Biology subjects

Speirs, V.

Publications and source records attributed to Speirs, V..

3 recordsLinked to original sources

bioRxiv2026

Sexual Dimorphism of Cancer-Associated Fibroblasts Governs Matrix and Vascular Organisation in Breast Cancer

Breast cancer (BC) shows greatest sexual diversity. Increased diagnosis and poorer outcomes in men highlights the need to better understand its biology. We hypothesised that cancer-associated fibroblasts (CAFs), the most abundant cell type in the tumour microenvironment, might define sex-related differences. Using phenotypically matched male and female CAFs generated from breast cancer tissues, we demonstrate distinct transcriptional programmes and functional behaviours associated with extracellular matrix remodelling, cell adhesion, migration and vascular development. Compared to CAFs generated from females BC, those from males generated denser, more complex matrices promoting stronger tumour and endothelial cell adhesion, vascular growth, but less organised capillary network formation. Findings reveal fundamental sex-related variations in CAF phenotype and biology in BC. These findings highlight the need to integrate biological sex into precision oncology to identify opportunities for sex-specific therapeutic strategies in BC.

cancer biology↗

bioRxiv2025

A compendium of adipocyte morphologies across different breast pathologies

Adipocytes are abundant in the breast tissue microenvironment. In breast cancer, they can change morphologically according to their proximity to tumour cells, with the closest becoming cancer-associated adipocytes (CAAs). It remains unclear whether breast cancer risk factors, including menopausal status, body mass index (BMI), and mammographic density (MD), influence CAAs morphology in breast carcinogenesis. This study aimed to quantify morphological differences in adipocytes across breast cancer pathologies and associated risk factors. Whole slide images of hematoxylin and eosin stained cancer (n = 149) and normal (n = 182) breast tissue samples were analysed. Parameters representative of adipocyte morphology: perimeter, area, concavity, and aspect ratio, were measured using ImageJ. Adipocytes were considered close ([≤] 2 mm) or distant (>2 mm) to cancer cells in cancer samples or breast epithelial cells in normal samples. Close adipocytes in cancer samples were designated CAAs. CAAs decreased in size compared to distant adipocytes (p [≤] 0.0001). A similar trend was observed between close and distant adipocytes in normal (p [≤] 0.0001). CAAs size increased post menopause (p [≤] 0.0001). CAAs size positively correlated with BMI (p [≤] 0.0001). In cancer cases, distant adipocyte size increased and concavity decreased with increasing MD (p [≤] 0.01). Smaller CAAs were associated with poorer survival (p [≤] 0.05). Morphological differences were identified in adipocytes dependent on location within the breast, tissue, pathology and risk factors. Understanding what drives these morphological differences could provide mechanistic insight into whether risk factor-induced alterations in adipocytes influence their role in breast carcinogenesis.

cancer biology↗

bioRxiv2023

An Nav1.5-dependent feedback mechanism driving glycolytic acidification in breast cancer metastasis

Solid tumours have abnormally high intracellular [Na+]. The activity of various Na+ channels may underlie this Na+ accumulation. Voltage-gated Na+ channels (VGSCs) have been shown to be functionally active in cancer cell lines, where they promote invasion. However, the mechanisms involved, and clinical relevance, are incompletely understood. Here, we show that protein expression of the Nav1.5 VGSC subtype strongly correlates with increased metastasis and shortened cancer-specific survival in breast cancer patients. In addition, VGSCs are functionally active in patient-derived breast tumour cells, cell lines, and cancer-associated fibroblasts. Knock down of Nav1.5 in a mouse model of breast cancer suppresses expression of invasion-regulating genes. Nav1.5 activity increases glycolysis in breast cancer cells, likely by up-regulating activity of the Na+/K+ ATPase, thus promoting H+ production and extracellular acidification. The pH of murine xenograft tumours is lower at the periphery than in the core, in regions of higher proliferation and lower apoptosis. In turn, acidic extracellular pH elevates persistent Na+ influx through Nav1.5 into breast cancer cells. Together, these findings show positive feedback between extracellular acidification and movement of Na+ into cancer cells which can facilitate invasion. These results highlight the clinical significance of Nav1.5 activity as a potentiator of breast cancer metastasis and provide further evidence supporting the use of VGSC inhibitors in cancer treatment.

cancer biology↗