Netrin-1 feedforward mechanism promotes pancreatic cancer liver metastasis via hepatic stellate cell activation, retinoid, and ELF3 signaling.

Autor:	Dudgeon C; Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA., Casabianca A; Department of Surgery, Division of Surgical Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA; Wilmot Cancer Center, University of Rochester, Rochester, NY, USA., Harris C; Department of Surgery, Division of Surgical Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA; Wilmot Cancer Center, University of Rochester, Rochester, NY, USA., Ogier C; Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA., Bellina M; Apoptosis, Cancer and Development Laboratory - Equipe labellisée 'La Ligue,' LabEx DEVweCAN, Institut Convergence PLAsCAN, Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM U1052-CNRS UMR5286, Université de Lyon, Université Claude Bernard Lyon 1, Centre Léon Bérard, 69008 Lyon, France; Netris Pharma, 69008 Lyon, France., Fiore S; Apoptosis, Cancer and Development Laboratory - Equipe labellisée 'La Ligue,' LabEx DEVweCAN, Institut Convergence PLAsCAN, Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM U1052-CNRS UMR5286, Université de Lyon, Université Claude Bernard Lyon 1, Centre Léon Bérard, 69008 Lyon, France., Bernet A; Apoptosis, Cancer and Development Laboratory - Equipe labellisée 'La Ligue,' LabEx DEVweCAN, Institut Convergence PLAsCAN, Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM U1052-CNRS UMR5286, Université de Lyon, Université Claude Bernard Lyon 1, Centre Léon Bérard, 69008 Lyon, France; Netris Pharma, 69008 Lyon, France., Ducarouge B; Netris Pharma, 69008 Lyon, France., Goldschneider D; Netris Pharma, 69008 Lyon, France., Su X; Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA., Pitarresi J; Department of Medicine, Division of Hematology/Oncology, University of Massachusetts, Worcester, MA, USA., Hezel A; Department of Medicine, Division of Medical Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA., De S; Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA., Narrow W; Department of Surgery, Division of Surgical Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA; Wilmot Cancer Center, University of Rochester, Rochester, NY, USA., Soliman F; Rutgers Robert Wood-Johnson Medical School, New Brunswick, NJ, USA., Shields C; Wilmot Cancer Center, University of Rochester, Rochester, NY, USA., Vendramini-Costa DB; Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA., Prela O; Department of Surgery, Division of Surgical Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA., Wang L; Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA., Astsaturov I; Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA., Mehlen P; Apoptosis, Cancer and Development Laboratory - Equipe labellisée 'La Ligue,' LabEx DEVweCAN, Institut Convergence PLAsCAN, Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM U1052-CNRS UMR5286, Université de Lyon, Université Claude Bernard Lyon 1, Centre Léon Bérard, 69008 Lyon, France; Netris Pharma, 69008 Lyon, France., Carpizo DR; Department of Surgery, Division of Surgical Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA; Wilmot Cancer Center, University of Rochester, Rochester, NY, USA. Electronic address: darren_carpizo@urmc.rochester.edu.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2023 Nov 28; Vol. 42 (11), pp. 113369. Date of Electronic Publication: 2023 Nov 03.
DOI:	10.1016/j.celrep.2023.113369
Abstrakt:	The biology of metastatic pancreatic ductal adenocarcinoma (PDAC) is distinct from that of the primary tumor due to changes in cell plasticity governed by a distinct transcriptome. Therapeutic strategies that target this distinct biology are needed. We detect an upregulation of the neuronal axon guidance molecule Netrin-1 in PDAC liver metastases that signals through its dependence receptor (DR), uncoordinated-5b (Unc5b), to facilitate metastasis in vitro and in vivo. The mechanism of Netrin-1 induction involves a feedforward loop whereby Netrin-1 on the surface of PDAC-secreted extracellular vesicles prepares the metastatic niche by inducing hepatic stellate cell activation and retinoic acid secretion that in turn upregulates Netrin-1 in disseminated tumor cells via RAR/RXR and Elf3 signaling. While this mechanism promotes PDAC liver metastasis, it also identifies a therapeutic vulnerability, as it can be targeted using anti-Netrin-1 therapy to inhibit metastasis using the Unc5b DR cell death mechanism. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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