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Chemotaxis-Driven Instabilities Govern Size, Shape and Migration Efficiency of Multicellular Clusters

Monika Sanoria1,*, Gema Malet-Engra2, Giorgio Scita2,3, Nir Gov4,5,†, and Ajay Gopinathan1,6,‡

  • *Contact author: msanoria@ucmerced.edu
  • †Contact author: nir.gov@weizmann.ac.il
  • ‡Contact author: agopinathan@ucmerced.edu
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PRX Life 4, 013004 – Published 9 January, 2026

DOI: https://doi.org/10.1103/fxvc-cxy8

Abstract

The collective chemotaxis of multicellular clusters is an important phenomenon in various physiological contexts, ranging from embryonic development to cancer metastasis. Such clusters often display interesting shape dynamics and instabilities, but their physical origin, functional benefits, and role in overall chemotactic migration remain unclear. Here we combine computational modeling and experimental observations of malignant lymphocyte cluster migration in vitro to understand how these dynamics arise from an interplay of chemotactic response and intercellular interactions. Our cell-based computational model incorporates active self-propulsion of cells, contact inhibition of locomotion, chemoattractant response, as well as alignment, adhesive, and exclusion interactions between cells. We find that clusters remain fluid and maintain cohesive forward migration in low chemoattractant gradients. However, above a threshold gradient, clusters display an instability driven by local cluster-shape dependent velocity differentials that causes them to elongate perpendicular to the gradient and eventually break apart. Comparison with our in vitro data shows the predicted transition to the cluster instability regime with increased gradient, as well as quantitative agreement with key features such as cluster aspect ratio, orientation, and breaking frequency. This instability naturally limits the size of multicellular aggregates, and, in addition, clusters in the instability regime display optimal forward migration speeds, suggesting functional implications in vivo. Our work provides valuable insights into generic instabilities of chemotactic clusters, elucidates physical factors that could contribute to metastatic spreading, and can be extended to other living or synthetic systems of active clusters.

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PRX Life 4, 013004– Published 9 January, 2026
  • Received 3 June 2025
  • Accepted 1 December 2025
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Published by the American Physical Society under the terms of the Creative Commons Attribution 4.0 International license. Further distribution of this work must maintain attribution to the author(s) and the published article's title, journal citation, and DOI.

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