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Trop-2 induces ADAM...
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Guerra, EmanuelaG dAnnunzio Univ Chieti Pescara, Italy; G dAnnunzio Univ Chieti Pescara, Italy
(författare)
Trop-2 induces ADAM10-mediated cleavage of E-cadherin and drives EMT-less metastasis in colon cancer
- Artikel/kapitelEngelska2021
Förlag, utgivningsår, omfång ...
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Elsevier Science INC,2021
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electronicrdacarrier
Nummerbeteckningar
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LIBRIS-ID:oai:DiVA.org:liu-179150
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https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-179150URI
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https://doi.org/10.1016/j.neo.2021.07.002DOI
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Språk:engelska
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Sammanfattning på:engelska
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Klassifikation
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Ämneskategori:ref swepub-contenttype
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Ämneskategori:art swepub-publicationtype
Anmärkningar
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Funding Agencies|grants of Fondazione of the Cassa di Risparmio della Provincia di Chieti; Compagnia di San PaoloCompagnia di San Paolo [2489IT]; Italian Ministry of Development [MI01_00424]; Region Abruzzo (POR FESR) [C78C14000100005]; Oncoxx Biotech (Italian Ministry of University and Research, Smart Cities and Communities) [SCN_00558]; Programma Per Giovani Ricercatori "Rita Levi Montalcini", Italian Ministry of University and Research [PGR12I7N1Z]
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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.
Ämnesord och genrebeteckningar
Biuppslag (personer, institutioner, konferenser, titlar ...)
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Trerotola, MarcoG dAnnunzio Univ Chieti Pescara, Italy; G dAnnunzio Univ Chieti Pescara, Italy
(författare)
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Relli, ValeriaG dAnnunzio Univ Chieti Pescara, Italy; Oncoxx Biotech, Italy
(författare)
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Lattanzio, RossanoG dAnnunzio Univ Chieti Pescara, Italy; G dAnnunzio Univ Chieti Pescara, Italy
(författare)
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Tripaldi, RominaG dAnnunzio Univ Chieti Pescara, Italy
(författare)
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Vacca, GiovannaG dAnnunzio Univ Chieti Pescara, Italy
(författare)
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Ceci, MartinaG dAnnunzio Univ Chieti Pescara, Italy
(författare)
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Boujnah, KhouloudUniv Messina, Italy
(författare)
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Garbo, ValeriaUniv Messina, Italy
(författare)
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Moschella, AntoninoUniv Messina, Italy
(författare)
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Zappacosta, RominaG dAnnunzio Univ Chieti Pescara, Italy
(författare)
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Simeone, PasqualeG dAnnunzio Univ Chieti Pescara, Italy
(författare)
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de Lange, RobertRoche Diagnost GmbH, Germany
(författare)
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Weidle, Ulrich H.Roche Diagnost GmbH, Germany
(författare)
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Rotelli, Maria TeresaUniv Aldo Moro, Italy
(författare)
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Picciariello, ArcangeloUniv Aldo Moro, Italy
(författare)
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Depalo, RaffaellaOncol Inst IRCCS Giovanni Paolo II, Italy
(författare)
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Querzoli, PatriziaUniv Ferrara, Italy
(författare)
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Pedriali, MassimoUniv Hosp, Italy
(författare)
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Bianchini, EnzoUniv Hosp, Italy
(författare)
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Angelucci, DomenicoChieti Hosp, Italy
(författare)
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Pizzicannella, GiuseppeASL2 Chieti Lanciano Vasto, Italy
(författare)
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Di Loreto, CarlaUniv Udine, Italy
(författare)
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Piantelli, MauroG dAnnunzio Univ Chieti Pescara, Italy; G dAnnunzio Univ Chieti Pescara, Italy
(författare)
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Antolini, LauraUniv Milano Bicocca, Italy
(författare)
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Sun, Xiao-FengLinköpings universitet,Avdelningen för kirurgi, ortopedi och onkologi,Medicinska fakulteten,Region Östergötland, Onkologiska kliniken US(Swepub:liu)xiasu45
(författare)
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Altomare, Donato F.Roche Diagnost GmbH, Germany; Univ Aldo Moro, Italy
(författare)
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Alberti, SaverioG dAnnunzio Univ Chieti Pescara, Italy; Oncoxx Biotech, Italy; Univ Messina, Italy
(författare)
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G dAnnunzio Univ Chieti Pescara, Italy; G dAnnunzio Univ Chieti Pescara, ItalyG dAnnunzio Univ Chieti Pescara, Italy; Oncoxx Biotech, Italy
(creator_code:org_t)
Sammanhörande titlar
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Ingår i:Neoplasia: Elsevier Science INC23:9, s. 898-9111522-80021476-5586
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Till lärosätets databas
- Av författaren/redakt...
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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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visa fler...
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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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visa färre...
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