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Trop-2 induces ADAM...
Trop-2 induces ADAM10-mediated cleavage of E-cadherin and drives EMT-less metastasis in colon cancer
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- Guerra, Emanuela (author)
- G dAnnunzio Univ Chieti Pescara, Italy; G dAnnunzio Univ Chieti Pescara, Italy
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- Trerotola, Marco (author)
- G dAnnunzio Univ Chieti Pescara, Italy; G dAnnunzio Univ Chieti Pescara, Italy
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- Relli, Valeria (author)
- G dAnnunzio Univ Chieti Pescara, Italy; Oncoxx Biotech, Italy
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- Lattanzio, Rossano (author)
- G dAnnunzio Univ Chieti Pescara, Italy; G dAnnunzio Univ Chieti Pescara, Italy
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- Tripaldi, Romina (author)
- G dAnnunzio Univ Chieti Pescara, Italy
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- Vacca, Giovanna (author)
- G dAnnunzio Univ Chieti Pescara, Italy
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- Ceci, Martina (author)
- G dAnnunzio Univ Chieti Pescara, Italy
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- Boujnah, Khouloud (author)
- Univ Messina, Italy
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- Garbo, Valeria (author)
- Univ Messina, Italy
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- Moschella, Antonino (author)
- Univ Messina, Italy
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- Zappacosta, Romina (author)
- G dAnnunzio Univ Chieti Pescara, Italy
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- Simeone, Pasquale (author)
- G dAnnunzio Univ Chieti Pescara, Italy
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- de Lange, Robert (author)
- Roche Diagnost GmbH, Germany
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- Weidle, Ulrich H. (author)
- Roche Diagnost GmbH, Germany
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- Rotelli, Maria Teresa (author)
- Univ Aldo Moro, Italy
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- Picciariello, Arcangelo (author)
- Univ Aldo Moro, Italy
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- Depalo, Raffaella (author)
- Oncol Inst IRCCS Giovanni Paolo II, Italy
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- Querzoli, Patrizia (author)
- Univ Ferrara, Italy
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- Pedriali, Massimo (author)
- Univ Hosp, Italy
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- Bianchini, Enzo (author)
- Univ Hosp, Italy
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- Angelucci, Domenico (author)
- Chieti Hosp, Italy
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- Pizzicannella, Giuseppe (author)
- ASL2 Chieti Lanciano Vasto, Italy
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- Di Loreto, Carla (author)
- Univ Udine, Italy
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- Piantelli, Mauro (author)
- G dAnnunzio Univ Chieti Pescara, Italy; G dAnnunzio Univ Chieti Pescara, Italy
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- Antolini, Laura (author)
- Univ Milano Bicocca, Italy
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- Sun, Xiao-Feng (author)
- Linköpings universitet,Avdelningen för kirurgi, ortopedi och onkologi,Medicinska fakulteten,Region Östergötland, Onkologiska kliniken US
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- Altomare, Donato F. (author)
- Roche Diagnost GmbH, Germany; Univ Aldo Moro, Italy
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- Alberti, Saverio (author)
- G dAnnunzio Univ Chieti Pescara, Italy; Oncoxx Biotech, Italy; Univ Messina, Italy
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(creator_code:org_t)
- Elsevier Science INC, 2021
- 2021
- English.
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In: Neoplasia. - : Elsevier Science INC. - 1522-8002 .- 1476-5586. ; 23:9, s. 898-911
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https://doi.org/10.1...
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Abstract
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- We recently reported that activation of Trop-2 through its cleavage at R87-T88 by ADAMIO 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 Delta cytoTrop-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 beta-actin, and loss of cell-cell adhesion, acquisition of invasive capability, and membrane-driven activation of beta-catenin signaling, which were further enhanced by the Delta cytoTrop-2 mutant. This Trop-2/E-cadherin/beta-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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Keyword
- E-cadherin; beta-catenin; Trop-2; proteolytic cleavage; Metastasis; Signaling networks; Epithelial-mesenchymal transition
Publication and Content Type
- ref (subject category)
- art (subject category)
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Neoplasia
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- By the author/editor
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Guerra, Emanuela
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Trerotola, Marco
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Relli, Valeria
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Lattanzio, Rossa ...
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Tripaldi, Romina
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Vacca, Giovanna
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show more...
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Ceci, Martina
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Boujnah, Khoulou ...
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Garbo, Valeria
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Moschella, Anton ...
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Zappacosta, Romi ...
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Simeone, Pasqual ...
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de Lange, Robert
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Weidle, Ulrich H ...
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Rotelli, Maria T ...
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Picciariello, Ar ...
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Depalo, Raffaell ...
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Querzoli, Patriz ...
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Pedriali, Massim ...
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Bianchini, Enzo
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Angelucci, Domen ...
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Pizzicannella, G ...
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Di Loreto, Carla
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Piantelli, Mauro
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Antolini, Laura
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Sun, Xiao-Feng
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Altomare, Donato ...
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Alberti, Saverio
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Cancer and Oncol ...
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Neoplasia
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Linköping University