Rab11-FIP1/RCP Functions as a Major Signalling Hub in the Oncogenic Roles of Mutant p53 in Cancer

Rab11-FIP1 is a Rab effector protein that is involved in endosomal recycling and trafficking of various molecules throughout the endocytic compartments of the cell. The consequence of this can be increased secretion or increased membrane expression of those molecules. In general, expression of Rab11-FIP1 coincides with more tumourigenic and metastatic cell behaviour. Rab11-FIP1 can work in concert with oncogenes such as mutant p53, but has also been speculated to be an oncogene in its own right. In this perspective, we will discuss and speculate upon our observations that mutant p53 promotes Rab11-FIP1 function to not only promote invasive behaviour, but also chemoresistance by regulating a multitude of different proteins.

The Critical Importance of Spatial and Temporal Scales in Designing and Interpreting Immune Cell Migration Assays

Intravital microscopy and other direct-imaging techniques have allowed for a characterisation of leukocyte migration that has revolutionised the field of immunology, resulting in an unprecedented understanding of the mechanisms of immune response and adaptive immunity. However, there is an assumption within the field that modern imaging techniques permit imaging parameters where the resulting cell track accurately captures a cell’s motion. This notion is almost entirely untested, and the relationship between what could be observed at a given scale and the underlying cell behaviour is undefined. Insufficient spatial and temporal resolutions within migration assays can result in misrepresentation of important physiologic processes or cause subtle changes in critical cell behaviour to be missed. In this review, we contextualise how scale can affect the perceived migratory behaviour of cells, summarise the limited approaches to mitigate this effect, and establish the need for a widely implemented framework to account for scale and correct observations of cell motion. We then extend the concept of scale to new approaches that seek to bridge the current “black box” between single-cell behaviour and systemic response.

Modelling of Stem Cells Microenvironment Using Carbon-Based Scaffold for Tissue Engineering Application—A Review

A scaffold is a crucial biological substitute designed to aid the treatment of damaged tissue caused by trauma and disease. Various scaffolds are developed with different materials, known as biomaterials, and have shown to be a potential tool to facilitate in vitro cell growth, proliferation, and differentiation. Among the materials studied, carbon materials are potential biomaterials that can be used to develop scaffolds for cell growth. Recently, many researchers have attempted to build a scaffold following the origin of the tissue cell by mimicking the pattern of their extracellular matrix (ECM). In addition, extensive studies were performed on the various parameters that could influence cell behaviour. Previous studies have shown that various factors should be considered in scaffold production, including the porosity, pore size, topography, mechanical properties, wettability, and electroconductivity, which are essential in facilitating cellular response on the scaffold. These interferential factors will help determine the appropriate architecture of the carbon-based scaffold, influencing stem cell (SC) response. Hence, this paper reviews the potential of carbon as a biomaterial for scaffold development. This paper also discusses several crucial factors that can influence the feasibility of the carbon-based scaffold architecture in supporting the efficacy and viability of SCs.

Mechanotransduction as a major driver of cell behaviour: mechanisms, and relevance to cell organization and future research

How do cells process environmental cues to make decisions? This simple question is still generating much experimental and theoretical work, at the border of physics, chemistry and biology, with strong implications in medicine. The purpose of mechanobiology is to understand how biochemical and physical cues are turned into signals through mechanotransduction. Here, we review recent evidence showing that (i) mechanotransduction plays a major role in triggering signalling cascades following cell–neighbourhood interaction; (ii) the cell capacity to continually generate forces, and biomolecule properties to undergo conformational changes in response to piconewton forces, provide a molecular basis for understanding mechanotransduction; and (iii) mechanotransduction shapes the guidance cues retrieved by living cells and the information flow they generate. This includes the temporal and spatial properties of intracellular signalling cascades. In conclusion, it is suggested that the described concepts may provide guidelines to define experimentally accessible parameters to describe cell structure and dynamics, as a prerequisite to take advantage of recent progress in high-throughput data gathering, computer simulation and artificial intelligence, in order to build a workable, hopefully predictive, account of cell signalling networks.

Correct regionalisation of a tissue primordium is essential for coordinated morphogenesis

During organ development, tubular organs often form from flat epithelial primordia. In the placodes of the forming tubes of the salivary glands in the Drosophila embryo, we previously identified spatially defined cell behaviours of cell wedging, tilting and cell intercalation that are key to the initial stages of tube formation. Here we address what the requirements are that ensure the continuous formation of a narrow symmetrical tube from an initially asymmetrical primordium whilst overall tissue geometry is constantly changing. We are using live-imaging and quantitative methods to compare wild-type placodes and mutants that either show disrupted cell behaviours or an initial symmetrical placode organisation, with both resulting in severe impairment of the invagination. We find that early transcriptional patterning of key morphogenetic transcription factors drives the selective activation of downstream morphogenetic modules, such as GPCR signalling that activates apical-medial actomyosin activity to drive cell wedging at the future asymmetrically-placed invagination point. Over time, transcription of key factors expands across the rest of the placode and cells switch their behaviour from predominantly intercalating to predominantly apically constricting as their position approaches the invagination pit. Misplacement or enlargement of the initial invagination pit leads to early problems in cell behaviours that eventually result in a defective organ shape. Our work illustrates that the dynamic patterning of the expression of transcription factors and downstream morphogenetic effectors ensures positionally fixed areas of cell behaviour with regards to the invagination point. This patterning in combination with the asymmetric geometrical set-up ensures functional organ formation.

The histone acetyltransferase HBO1 (KAT7) promotes efficient tip cell sprouting during angiogenesis

Blood vessel growth and remodelling are essential during embryonic development and disease pathogenesis. The diversity of endothelial cells (ECs) is transcriptionally evident and ECs undergo dynamic changes in gene expression during vessel growth and remodelling. Here, we investigated the role of the histone acetyltransferase HBO1 (KAT7), which is important for activating genes during development and histone H3 lysine 14 acetylation (H3K14ac). Loss of HBO1 and H3K14ac impaired developmental sprouting angiogenesis and reduced pathological EC overgrowth in the retinal endothelium. Single-cell RNA-sequencing of retinal ECs revealed an increased abundance of tip cells in Hbo1 deleted retinas, which lead to EC overcrowding in the retinal sprouting front and prevented efficient tip cell migration. We found that H3K14ac was highly abundant in the endothelial genome in both intra- and intergenic regions suggesting that the role of HBO1 is as a genome organiser that promotes efficient tip cell behaviour necessary for sprouting angiogenesis.