β3-Integrin controls pericyte metabolic states and shapes tumour-stromal metabolic crosstalk in breast cancer

Abstract

Pericytes are emerging as dynamic regulators of the tumour microenvironment. Yet, their role in tumour metabolism remains elusive. Here, we investigate whether {beta}3-integrin regulates pericyte metabolic state and shapes stromal-tumour metabolic interactions in breast cancer. By integrating spatial and single-cell transcriptomics from human breast tumours with multi-omics profiling of tumour-derived pericytes in vitro, we identify two {beta}3-integrin-dependent metabolic states. {beta}3-integrin-high pericytes display a metabolically active phenotype characterised by increased glycolysis and enhanced de novo serine/glycine synthesis, supporting collagen production. In contrast, {beta}3-integrin loss induces a lipid-associated state, marked by neutral lipid accumulation and lipid droplets. Mechanistically, {beta}3-integrin regulates this metabolic switch via mTOR signalling. Importantly, these states extend beyond pericytes, with adjacent cancer cells shifting towards fatty acid oxidation and lipid use near {beta}3-integrin-low pericytes. Together, our findings establish {beta}3-integrin as a key metabolic switch in pericytes and highlight their role in driving tumour metabolic plasticity.