Cross-tissue multicellular coordination and its rewiring in cancer

The multicellular coordination that underlies tissue homeostasis and disease progression is of fundamental interest1–5. However, how diverse cell types are organized within tissue niches for cohesive functioning remains largely unknown. Here we systematically characterized cross-tissue coordinated cellular modules in healthy tissues, uncovering their spatiotemporal dynamics and phenotypic associations, and examined their rewiring in cancer. We first compiled a comprehensive single-cell transcriptomic atlas from 35 human tissues, revealing substantial inter-tissue variability in cellular composition. By leveraging covariance in cellular abundance, we identified 12 cellular modules with distinct cellular compositions, tissue prevalences and spatial organizations, and demonstrated coordinated intercellular communication within cellular modules using in situ spatial and in vivo perturbation data. Among them, two immune cellular modules in the spleen showed contrasting chronological dynamics with ageing. Analysis of multicellular changes in the breast revealed a menopausal trajectory associated with fibroblast dynamics. Furthermore, interrogation across cancer types uncovered simultaneous rewiring of two types of multicellular ecosystem during tumour progression, including the loss of tissue-specific healthy organization and the emergence of a convergent cancerous ecosystem. These findings reveal fundamental organizing principles of multicellular ecosystems in health and cancer, laying a foundation for further investigations into tissue-level functional coordination across diverse contexts.