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Peer-reviewedCC BYThe Journal of cell biology

Nonadhesive functions of E-cadherin promote cancer cell survival and metastasis.

  • Ryan L Huizar1,2,3
  • James V McCann1
  • Malak Amer1,2,3
  • Beza Woldemeskel1
  • Daisuke Murata1
  • Nanami Senoo4
  • Abhijit Deb Roy5
  • Benjamin C Orsburn6,7
  • Steven M Claypool4
  • Hiromi Sesaki1
  • Miho Iijima1
  • Namandjé N Bumpus6
2 more authors
  • Takanari Inoue1
  • Andrew J Ewald1,2,3
7 affiliations
  1. 1Department of Cell Biology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  2. 2Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  3. 3Giovanis Institute for Translational Cell Biology, The Johns Hopkins University School of Medicine , Baltimore, MD, USA.
  4. 4Department of Physiology, Pharmacology and Therapeutics, Mitochondrial Phospholipid Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  5. 5Center for Cell Analysis and Modeling and Department of Cell Biology, University of Connecticut School of Medicine, Farmington, CT, USA.
  6. 6Organ Pathobiology and Therapeutics Institute, The University of Pittsburgh , Pittsburgh, PA, USA.
  7. 7Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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Abstract

E-cadherin suppresses invasion and promotes metastasis in invasive ductal breast cancer, through suppression of reactive oxygen species (ROS). We sought to determine the cellular source of apoptosis-inducing ROS and to identify the domains of E-cadherin that are essential for cancer cell survival. Inhibition of mitochondria-derived ROS was sufficient to rescue cell death following E-cadherin deletion, in both 3D colony formation and in vivo metastasis assays. We next generated Cdh1 constructs by mutating amino acids or deleting domains, then tested their ability to rescue colony formation in E-cadherin-deleted cells. Surprisingly, E-cadherin constructs in which the extracellular domains were deleted, adhesion was compromised, or catenin interactions were blocked could rescue elevated mitochondrial ROS and 3D colony formation. Conversely, a construct lacking the cytoplasmic domain was unable to rescue ROS or cell death. Our findings reveal that E-cadherin's ability to regulate mitochondrial ROS, cancer cell survival, and metastatic outgrowth is separable from its role in intercellular adhesion.

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Cite

BibTeXRIS
BibTeX
@article{huizar2026nonadhesive,
  title = {{Nonadhesive functions of E-cadherin promote cancer cell survival and metastasis.}},
  author = {Ryan L Huizar and James V McCann and Malak Amer and Beza Woldemeskel and Daisuke Murata and Nanami Senoo and Abhijit Deb Roy and Benjamin C Orsburn and Steven M Claypool and Hiromi Sesaki and Miho Iijima and Namandjé N Bumpus and Takanari Inoue and Andrew J Ewald},
  journal = {The Journal of cell biology},
  year = {2026},
  month = oct,
  doi = {10.1083/jcb.202507222},
  url = {https://europepmc.org/article/MED/42911134},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Nonadhesive functions of E-cadherin promote cancer cell survival and metastasis.
AU  - Ryan L Huizar
AU  - James V McCann
AU  - Malak Amer
AU  - Beza Woldemeskel
AU  - Daisuke Murata
AU  - Nanami Senoo
AU  - Abhijit Deb Roy
AU  - Benjamin C Orsburn
AU  - Steven M Claypool
AU  - Hiromi Sesaki
AU  - Miho Iijima
AU  - Namandjé N Bumpus
AU  - Takanari Inoue
AU  - Andrew J Ewald
PY  - 2026
DA  - 2026/10/22
JO  - The Journal of cell biology
DO  - 10.1083/jcb.202507222
UR  - https://europepmc.org/article/MED/42911134
AB  - E-cadherin suppresses invasion and promotes metastasis in invasive ductal breast cancer, through suppression of reactive oxygen species (ROS). We sought to determine the cellular source of apoptosis-inducing ROS and to identify the domains of E-cadherin that are essential for cancer cell survival. Inhibition of mitochondria-derived ROS was sufficient to rescue cell death following E-cadherin deletion, in both 3D colony formation and in vivo metastasis assays. We next generated Cdh1 constructs by mutating amino acids or deleting domains, then tested their ability to rescue colony formation in E-cadherin-deleted cells. Surprisingly, E-cadherin constructs in which the extracellular domains were deleted, adhesion was compromised, or catenin interactions were blocked could rescue elevated mitochondrial ROS and 3D colony formation. Conversely, a construct lacking the cytoplasmic domain was unable to rescue ROS or cell death. Our findings reveal that E-cadherin's ability to regulate mitochondrial ROS, cancer cell survival, and metastatic outgrowth is separable from its role in intercellular adhesion.
SN  - 0021-9525
SN  - 1540-8140
ER  -