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

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 BianchiniDomenico Angelucci, Giuseppe Pizzicannella, Carla Di Loreto, Mauro Piantelli, Laura Antolini, Xiao Feng Sun, Donato F. Altomare, Saverio Alberti

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)898-911
Number of pages14
JournalNeoplasia (United States)
Volume23
Issue number9
DOIs
Publication statusPublished - Sep 2021

Keywords

  • E-cadherin
  • Epithelial-mesenchymal transition
  • Metastasis
  • proteolytic cleavage
  • Signaling networks
  • Trop-2
  • β-catenin

ASJC Scopus subject areas

  • Cancer Research

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