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

• DOI: 10.1016/j.neo.2021.07.002
• Publication Date: 2021-07-25T15:29:18Z
• 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 Picciar...; Raffaella Depalo; Patrizia Querzoli; Massimo Pedriali; Enzo Bianchini; Domenico Angelucci; Giuseppe Pizzican...; Carla Di Loreto; Mauro Piantelli; Laura Antolini; Xiao-Feng Sun; Donato F. Altomare; Saverio Alberti
• Keywords: 0301 basic medicine; Epithelial-Mesenchymal Transition; Trop-2; proteolytic cleavage; Mice, Nude; Mice, Transgenic; E-cadherin; Epithelial-mesenchymal transition; Metastasis; proteolytic cleavage; Signaling networks; Trop-2; β-catenin; Metastasi; Metastasis; ADAM10 Protein; Mice; 03 medical and health sciences; Signaling network; Antigens, CD; Antigens, Neoplasm; Signaling networks; Animals; Humans; RC254-282; Original Research; Cancer och onkologi; E-cadherin, Epithelial-mesenchymal transition, Metastasis, proteolytic cleavage, Signaling networks, Trop-2, β-catenin; E-cadherin; beta-catenin; Trop-2; proteolytic cleavage; Metastasis; Signaling networks; Epithelial-mesenchymal transition; Gene Expression Profiling; E-cadherin; Neoplasms. Tumors. Oncology. Including cancer and carcinogens; Membrane Proteins; β-catenin; Epithelial-mesenchymal transition; Cadherins; HCT116 Cells; Xenograft Model Antitumor Assays; 3. Good health; Survival Rate; Cancer and Oncology; Colonic Neoplasms; E-cadherin; Epithelial-mesenchymal transition; Metastasis; Signaling networks; Trop-2; proteolytic cleavage; β-catenin; Female; Amyloid Precursor Protein Secretases; Cell Adhesion Molecules; HT29 Cells

We recently reported that activation of Trop-2 through its cleavage at R87-T88 by ADAM10 underlies Trop-2-driven progression of colon cancer. However, the mechanism of action and pathological impact of Trop-2 in metastatic diffusion remain unexplored. Through searches for molecular determinants of cancer metastasis, we identified TROP2 as unique in its up-regulation across independent colon cancer metastasis models. Overexpression of wild-type Trop-2 in KM12SM human colon cancer cells increased liver metastasis rates in vivo in immunosuppressed mice. Metastatic growth was further enhanced by a tail-less, activated ΔcytoTrop-2 mutant, indicating the Trop-2 tail as a pivotal inhibitory signaling element. In primary tumors and metastases, transcriptome analysis showed no down-regulation of CDH1 by transcription factors for epithelial-to-mesenchymal transition, thus suggesting that the pro-metastatic activity of Trop-2 is through alternative mechanisms. Trop-2 can tightly interact with ADAM10. Here, Trop-2 bound E-cadherin and stimulated ADAM10-mediated proteolytic cleavage of E-cadherin intracellular domain. This induced detachment of E-cadherin from β-actin, and loss of cell-cell adhesion, 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 led to anti-apoptotic signaling, increased cell migration, and enhanced cancer-cell survival. In patients with colon cancer, activation of this Trop-2-centered program led to significantly reduced relapse-free and overall survival, indicating a major impact on progression to metastatic disease. Recently, the anti-Trop-2 mAb Sacituzumab govitecan-hziy was shown to be active against metastatic breast cancer. Our findings define the key relevance of Trop-2 as a target in metastatic colon cancer.