Du Kong, Peng Lin, Yifan Guo, Kai Lin, Sihua Zhao, Shuai Yang, Xianping Wang, Guangzhao Zhu, Lesi Xie, Shotaro Tatekawa, Jiadong Zheng, Wenyan Xu, Li He, Hideshi Ishii, Bin Jin, Kangwen Cheng, Qi Xie, Xianjue Ma
Intratumoral heterogeneity fuels cancer progression and therapy resistance, yet the cooperative mechanisms between distinct subclones remain poorly defined. Here, we uncover a tumor-promoting form of cell competition wherein malignant clones hijack interclonal Hedgehog (Hh) and Wnt signaling to convert competitive pressure into a pro-tumorigenic force. In Drosophila, we find that Pp1-87B depleted, RAS-mutant "loser" cells undergo Hh-mediated apoptosis while secreting Wingless (Wg). This paracrine Wg signal hyperactivate β-catenin in neighboring RAS "winner" clones, reprogramming them into invasive super-competitors. This mechanism is conserved in human pancreatic ductal adenocarcinoma (PDAC), where PPP1CA loss in KRAS-mutant cells induces analogous Hh-Wnt synergy, accelerating tumor growth in mouse xenograft models and correlating with clonal selection in patient specimens. Our study elucidates a paradoxical role for cell competition in intratumoral heterogeneity, where distinct tumor clones across species exploit conserved developmental signaling pathways to fuel malignancy. These findings establish interclonal communication as a critical driver of tumor ecosystem dynamics and identify Hh-Wnt crosstalk as a promising therapeutic vulnerability in heterogeneous cancers.