Chenzhao Feng, Yunyi Yang, Guanchu Li, Zixuan Fang, Bin Yang, Fang Zhao, Xingyu Chen, Shuyi Liu, Di Wu, Xingyuan Hu, Jingjing Yin, Siyang Zhang, Junpeng Fan, Wenju Peng, Zhe Hu, Zimeng Wu, Yu Fu, Funian Lu, Tianyu Qin, Beibei Wang, Gordon B. Mills, Xin Zhou, Jing Li, Tao Zhu, Peng Fei, Peng Wang, Ding Ma, Fuxia Li, Gang Chen, Chaoyang Sun
Ovarian cancer is an aggressive disease characterized by intraperitoneal dissemination and a distinctive microenvironment. By generating metastatic cohorts encompassing approximately 60 pairs of whole-genome and RNA sequencing, 100 single-cell samples, and 2.5 million spatial transcriptomics (ST) spots, we delineate site-specific tumor-host colocalization patterns. Utilizing our STARLETS framework, we elucidate a Darwinian evolutionary trajectory in which hypoxia and immune pressures select for clones that eventually metastasize. High-resolution ST and ultimate dimensional imaging of solvent-cleared organs (uDISCO) imaging further identify a tripartite ensemble comprising MMP11 + myCAFs, epithelial cells, and SPP1 + macrophages in ascites and metastases, which can be modulated via SPP1-CD44 inhibition. SPP1 + macrophages predict therapeutic responses in clinical trials, including oncolytic virus and poly(ADP-ribose) polymerase inhibitor treatments. Collectively, our study advances insights into spatial dynamics that hold promise for therapeutic approaches in ovarian cancer.