Missense-type p53 mutations have shown to acquire novel oncogenic roles through gain-of-function mechanism. However, there is an intratumor heterogeneity in stabilization of mutant p53 protein, and it has not been well understood about interaction of p53-stabilized and p53-destabilized cells in the same tumors. We established mouse intestinal tumor-derived organoids carrying Apcδ716, KrasG12D, and Tgfbr2-/- mutations with Trp53R270H or Trp53Null mutation (AKTPR270H and AKTPNull, respectively). Using these organoids, we found that the activation level of Wnt/β-catenin signaling is significantly higher in AKTPR270H cells compared to AKTPNull cells. Notably, Wnt activation in the AKTPNull cells was significantly increased when cocultured with AKTPR270H cells. Expression analysis revealed that cyclooxygenase (COX)-2 is significantly upregulated in AKTPR270H but not in AKTPNull cells, suggesting that mutant p53 induces COX-2/prostaglandin E2 (PGE2) pathway. Importantly, Wnt activation in cocultured AKTPNull cells with AKTPR270H was significantly suppressed when treated with COX-2 inhibitor or PGE2 receptor EP2/EP4 inhibitor. Furthermore, stimulation with PGE2 increased Wnt signaling activity in AKTPNull cells. These results indicate that COX-2/PGE2 pathway is activated in the p53-stabilized cells in the missense-type p53 mutant cancer, and secreted PGE2 may transactivate Wnt/β-catenin signaling in neighboring p53-destabilized tumor cells in the intratumor microenvironment. Therefore, targeting stabilized mutant p53 or COX-2/PGE2 pathway may suppress Wnt/β-catenin signaling of both mutant p53-stabilized and destabilized cells, thus can be a possible preventive or therapeutic strategy.