Tumors exploit interclonal Hedgehog-Wnt crosstalk to drive tumor-promoting cell competition.

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.