E-cadherin-mediated neighborhood surveillance dictates pre-malignant outcomes

Abstract

Stratified epithelia accumulate oncogenic mutations throughout life, yet overgrowths are rare. How epithelia detect and eliminate aberrant clones remains poorly understood. Using a mouse model of oncogenic clonal mosaicism in the skin, we find that pre-malignant epidermal cells redistribute E-cadherin to interfaces shared with wild-type neighbors, generating local tension heterogeneity that triggers elimination by cell competition. We show that gain or loss of E-cadherin can each drive competitive elimination, and although mechanical routes differ, both establish tension heterogeneity between neighbors, rather than any absolute adhesion state, as the critical determinant of epidermal fitness. This mechanism carries the seeds of its own failure: these tension differentials precipitate clonal sorting, depleting the wild-type contacts that surveillance requires. Pre-malignant cells then become supercompetitors, eliminating wild-type neighbors and expanding hyperplastically. Mechanical heterogeneity therefore endows tissues with an active, yet inherently fragile error-correction system whose collapse initiates a switch in competitive status, increasing tumorigenesis susceptibility.

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Cite

BibTeX RIS

BibTeX

@misc{thompson2026ecadherinmediated,
  title = {{E-cadherin-mediated neighborhood surveillance dictates pre-malignant outcomes}},
  author = {E. A. N. Thompson and C. Schimmer and T. Omelchenko and M. Paganini and J. S. S. Novak and S. T. Muller and A. R. Bonny and M. Schernthanner and S. M. Sajjath and C. J. Bell and A. Gorgulu and S. M. Parigi and K. S. Stewart and P. Banerjee and E. Fuchs and S. J. Ellis},
  howpublished = {bioRxiv},
  year = {2026},
  month = sep,
  doi = {10.64898/2026.09.02.748765},
  url = {https://www.biorxiv.org/content/10.64898/2026.09.02.748765v1},
  note = {CC BY},
}

RIS

TY  - UNPB
TI  - E-cadherin-mediated neighborhood surveillance dictates pre-malignant outcomes
AU  - E. A. N. Thompson
AU  - C. Schimmer
AU  - T. Omelchenko
AU  - M. Paganini
AU  - J. S. S. Novak
AU  - S. T. Muller
AU  - A. R. Bonny
AU  - M. Schernthanner
AU  - S. M. Sajjath
AU  - C. J. Bell
AU  - A. Gorgulu
AU  - S. M. Parigi
AU  - K. S. Stewart
AU  - P. Banerjee
AU  - E. Fuchs
AU  - S. J. Ellis
PY  - 2026
DA  - 2026/09/02
PB  - bioRxiv
DO  - 10.64898/2026.09.02.748765
UR  - https://www.biorxiv.org/content/10.64898/2026.09.02.748765v1
AB  - Stratified epithelia accumulate oncogenic mutations throughout life, yet overgrowths are rare. How epithelia detect and eliminate aberrant clones remains poorly understood. Using a mouse model of oncogenic clonal mosaicism in the skin, we find that pre-malignant epidermal cells redistribute E-cadherin to interfaces shared with wild-type neighbors, generating local tension heterogeneity that triggers elimination by cell competition. We show that gain or loss of E-cadherin can each drive competitive elimination, and although mechanical routes differ, both establish tension heterogeneity between neighbors, rather than any absolute adhesion state, as the critical determinant of epidermal fitness. This mechanism carries the seeds of its own failure: these tension differentials precipitate clonal sorting, depleting the wild-type contacts that surveillance requires. Pre-malignant cells then become supercompetitors, eliminating wild-type neighbors and expanding hyperplastically. Mechanical heterogeneity therefore endows tissues with an active, yet inherently fragile error-correction system whose collapse initiates a switch in competitive status, increasing tumorigenesis susceptibility.
ER  -

Abstract

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