Abstract 2631: Trop-2 is expressed in tumor budding cells and drives colon cancer cell migration and invasion through a β-catenin, CDC42, PKCα, Akt signaling network

Abstract TROP2 was previously shown to drive metastatic diffusion of colorectal cancer (CRC), upon proteolytic activation by ADAM10. Trop-2 activation was shown to lead to cleavage of E-cadherin, with release from the scaffolding cytoskeleton and disruption of cell-cell junctions. This suggested that Trop-2-driven loss of cell adhesion is pivotal for the acquisition of invasion capacity in CRC. Tumor budding was shown to play a role in CRC invasion at the tumor/stroma interface and to impact on disease outcome. We thus investigated whether Trop-2 is associated with CRC cell budding. Our findings show that essentially all CRC buds express Trop-2. Trop-2-positive tumor cell buds and poorly differentiated clusters associated with metastatic relapse in CRC patients in independent CRC case series. Trop-2 was shown to drive cell migration and matrix invasion upon induction of β-catenin signaling, via expression of CDC42, phosphorylation/activation of PKCα at Ser657 and of Akt at Thr308. The highest impact on CRC patient prognosis was jointly shown by Trop-2, CDC42 and phosphorylated PKCα, supporting a model of Trop-2-driven CRC progression through induction of migration and invasion of tumor budding cells. Citation Format: Saverio Alberti, Valeria Barresi, Rossano Lattanzio, Marco Trerotola, Emanuela Guerra, Martina Ceci, Roberta Di Pietro, Donato F. Altomare, Raffaella Depalo, Arcangelo Picciariello, Laura Antolini, Federica M. Previtera. Trop-2 is expressed in tumor budding cells and drives colon cancer cell migration and invasion through a β-catenin, CDC42, PKCα, Akt signaling network [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2631.