The study shows that the transmembrane receptor Trop-2 induces an ADAM10-mediated cleavage of E-cadherin, and this event triggers a metastatization program in colorectal cancer cells without involvement of epithelial-to-mesenchymal transition (EMT).

Recent findings by Prof. Trerotola’s group showed that ADAM10 cleaves the extracellular domain of Trop-2 in cancer cells and stimulates Trop-2 to induce proliferation (Neoplasia 2021, vol. 23 issue 4: p.415-428). In this new study, overexpression of wild-type Trop-2 in human colon cancer cells is demonstrated to induce metastatic dissemination to the liver in vivo. Metastatic growth is further enhanced by overexpression of a tail-less, activated ΔcytoTrop-2 mutant, indicating the Trop-2 tail encompasses inhibitory signaling elements. In primary tumors and metastases, transcriptome analysis showed no down-regulation of CDH1 by EMT transcription factors, thus suggesting that the pro-metastatic activity of Trop-2 is through alternative mechanisms. Consistent with this, Trop-2 is found to bind E-cadherin and stimulate ADAM10-mediated proteolytic cleavage of the E-cadherin intracellular domain, with consequent detachment of E-cadherin from β-actin, and loss of cell-cell adhesions. This leads to the acquisition of invasive capability, and membrane-driven activation of β-catenin signaling, which were further enhanced by the ΔcytoTrop-2 mutant. This Trop-2/E-cadherin/β-catenin program leads to anti-apoptotic signaling, increased migration and enhanced survival. In patients with colon cancer, activation of this Trop-2–centered program leads to significantly reduced relapse-free and overall survival, indicating a major impact on progression to metastatic disease.

Title: Trop-2 induces ADAM10-mediated cleavage of E-cadherin and drives EMT-less metastasis in colon cancer

Authors: Emanuela Guerra*, Marco Trerotola*, Valeria Relli, Rossano Lattanzio, Romina Tripaldi, Giovanna Vacca, Martina Ceci, Khouloud Boujnah, Valeria Garbo, Antonino Moschella, Romina Zappacosta, Pasquale Simeone, Robert de Lange, Ulrich H. Weidle, Maria Teresa Rotelli, Arcangelo Picciariello, Raffaella Depalo, Patrizia Querzoli, Massimo Pedriali, Enzo Bianchini, Domenico Angelucci, Giuseppe Pizzicannella, Carla Di Loreto, Mauro Piantelli, Laura Antolini, Xiao-Feng Sun, Donato F. Altomare and Saverio Alberti

* co-first authors