Biology subjects

Woolner, S.

Publications and source records attributed to Woolner, S..

5 recordsLinked to original sources

bioRxiv2025

Travelling Waves in Gene Expression: A Mathematical Model of Cell-State Dynamics in Melanoma

Melanoma is a cancer of the melanocyte, known to have an ability to readily switch between different transcriptional cell states that convey different phenotypic properties (e.g. hyper-differentiated, neural crest-like). This ability is believed to underpin intratumour heterogeneity and plastic adaptation, which contributes to resistance to therapy and immune evasion of the tumour. Therefore, understanding the mechanisms underlying acquisition of transcriptional cell states and cell-state switching is crucial for the development of therapies. We model a minimal gene regulatory network comprising three key transcription factors, whose varying gene expression encodes different melanoma cell states, and use deterministic spatiotemporal differential-equation models to study gene-expression dynamics. We exploit an approximation, based on cooperative binding of transcription factors, in which the models are piecewise-linear. We classify stable states of the local model in a biologically relevant manner and, using a naive model of intercellular communication, we explore how a population of cells can take on a shared characteristic through travelling waves of gene expression. We derive a condition determining which characteristic will become dominant, under sufficiently strong cell-cell signalling, which creates a partition of parameter space.

cancer biology↗

bioRxiv2024

Mitotic spindle orientation and dynamics are fine-tuned by anisotropic tissue stretch via NuMA localisation

Cell division orientation, which is key to cell fate and tissue morphogenesis, is influenced by mechanical forces. However, uncoupling whether divisions orient in direct response to force or indirectly via interphase cell shape remains challenging. By applying an external stretch to epithelial tissue and monitoring mitotic spindle dynamics, we show that the spindle orientation protein, NuMA, is recruited to the cell cortex earlier during mitosis in stretched tissue. This stretch-induced recruitment of NuMA coincides with the onset and subsequent amplification of dynamic spindle oscillations. We show by mathematical modelling that increased spindle oscillation indicates increased cortical force generation to orient the spindle. Additionally, we show that knockdown of NuMA reduces spindle oscillations and disrupts division orientation according to stretch and cell shape. Our results indicate that a mechanosensitive re-localisation of NuMA provides a direct response to mechanical force, fine-tuning spindle dynamics and orientation during mitosis and ensuring the accurate alignment of divisions with cell shape and anisotropic tension.

cell biology↗

bioRxiv2024

Apical Size Reduction by Macropinocytosis Alleviates Tissue Crowding

Tissue crowding represents a critical challenge to epithelial tissues, which often respond via the irreversible process of live cell extrusion. We report cell size reduction via macropinocytosis as an alternative mechanism. Macropinocytosis is triggered by tissue crowding via mechanosensory signaling, leading to substantial internalization of apical membrane and driving a reduction in apical cell size that remodels the epithelium to alleviate crowding. We report that this mechanism regulates the long-term organization of developing epithelium in response to proliferation-induced crowding but also serves as an immediate response to acute external compression. In both cases, inhibiting macropinocytosis induces a dramatic increase in cell extrusion suggesting cooperation between cell extrusion and macropinocytosis in response to compression. Our findings implicate macropinocytosis as an important regulator of dynamic epithelial remodeling.

cell biology↗

bioRxiv2019

Dysregulated wild-type cell division at the interface between host and oncogenic epithelium

Epithelial tissues are highly sensitive to anisotropies in mechanical force, with cells altering fundamental behaviours such as cell adhesion, migration and cell division [1-5]. It is well known that in the later stages of carcinoma (epithelial cancer), the presence of tumours alters the mechanical properties of a host tissue and that these changes contribute to disease progression [6-9]. However, in the earliest stages of carcinoma, when a clonal cluster of oncogene-expressing cells first establishes in the epithelium, the extent to which mechanical changes alter cell behaviour in the tissue as a whole remains unclear. This is despite knowledge that many common oncogenes, such as oncogenic Ras, alter cell stiffness and contractility [10-13]. Here, we investigate how mechanical changes at the cellular level of an oncogenic cluster can translate into the generation of anisotropic strain across an epithelium, altering cell behaviour in neighbouring host tissue. We generated clusters of oncogene-expressing cells within otherwise normal in vivo epithelium, using Xenopus laevis embryos. We find that cells in kRasV12, but not cMYC, clusters have increased contractility, which introduces radial stress in the tissue and deforms surrounding host cells. The strain imposed by kRasV12 clusters leads to increased cell division and altered division orientation in the neighbouring host tissue, effects that can be rescued by reducing actomyosin contractility specifically in the kRasV12 cells. Our findings indicate that some oncogenes can alter the mechanical and proliferative properties of host tissue from the very earliest stages of cancer development, changes which have the potential to contribute to tumorigenesis.

cell biology↗

bioRxiv2017

Whole-tissue stretching reveals a shape-dependent mechanism of orienting the mitotic spindle and a role for mechanical stress in cueing mitosis

Distinct mechanisms involving cell shape and mechanical force are known to influence the rate and orientation of division in cultured cells. However, uncoupling the impact of shape and force in tissues remains challenging. Combining stretching of Xenopus laevis tissue with a novel method of inferring relative mechanical stress, we find separate roles for cell shape in orientating division and mechanical stress in cueing division. We demonstrate that division orientation is best predicted by an axis of cell shape defined by the position of tricellular junctions (TCJs), which aligns exactly with the principal axis of local cell stress rather than the tissue-level stress. The alignment of division to cell shape requires functional cadherin and the localisation of the spindle orientation protein, LGN, to TCJs, but is not sensitive to relative cell stress magnitude. In contrast, cell proliferation rate is more directly regulated by mechanical stress, being correlated with relative isotropic stress, and can be decoupled from cell shape when myosin II is depleted.

cell biology↗