CSC clustering near each other but away from CDCs. Surprisingly, single cell time series reveal spontaneous reprogramming events from CDC to CSC even in unperturbed populations. We identify that such transitions are prone to arise during the cell cycle. Moreover, lineage analysis shows that the phenotype is partially inherited from ancestor cells. However, such heredity is not sufficient to explain the spatial properties of the cell population, which also depend on cell-cell interactions. Indeed, we identified that phenotypic transitions of cancer cells are influenced by the phenotypic state of neighboring cells. Reprogramming into CSCs is respectively promoted and inhibited by the presence of CSCs and CDCs in the neighborhood. Altogether, our results disentangle how phenotypic inheritance and intercellular interactions orchestrate the spatio-temporal self-organization of cancer cell heterogeneity, maintaining a subpopulation of CSCs within niches.

systems biology↗

bioRxiv2022

Quantitative modeling of pentose phosphate pathway response to oxidative stress reveals a cooperative regulatory strategy

Living cells use signaling and regulatory mechanisms to adapt to environmental stresses. In the case of oxidative stress due for instance to hydrogen peroxide exposure, the adaptation response relies on co-regulation of enzymes in both glycolysis and pentose phosphate pathways (PPP), so as to support PPP-dependent NADPH and redox homeostasis. To understand the regulatory logic underlying early oxidative stress response, available metabolomics and 13C fluxomics dataset are used to infer a probabilistic ensemble of kinetic models. Model ensemble properties of parameter distributions, transient dynamics, dose-response curves and loss-of-function phenotypes all highlights significant and cooperative effects of allosteric regulations of G6PD, PGI and GAPD in early oxidative response. Indeed, efficient flux rerouting into PPP is shown to require dose-dependent coordination between upregulated G6PD enzyme and increased G6P metabolite, the latter requiring fine-tuned inhibition of upper and lower glycolytic enzymes. This set of allosteric regulation also combines negative and positive feedback loops in a subtle manner prone to generate paradoxical perturbation phenotypes for instance related to 6PGD modulation.

systems biology↗

bioRxiv2021

Fine-tuned control of stress priming and thermotolerance

A common signature of cell adaptation to stress is the improved resistance upon priming by prior stress exposure. In the context of hyperthermia, priming or preconditioning with sublethal heat shock can be a useful tool to confer thermotolerance and competitive advantage to cells. In the present study, we develop a data-driven modeling framework that is simple and generic enough to capture a broad set of adaptation behaviors to heat stress at both molecular and cellular levels. The model recovers the main features of thermotolerance and clarifies the tradeoff principles which maximize the thermotolerance effect. It therefore provides an effective predictive tool to design preconditioning and fractionation hyperthermia protocols for therapeutic purpose.

biochemistry↗