ΔNp73 and its effector targets promote colorectal peritoneal carcinosis and predict survival

Abstract

Peritoneal metastasis of colorectal origin appears in ~10-15% of patients at the time of diagnosis and in 30-40% of cases with disease progression. Locoregional spread through the peritoneum is considered stage IVc and is associated with a poor prognosis. The development of a regional therapeutic strategy based on cytoreductive surgery, and hyperthermic intra-abdominal chemotherapy has significantly altered the course of the disease. Although recent evidence supports the benefits of cytoreductive surgery, the benefits of hyperthermic intra-abdominal chemotherapy are, however, still a matter of debate. Understanding the molecular alterations underlying the disease is crucial for developing new therapeutic strategies. Here, we evaluated the involvement in peritoneal dissemination of the oncogenic isoform of TP73, ΔNp73, and its effector targets in in vitro and mouse models, and in 30 patients diagnosed with colorectal peritoneal metastasis. In an orthotopic mouse model, we observed that tumor cells overexpressing ΔNp73 present a higher avidity for the peritoneum and that extracellular vesicles secreted by ΔNp73-upregulating tumor cells enhance their dissemination. In addition, we identified that tumor cells overexpressing ΔNp73 present with dysregulation of genes associated with an epithelial/mesothelial-to-mesenchymal transition (MMT) and that mesothelial cells exposed to the conditioned medium of tumor cells with upregulated ΔNp73 present a mesenchymal phenotype. Lastly, ΔNp73 and its effector target RNAs were dysregulated in our patient series, there were positive correlations between ΔNp73 and its effector targets, and MSN and ITGB4 (ΔNp73 effectors) predicted patient survival. In conclusion, ΔNp73 and its effector targets are involved in the peritoneal dissemination of colorectal cancer and predict patient survival. The promotion of the EMT/MMT and modulation of the adhesion capacity in colorectal cancer cells might be the mechanisms triggered by ΔNp73. Remarkably, ΔNp73 protein is a druggable protein and should be the focus of future studies. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.