The crucial role of Apc inactivation and dysregulation of Wnt/β-catenin signaling in obesity is shown in a study demonstrating that inactivation of Pten in Lgr5+ ISCs, whether alone or in combination with obesity, is insufficient to drive adenoma formation in mice, but combination of Pten deletion with Apc loss increases tumor burden and worsens survival (87). Here, PTEN is linked to obesity due to melanocortin 4 receptor deficiency.