Netrin-1 feedforward mechanism promotes pancreatic cancer liver metastasis via hepatic stellate cell activation, retinoid, and ELF3 signaling
Crissy Dudgeon,
Anthony Casabianca,
Chris Harris,
Charline Ogier,
Mélanie Bellina,
Stephany Fiore,
Agnes Bernet,
Benjamin Ducarouge,
David Goldschneider,
Xiaoyang Su,
Jason Pitarresi,
Aram Hezel,
Subhajyoti De,
Wade Narrow,
Fady Soliman,
Cory Shields,
Debora Barbosa Vendramini-Costa,
Orjola Prela,
Lan Wang,
Igor Astsaturov,
Patrick Mehlen,
Darren R. Carpizo
Affiliations
Crissy Dudgeon
Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
Anthony Casabianca
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
Chris Harris
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
Charline Ogier
Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA
Mélanie Bellina
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
Stephany Fiore
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
Agnes Bernet
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
Benjamin Ducarouge
Netris Pharma, 69008 Lyon, France
David Goldschneider
Netris Pharma, 69008 Lyon, France
Xiaoyang Su
Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
Jason Pitarresi
Department of Medicine, Division of Hematology/Oncology, University of Massachusetts, Worcester, MA, USA
Aram Hezel
Department of Medicine, Division of Medical Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
Subhajyoti De
Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
Wade Narrow
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
Fady Soliman
Rutgers Robert Wood-Johnson Medical School, New Brunswick, NJ, USA
Cory Shields
Wilmot Cancer Center, University of Rochester, Rochester, NY, USA
Debora Barbosa Vendramini-Costa
Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA
Orjola Prela
Department of Surgery, Division of Surgical Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
Lan Wang
Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
Igor Astsaturov
Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA
Patrick Mehlen
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
Darren R. Carpizo
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; Corresponding author
Summary: 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.
