Cancer-associated adipomes promote invadopodia formation and enhance metastatic potential in triple-negative breast cancer.

Triple-Negative Breast Cancer (TNBC), which accounts for 15-20% of all breast cancer cases, remains one of the most aggressive and therapeutically challenging subtypes due to its lack of hormone receptors and HER2 expression, leaving chemotherapy as the primary treatment option. TNBC is characterized by early relapses and visceral metastasis, underscoring the urgent need to elucidate the mechanisms driving metastasis. The metastatic cascade begins with cancer cell invasion of the surrounding stroma, a process mediated by actin-rich protrusions called invadopodia that degrade the extracellular matrix (ECM). While the molecular machinery of invadopodia is well characterized, the upstream tumor microenvironment (TME) signals that regulate their formation remain poorly understood. In breast cancer, the TME is predominantly composed of mammary adipose tissue, where adipocytes undergo reprogramming into cancer-associated adipocytes (CAAs) that release extracellular vesicles, termed 'adipomes'. These adipomes serve as intercellular messengers, transferring bioactive molecules that can alter tumor cell behavior. Using a novel purification method, large (L)-adipomes were isolated from the plasma of TNBC subjects as well as from tumor-associated mammary fat (TAMF) using a murine TNBC model (EO771-C57BL/6) to investigate their role in invasion. Circulating L-adipomes from metastatic TNBC subjects induced epithelial-to-mesenchymal transition (EMT) and stemness signaling and promoted invadopodia formation in human non-tumorigenic breast epithelial cells, while TAMF-derived L-adipomes from metastatic-stage mice were enriched in phospholipids and promoted transcriptional and functional reprogramming in murine TNBC cells. Integrated transcriptomic and proteomic analyses revealed that adipomes activate stress-responsive MAPK signaling and upregulate proteins involved in actin cytoskeletal remodeling, mitochondrial metabolism, and translational machinery, pathways known to support invadopodia formation and extracellular matrix (ECM) degradation. Together, these findings establish adipocyte-derived adipomes as potent regulators of TNBC invasion and metastasis and reveal a previously unrecognized tumor-adipocyte signaling axis that may present new opportunities for therapeutic targeting.