Spatiotemporal dynamics of tumor microenvironment remodelling

During tumorigenesis, interactions between tumor and stromal cells progressively remodel the tumor microenvironment (TME) towards pro-tumoral functions. Understanding early TME remodeling dynamics is therefore crucial for developing interceptive therapies. However, clinical samples typically provide isolated, late tumorigenesis snapshots. To overcome this limitation, we generated triple-negative breast cancer mice that develop multifocal, asynchronous tumors along a continuous luminal-to-basal transdifferentiation trajectory. Ordering spatial transcriptomes from 100+ ducts along this trajectory reveals the spatiotemporal dynamics and molecular mechanisms of TME remodeling, identifying early stromal programs and signaling axes as potential targets for disease interception before establishment of invasive niches. The stromal spatiotemporal remodeling dynamics are conserved across genetically heterogeneous patient-derived xenograft models and treatment naive human TNBC cohorts, supporting the translational relevance of our findings. Our study shows that temporal ordering of spatially-resolved disease snapshots unravels some of the molecular forces that, starting from the cell-of-origin, propel cells/microenvironments along a disease trajectory.