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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,9,15]]},"abstract":"<jats:p>Single cells confined by the extracellular matrix can exhibit rotational motion, yet the physical mechanisms underlying its onset and persistence remain unclear. Here, we address this gap with a cellular phase field model that couples cell deformation, cell polarization governed by stochastic excitable dynamics, and confinement. We identify the confinement strength as a bifurcation parameter determining three regimes: Strong confinement prevents rotation through spatial constraints, intermediate confinement induces stochastic transitions between rotating and nonrotating states, and weak confinement allows persistent rotations. For the intermediate regime, we develop a semi-Markovian renewal process framework that characterizes the stochastic dynamics through dwell time statistics, transition probabilities, and first-passage times. For the weak confinement regime, we reveal that a mechanochemical feedback enables coherent rotations despite internal noise through the reduction of local excitability mediated by mechanical contraction. We formalize this feedback analytically using Kramers escape theory. Experiments on epithelial MCF10A cells in Matrigel demonstrate three types of cell dynamics that recapitulate those observed in each confinement regime. Our results establish a theoretical approach for understanding single-cell rotations under confinement, with implications for controlling single-cell dynamics by tuning extracellular matrix properties.<\/jats:p>","DOI":"10.1073\/pnas.2602259123","type":"journal-article","created":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T17:02:15Z","timestamp":1789059735000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["Confinement controls the stochastic onset of single-cell rotation"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7051-3918","authenticated-orcid":false,"given":"Sebasti\u00e1n","family":"Echeverr\u00eda-Alar","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0168r3w48","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Physics, University of California","place":["San Diego"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2936-0398","authenticated-orcid":false,"given":"Badri Narayanan","family":"Narasimhan","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0168r3w48","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Bioengineering, University of California","place":["San Diego"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1548-4442","authenticated-orcid":false,"given":"Stephanie I.","family":"Fraley","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0168r3w48","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Bioengineering, University of California","place":["San Diego"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3833-7197","authenticated-orcid":false,"given":"Wouter-Jan","family":"Rappel","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0168r3w48","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Physics, University of California","place":["San Diego"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2026,9,10]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2406293121"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1137\/S0036139903437424"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1103\/PhysRevLett.83.1247"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-04889-6"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1103\/PRXLife.2.033006"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1103\/PhysRevLett.110.228701"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1119578109"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41567-021-01336-7"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2024.11.021"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-019-0172-9"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1002\/cm.20077"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1414498111"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1103\/PhysRevLett.114.228102"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8240(05)80008-4"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41567-020-0894-9"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41567-024-02626-6"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.272.5259.277"},{"key":"e_1_3_4_18_2","first-page":"031041","article-title":"Geometry adaptation of protrusion and polarity dynamics in confined cell migration","volume":"12","author":"Br\u00fcckner D. 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Echeverr\u00eda-Alar B. N. Narasimhan S. I. Fraley W. J. Rappel Codes for \u201cConfinement controls the stochastic onset of single-cell rotation.\u201d Zenodo. https:\/\/doi.org\/10.5281\/zenodo.18038143. 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