Background: Tumor metastasis is the main cause of death of cancer patients and the biggest hurdle for cancer cure. The identification of decisive drivers of metastasis is thus an urgent therapeutic need. Methods: Cancer cell spheroids, wound healing and cell aggregation assays were utilized to explore cell-cell adhesion capacity. Immunofluorescence confocal microscopy and flow cytometry analysis were utilized to quantify expression of target proteins, IHC analysis quantified the expression of target molecules in primary tumors and metastases. Pre-clinical models of orthotopic growth of colon cancer and metastatic diffusion to the liver were utilized. Xenotransplant transcriptome analysis assessed EMT determinant transcription. Patients: 24 distinct case series of breast, colon, uterus, ovary, stomach, lung, and pancreatic cancers, for a total number of 13,042 primary tumors were analyzed. KaplaneMeier plots were used to illustrate survival and metastatic relapse in investigated cohorts. Results: We identify functional inactivation of highly expressed E-cadherin as a pivotal driver of metastatic diffusion in human cancer. E-cadherin is inactivated by binding to Trop-2, which causes release from the cytoskeleton, loss of cell-cell adhesion and activation of b-catenin, while maintaining epithelial differentiation. This leads to antiapoptotic signaling, increased cell migration capacity and enhanced cancer cell survival. This global, Trop-2/E-cadherin/b-catenin-driven pro-metastatic program was recapitulated in human cancer, and was shown to profoundly impact on breast, colon, ovary, uterus, stomach cancer metastatic diffusion. Conclusions: We identify functional inactivation of E-cadherin by Trop-2 as a pivotal driver of EMT-less metastatic diffusion in human cancer. This global, Trop-2/E-cadherin/ b-cateninedriven pro-metastatic program profoundly impacts on the survival of patients bearing breast, colon, uterus, ovary, stomach, lung, pancreas tumours, paving the way for novel diagnostic procedures and anti-cancer therapies.
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