Phosphoproteomic and kinase networks reveal partial EMT and stress-adaptive growth programs in pediatric...

Peutz-Jeghers syndrome (PJS) is a rare inherited cancer predisposing disorder associated with pathogenic variants of the Serine Threonine Kinase11 (STK11 / LKB1). Morbidity in children is driven by small intestinal obstruction from polyps. The molecular mechanisms driving polyp initiation and growth are poorly understood. We hypothesized that integrated phosphoproteomic analysis of pediatric Peutz-Jeghers polyps would reveal signaling networks driving polyp growth.

Intestinal polyp and adjacent non-polyp mucosa from pediatric PJS patients undergoing therapeutic endoscopy-polypectomy underwent mass spectrometry-based proteomic and phosphoproteomic profiling. A bioinformatic pipeline and network analyses were performed to identify differential kinase activity, phosphopeptide enrichment, and signaling nodes relevant to polyp growth.

Polyp tissue was enriched for proliferative signaling and biosynthetic drivers, including CLK1 and PKCβ, MAPK10, and MAPK11. Non-polyp mucosa however, exhibited higher expression of regulatory kinases such as HIPK2, PLK2, LATS1, STK38, and PRKCZ/PRKCI, reinforcing apoptosis, polarity, and Wnt/mTOR restraint. Phosphoproteomic networks in polyps support a partial epithelial-mesenchymal transition phenotype, amplified transcription and translation, and a survival shift from BAD-14-3-3 signaling toward YAP/mTOR/NF-kB.

PJS polyps display a unique proteomic and phosphoproteomic signature that critically distinguishes PJS from other polyposis syndromes potentially lessening repeated invasive interventions in affected children.

Small intestinal pediatric Peutz-Jeghers polyps express a distinct phosphoproteomic and kinase activation profile when compared with adjacent mucosa. Integrated analysis reveals partial epithelial-mesenchymal transition, cytoskeletal remodeling, and transcriptional amplification as key drivers of polyp growth. Polarity and checkpoint signaling consistent with protective stress adaptation are conserved in non-polyp mucosa. This study is the first phosphoproteomic description of pediatric Peutz-Jeghers syndrome, identifying potential kinase biomarkers and therapeutic targets that could reduce the need for repeated invasive procedures in affected children.