Abu-Eid, R. | bioRxiv Science

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↗