Biology subjects

Tobin, N. P.

Publications and source records attributed to Tobin, N. P..

5 recordsLinked to original sources

bioRxiv2025

Decoding Cell Cycle Phase Variations in Cancer Hallmarks Across Breast Cancer Subgroups

Breast tumors have traditionally been categorized into four widely recognized subtypes. Recent single-cell advancements have, however, shown that individual tumors can contain more than one subtype, exhibiting their intrinsic heterogeneity. Relatedly, whilst the crucial role of cell cycle regulation in cancer development is widely acknowledged, the specific impact of cell cycle phases on oncogenic signaling and processes in each of these subtypes remains unresolved. Here, we examine the differences in transcriptomic cancer hallmarks across and within cell cycle phases and breast cancer subtypes in two large single-cell cohorts. We show that taking cell cycle phases into account identifies a broader pool of relevant cancer hallmark pathways while preserving the hallmarks found when cell cycle phases are ignored. Moreover, we identify FDA approved drugs that can target diverse hallmarks within specific phase-subtype cell combinations. This study highlights the critical role of cell cycle phases in advancing our understanding of breast cancer biology. The distinct biological mechanisms observed in each phase-subtype group suggest that targeting these hallmarks may provide a more precise and effective therapeutic strategy for breast cancer treatment.

bioinformatics↗

bioRxiv2022

Reclassifying Cancer: Defining tumour cell cycle activity in terms of its tissue of origin in over 13,000 samples

Genomic alterations resulting in loss of control over the cell cycle is a fundamental hallmark of human malignancies. Whilst pan-cancer studies have broadly assessed tumour genomics and their impact on oncogenic pathways, analyses taking the baseline signalling levels in normal tissue into account are lacking. To this end, we aimed to reclassify the cell cycle activity of tumours in terms of their tissue of origin and determine the DNA mutations, chromosome arm-level changes and signalling pathways driving cell cycle activity. Combining normal tissue and pan-cancer data from over 13,000 samples we demonstrate that tumours of gynaecological origin show the highest levels of baseline corrected cell cycle activity, partially owing to hormonal signalling and gene expression changes. We also show that normal and tumour tissues can be separated into groups (quadrants) of low/high cell cycle activity and propose the novel hypothesis of an upper limit on these activity levels in tumours.

cancer biology↗

bioRxiv2021

Survival analysis of pathway activity as a prognostic determinant in breast cancer

Most activities in a cell are dependent on sets of biomolecules, often referred to as pathways. Pathways are useful to study as their activities are frequently more directly related to the behavior of the cell than their components. Traditional pathway analysis gives significance to differences in the pathway components concentrations between sample groups. Here we instead advocate a singular value decomposition-based method for estimating individual samples pathway activities that allow us to investigate more advanced statistical models. Specifically, we investigate the pathway activities association with patients survival time based on the transcription profiles of the METABRIC dataset. Our implementation shows that pathway activities are better prognostic markers for survival time in METABRIC than the individual transcripts. We also demonstrate that we can regress out the effect of individual pathways on other pathways, which allows us to estimate the other pathways residual pathway activity on survival.

bioinformatics↗

bioRxiv2021

The Amot/Integrin protein complex transmits mechanical forces required for vascular expansion

Vascular development is a complex multistep process involving the coordination of cellular functions such as migration, proliferation and differentiation. Understanding the underlying mechanisms of these processes is of importance due to involvement of vessel expansion in various pathologies. How mechanical forces generated by cells and transmission of these physical forces control vascular development is poorly understood. Using an endothelial-specific genetic model in mice, we show that deletion of the scaffold protein, Angiomotin (Amot), inhibits migration and expansion of physical and pathological vascular network. We further show that Amot is required for tip cell migration and the extension of cellular filopodia. Exploiting in vivo and in vitro molecular approaches, we show that Amot binds talin and is essential for relaying forces between fibronectin and the cytoskeleton. Finally, we provide evidence that Amot is a novel component of the endothelial integrin adhesome and propose that Amot integrates spatial cues from the extra-cellular matrix in order to form a functional vascular network.

cell biology↗

bioRxiv2020

A pan-cancer analysis of the frequency of DNA alterations across cell cycle activity levels

BackgroundPan-cancer genomic analyses based on the magnitude of pathway activity are currently lacking. Focusing on the cell cycle, we examined the DNA mutations and chromosome arm-level aneuploidy within tumours with low, intermediate and high cell cycle activity. Patients and methodsMatching mRNA, gene mutational status, chromosomal arm-level aberrations and clinico-pathological data was assembled from pan-cancer studies of 9,515 patients with 32 different cancers. Cell cycle activity was estimated from mRNA data using the cell cycle score (CCS) signature. Barplots were used to visualise mutation and chromosomal aberration frequency within CCS subgroups. Kaplan-Meier and multivariable Cox-regression analyses were used to determine survival differences between CCS subgroups. ResultsCell cycle activity varied broadly across and within all cancers. TP53 and PIK3CA mutations were common in all CCS subgroups but with increasing frequency as cell cycle activity levels increased (P < 0.001). Mutations in BRAF and gains in 16p were less frequent CCS high tumours (P < 0.001). In Kaplan-Meier analysis, patients whose tumours were CCS Low had a longer PFI relative to intermediate or high (P < 0.001) and this significance remained in multivariable analysis (CCS intermediate: HR = 1.37; 95% CI 1.17 - 1.60, CCS high: 1.54; 1.29 - 1.84, CCS Low = Ref). ConclusionsCell cycle activity varies across and within cancers and whilst similar DNA alterations can be found at all activity levels, some notable exceptions exist. These data also demonstrate that independent prognostic information can be derived on a pan-cancer level from a simple measure of cell cycle activity.

genomics↗