Integrated Spatial and Bulk Transcriptomic Analysis Identifies a Multicellular Ecosystem Involved in Progression of Young Breast Cancer

ABSTRACT

Young breast cancer (YBC), defined as diagnosis at or before the age of 40 years, is characterized by an aggressive phenotype and poor prognosis. The tumor microenvironment (TME), comprising immune and stromal cells, plays a critical role in tumor initiation and progression and is closely associated with clinical outcomes. However, alterations in cell states and the organization of multicellular ecosystems within the YBC microenvironment remain poorly understood. We analyzed 7379 bulk transcriptome samples and spatial transcriptomic data from eight samples using EcoTyper and complementary spatial analyses. The abundance of CD4+ T cells (S07), fibroblasts (S05), monocytes/macrophages (S09), and epithelial cells (S05) was significantly lower in young than in older patients with breast cancer. CD4+ T cells (S07), fibroblasts (S05), and monocytes/macrophages (S09) formed a spatially organized multicellular ecosystem with putative interactions involving CDH1‐PTPRF/ERBB3. Lower ecosystem abundance was associated with poorer prognosis, including among patients who did not achieve a pathological complete response after neoadjuvant therapy. These findings identify a distinct multicellular ecosystem within the YBC microenvironment, providing insights into the microenvironmental features associated with disease progression.