The atypical cadherin CELSR2 regulates distinct epithelial–mesenchymal states and oxidative phosphorylation in triple-negative breast cancer

Triple-negative breast cancer (TNBC) is characterized by marked intratumoral heterogeneity, which contributes to metastatic dissemination, therapeutic resistance, and poor clinical outcome. Epithelial-mesenchymal plasticity is a major contributor to this heterogeneity. Identifying the molecular regulators governing epithelial-mesenchymal plasticity is therefore essential to understanding how distinct tumor cell populations arise and fuel TNBC progression.

Here, we identify the adhesion G protein-coupled receptor CELSR2 as an independent poor-prognosis marker and regulator of epithelial-mesenchymal plasticity in TNBC. Spatial transcriptomic analyses revealed segregation of CELSR2 ^high tumor cells within the epithelial tumor core and CELSR2 ^low tumor cells at the invasive front. In line with the latter observation, CELSR2 expression decreases during EMT and its loss promotes acquisition of a hybrid epithelial-mesenchymal state. CELSR2 ^high tumor cells display a CREB-associated oxidative phosphorylation (OXPHOS) program and promote cell proliferation and primary tumor growth. Conversely, CELSR2 ^low cells display features of a more migratory phenotype.

Collectively, our findings identify CELSR2 as a previously unknown regulator of epithelial-mesenchymal plasticity and reveal that heterogeneous CELSR2 expression shapes spatially and functionally distinct tumor cell populations, thereby contributing to intratumoral heterogeneity in TNBC.