Tumor-adipose assembloids reveal cell-fate-transition-triggered multistage collective invasions

Tumor invasion constitutes a multifaceted process encompassing collective cellular migration and dynamic cell-fate transitions. Although these aspects have been studied separately by physicists and biologists, their spatiotemporal coupling remains unclear. To bridge this gap, we introduce a tumor-adipose assembloid model that facilitates live tracking and temporal analysis of cancer cells and adipocytes. The tumor assembloids manifest two discrete phases of morphogenic behavior, delineated by the reprogramming of adipocytes. In the initial phase, the biophysical interactions between cancer cells and adipocytes can be modeled as contact between viscoelastic drops. This interaction precedes the adipocytes' dedifferentiation and subsequent myofibrogenic reprogramming. The emergence of adipocyte-derived myofibroblasts instigates assembloid invasion through the mechanical remodeling of surrounding collagen networks. Our findings unveil a paradigm shift in understanding the evolutionary dynamics of heterotypic multicellular systems, wherein cell-fate transitions act as catalytic events that initiate serial patterns of collective morphogenesis via alterations in extracellular biophysical interactions.