p53 Orchestrates Cancer Metabolism: Unveiling Strategies to Reverse the Warburg Effect.

Cancer cells exhibit significant alterations in their metabolism, characterised by a reduction in oxidative phosphorylation (OXPHOS) and an increased reliance on glycolysis, even in the presence of oxygen. This metabolic shift, known as the Warburg effect, is pivotal in fuelling cancer's uncontrolled growth, invasion, and therapeutic resistance. While dysregulation of many genes contributes to this metabolic shift, the tumour suppressor gene p53 emerges as a master player.

Mathematical reconstruction of the metabolic network in an in-vitro multiple myeloma model.

It is increasingly apparent that cancer cells, in addition to remodelling their metabolism to survive and proliferate, adapt and manipulate the metabolism of other cells. This property may be a telling sign that pre-clinical tumour metabolism studies exclusively utilising in-vitro mono-culture models could prove to be limited for uncovering novel metabolic targets able to translate into clinical therapies. Although this is increasingly recognised, and work towards addressing the issue is becoming routinary much remains poorly understood.

Interplay of p53 and XIAP protein dynamics orchestrates cell fate in response to chemotherapy.

Chemotherapeutic drugs are used to treat almost all types of cancer, but the intended response, i.e., elimination, is often incomplete, with a subset of cancer cells resisting treatment.

Proline synthesis through PYCR1 is required to support cancer cell proliferation and survival in oxygen-limiting conditions.

The demands of cancer cell proliferation alongside an inadequate angiogenic response lead to insufficient oxygen availability in the tumor microenvironment. Within the mitochondria, oxygen is the major electron acceptor for NADH, with the result that the reducing potential produced through tricarboxylic acid (TCA) cycle activity and mitochondrial respiration are functionally linked. As the oxidizing activity of the TCA cycle is required for efficient synthesis of anabolic precursors, tumoral hypoxia could lead to a cessation of proliferation without another means of correcting the redox imbalance.

Calcium Dynamics and Water Transport in Salivary Acinar Cells.

Saliva is secreted from the acinar cells of the salivary glands, using mechanisms that are similar to other types of water-transporting epithelial cells. Using a combination of theoretical and experimental techniques, over the past 20 years we have continually developed and modified a quantitative model of saliva secretion, and how it is controlled by the dynamics of intracellular calcium. However, over approximately the past 5 years there have been significant developments both in our understanding of the underlying mechanisms and in the way these mechanisms should best be modelled.

A Multicellular Model of Primary Saliva Secretion in the Parotid Gland.

We construct a three-dimensional anatomically accurate multicellular model of a parotid gland acinus to investigate the influence that the topology of its lumen has on primary fluid secretion. Our model consists of seven individual cells, coupled via a common lumen and intercellular signalling. Each cell is equipped with the intracellular calcium ([Formula: see text])-signalling model developed by Pages et al, Bull Math Biol 81: 1394-1426, 2019.

A Model of [Formula: see text] Dynamics in an Accurate Reconstruction of Parotid Acinar Cells.

We have constructed a spatiotemporal model of [Formula: see text] dynamics in parotid acinar cells, based on new data about the distribution of inositol trisphophate receptors (IPR). The model is solved numerically on a mesh reconstructed from images of a cluster of parotid acinar cells. In contrast to our earlier model (Sneyd et al.

A Mathematical Model of Fluid Transport in an Accurate Reconstruction of Parotid Acinar Cells.

Salivary gland acinar cells use the calcium ([Formula: see text]) ion as a signalling messenger to regulate a diverse range of intracellular processes, including the secretion of primary saliva. Although the underlying mechanisms responsible for saliva secretion are reasonably well understood, the precise role played by spatially heterogeneous intracellular [Formula: see text] signalling in these cells remains uncertain. In this study, we use a mathematical model, based on new and unpublished experimental data from parotid acinar cells (measured in excised lobules of mouse parotid gland), to investigate how the structure of the cell and the spatio-temporal properties of [Formula: see text] signalling influence the production of primary saliva.

A Mathematical Model Supports a Key Role for Ae4 (Slc4a9) in Salivary Gland Secretion.

We develop a mathematical model of a salivary gland acinar cell with the objective of investigating the role of two [Formula: see text] exchangers from the solute carrier family 4 (Slc4), Ae2 (Slc4a2) and Ae4 (Slc4a9), in fluid secretion. Water transport in this type of cell is predominantly driven by [Formula: see text] movement. Here, a basolateral [Formula: see text] adenosine triphosphatase pump (NaK-ATPase) and a [Formula: see text]-[Formula: see text]-[Formula: see text] cotransporter (Nkcc1) are primarily responsible for concentrating the intracellular space with [Formula: see text] well above its equilibrium potential.