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 AstsaturovPatrick Mehlen, Darren R Carpizo

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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.

Original languageEnglish
Article number113369
Pages (from-to)113369
JournalCell Reports
Volume42
Issue number11
DOIs
StatePublished - Nov 28 2023

Keywords

  • Humans
  • Netrin-1
  • Retinoids
  • Hepatic Stellate Cells/metabolism
  • Cell Line, Tumor
  • Pancreatic Neoplasms/pathology
  • Carcinoma, Pancreatic Ductal/pathology
  • Liver Neoplasms/metabolism
  • Netrin Receptors
  • DNA-Binding Proteins
  • Transcription Factors
  • Proto-Oncogene Proteins c-ets
  • hepatic stellate cells
  • extracellular vesicles
  • metastatic niche
  • pancreatic cancer
  • retinoic acid
  • Elf3
  • metastasis
  • CP: Cancer
  • Unc5b
  • axon guidance

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