Contact percolation governs collective motility via mechano-chemical feedback in heterogeneous breast cancer
Breast carcinomas are heterogeneous tissues containing cell populations with distinct molecular programs and mechanical states. How this heterogeneity drives collective invasion remains unclear. Tissue fluidization, the shift from a crowded, solid-like state to a more deformable and mobile one, promotes collective motion of cancer cells. Using percolation theory, which explains how connected clusters generate system-wide behavior, here we show that a critical fraction of motile cells expressing RAB5A, a membrane-trafficking regulator, triggers an abrupt transition to coordinated, flock-like movement in heterogeneous breast cancer monolayers. Above this threshold, RAB5A cells form connected networks that mechanically and chemically reprogram neighboring control cells. Under these conditions, control cells acquire aligned migratory protrusions, soften and elongate through E-cadherin-dependent EGFR–MAPK signaling. They further activate a STAT1/STAT2-dependent inflammatory gene program through both cell contact and soluble signals. Our findings reveal a mechano-chemical switch through which local tumor heterogeneity organizes tissue-wide fluidization, inflammation and invasive behavior in breast cancer. Percolation describes how network components become progressively more interconnected until they form a connected cluster. Here, the authors discover that contact percolation controls motility and phenotype switching in heterogenous populations of breast cancer cells.
Authors
- Edoardo Bellini (ORCID: https://orcid.org/0000-0001-9766-7685)
- Brenda J. Green (ORCID: https://orcid.org/0000-0002-4274-0969)
- Simona Polo (ORCID: https://orcid.org/0000-0001-5536-9399)
- Joseph Ackermann
- Angela Cattaneo
- Leonardo Barzaghi (ORCID: https://orcid.org/0000-0002-3174-6441)
- Fabio Giavazzi (ORCID: https://orcid.org/0000-0003-4930-0592)
- Stefano Villa (ORCID: https://orcid.org/0000-0002-9159-0952)
- Giorgio Scita (ORCID: https://orcid.org/0000-0001-7984-1889)
- Raphaël Voituriez (ORCID: https://orcid.org/0000-0001-8746-5713)
- Andrew E. Massey (ORCID: https://orcid.org/0000-0001-7688-5501)
- Emanuela Frittoli (ORCID: https://orcid.org/0000-0002-6123-5861)
- Roberto Cerbino (ORCID: https://orcid.org/0000-0003-0434-7741)
- Chiara Guidolin (ORCID: https://orcid.org/0000-0002-8682-2114)
- Valeria Cancila (ORCID: https://orcid.org/0000-0002-9502-1191)
- Angela Bachi (ORCID: https://orcid.org/0000-0003-4842-6556)
- Andrea Palamidessi (ORCID: https://orcid.org/0000-0002-7134-7023)
- Alexander X. Cartagena‐Rivera (ORCID: https://orcid.org/0000-0001-6227-2499)
- Claudio Tripodo (ORCID: https://orcid.org/0000-0002-0821-6231)
- Camillo Mazzella
Institutions
- Centre National de la Recherche Scientifique (FR)
- University of Vienna (AT)
- National Institutes of Health (US)
- University of Milan (IT)
- Sorbonne Université (FR)
- National Institute of Biomedical Imaging and Bioengineering (US)
- Laboratoire Jean Perrin (FR)
- IFOM (IT)
- Institute of Biomedical Technologies (IT)
- European Institute of Oncology (IT)
- University of Palermo (IT)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-09-08
- DOI
- https://doi.org/10.1038/s41467-026-77357-8
- Primary Topic
- Force Microscopy Techniques and Applications
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Associazione Italiana per la Ricerca sul Cancro
- National Institute of Biomedical Imaging and Bioengineering