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  3. Breast tumors interfere with endothelial TRAIL at the premetastatic niche to promote cancer cell seeding

Breast tumors interfere with endothelial TRAIL at the premetastatic niche to promote cancer cell seeding

  • Sci Adv. 2023 Mar 22;9(12):eadd5028. doi: 10.1126/sciadv.add5028.
Carla Riera-Domingo 1 2,  Eduarda Leite-Gomes 1 2,  Iris Charatsidou 1 2,  Peihua Zhao 3 4,  Giovanna Carrá 5 6,  Federica Cappellesso 1 2,  Larissa Mourao 7 8,  Maxim De Schepper 9,  Dana Liu 1 2,  Jens Serneels 1 2,  Mohamad-Gabriel Alameh 10,  Vladimir V Shuvaev 11,  Tatjana Geukens 9,  Edoardo Isnaldi 9,  Hans Prenen 12,  Drew Weissman 10,  Vladimir R Muzykantov 11,  Stefaan Soenen 13 14,  Christine Desmedt 9,  Colinda L G J Scheele 7 8,  Anna Sablina 3 4,  Mario Di Matteo 1 2,  Rosa Martín-Pérez 1 2,  Massimiliano Mazzone 1 2
Affiliations

Affiliations

  • 1 Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium.
  • 2 Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium.
  • 3 Laboratory for Mechanisms of Cell Transformation, Center for Cancer Biology, VIB, Leuven, Belgium.
  • 4 Laboratory for Mechanisms of Cell Transformation, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium.
  • 5 Department of Clinical and Biological Sciences, University of Torino, Orbassano, Italy.
  • 6 Molecular Biotechnology Center, Torino, Italy.
  • 7 Laboratory for Intravital Imaging and Dynamics of Tumor Progression, Center for Cancer Biology, VIB, Leuven, Belgium.
  • 8 Laboratory for Intravital Imaging and Dynamics of Tumor Progression, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium.
  • 9 Laboratory for Translational Breast Cancer Research, Department of Oncology, KU Leuven, Leuven, Belgium.
  • 10 Penn Institute for RNA Innovation, University of Pennsylvania, Philadelphia, PA, USA.
  • 11 Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 12 Department of Oncology, University Hospital Antwerp, Edegem, Belgium.
  • 13 Leuven Cancer Institute, KU Leuven, Belgium.
  • 14 NanoHealth and Optical Imaging Group, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium.
PMID: 36947620 DOI: 10.1126/sciadv.add5028
Abstract

Endothelial cells (ECs) grant access of disseminated Cancer cells to distant organs. However, the molecular players regulating the activation of quiescent ECs at the premetastatic niche (PMN) remain elusive. Here, we find that ECs at the PMN coexpress tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its cognate Death Receptor 5 (DR5). Unexpectedly, endothelial TRAIL interacts intracellularly with DR5 to prevent its signaling and preserve a quiescent vascular phenotype. In absence of endothelial TRAIL, DR5 activation induces EC death and nuclear factor κB/p38-dependent EC stickiness, compromising vascular integrity and promoting myeloid cell infiltration, breast Cancer cell adhesion, and metastasis. Consistently, both down-regulation of endothelial TRAIL at the PMN by proangiogenic tumor-secreted factors and the presence of the endogenous TRAIL inhibitors Decoy Receptor 1 (DcR1) and DcR2 favor metastasis. This study discloses an intracrine mechanism whereby TRAIL blocks DR5 signaling in quiescent endothelia, acting as gatekeeper of the vascular barrier that is corrupted by the tumor during Cancer cell dissemination.

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