Unravelling the Metastatic Niche in Breast Cancer Patients with Bone Metastasis through Single-cell RNA Sequencing

Abstract Breast cancer (BRCA) is characterized by a unique metastatic pattern and often presents with bone metastasis (BoM), which poses significant clinical challenges. This study employed single-cell RNA sequencing (scRNA-seq) and TCGA data analysis to compare primary tumor (PT), lymph node metastasis (LN), and BoM data. Our investigation identified a metastatic niche in BoMs marked by an increased abundance of cancer-associated fibroblasts (CAFs) and a reduced immune cell count. A distinct subtype (State 1) of BRCA BoM cells associated with adverse prognosis was identified. State 1, characterized by heightened stemness traits, may represent an initiation phase for BoM in BRCA. Complex cell communications involving tumor, stromal, and immune cells were revealed. Interactions between FN1, SPP1, and MDK correlate with elevated immune cells in the BoM. CD46, MDK, and PTN interactions drive myofibroblast activation and proliferation, contributing to tissue remodelling. Additionally, MDK, PTN, and FN1 interactions influence FAP + CAF activation, impacting cell adhesion and migration in BoMs. These insights deepen our understanding of the metastatic niche in breast cancer BoMs.