인간 어셈블로이드를 이용한 종양 내 종양 세포와 종양 스트로마 간의 상호작용 연구

Abstract

Current organoid models are limited by their failure to account for multiple factors such as mature organ architecture and associated tissue microenvironments. Here, we created multilayer ‘assembloids’ by reconstituting tissue stem cells with stromal components to mimic an organized architecture with an epithelium surrounding stroma and an outer muscle layer. These assembloids exhibited characteristics of mature adult organs in cell composition and gene expression at the single-cell level, and recapitulated in vivo tissue dynamics of regenerative responses to tissue injury. Further, using three-dimensional bioprinting technology, we developed malignant counterpart tumor assembloids that recapitulate the in vivo pathophysiological features of patients’ tumor, including tumor–stroma interaction, drug responses to stroma-dependent anti-cancer drugs, immune cell infiltration and muscle invasion. Using the genetically manipulated tumor assembloid platform, we identified the dynamic interactions between tumor and tumor stroma in the control of tumor plasticity and the determination of therapy response to immunotherapy. We found tumoral FOXA1, induced by stromal BMP, as a master pioneer factor that drives enhancer reprogramming to determine tumor phenotype, suggesting the importance of the FOXA1–BMP–hedgehog signaling feedback axis between tumor and stroma in the control of tumor plasticity. In addition, we found that CAF, reprogrammed during tumor development, express PGF and SAA1 that induce the exhaustion of T cells to drive the resistance to immune checkpoint inhibitor, which provides a new insight into how the dynamic interactions of tumor, CAF, and T cells determine the response to cancer immunotherapy. Overall, our study provides a conceptual framework for the reconstitution of functional assembloids derived from tissue stem cells or tumor cells that mimic the biology of native tissues to study the dynamic interactions between tumor and tumor stroma in human cancer.