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Thereby, PSCs generate a stiffness gradient between the healthy pancreas and the tumor. This gradient induces durotaxis, a form of directional cell migration driven by differential stiffness. However, the molecular sensors behind durotaxis are still unclear. To investigate the role of mechanosensitive ion channels in PSC durotaxis, we established a two-dimensional stiffness gradient mimicking PDAC. Using pharmacological and genetic methods, we investigated the contribution of the ion channels Piezo1, TRPC1 and TRPV4 in PSC durotaxis. We found that PSC migration towards a stiffer substrate is diminished by altering Piezo1 activity. Moreover, disrupting TRPC1 along with TRPV4 abolishes PSC durotaxis even when Piezo1 is functional. Our results demonstrate that optimal PSC durotaxis requires an intermediary level of ion channel activity, which we simulated via a numerically discretized mathematical model. These findings suggest that mechanosensitive Piezo1 channels detect the differential stiffness microenvironment. The resulting intracellular signals are amplified by TRPV4 and TRPC1 channels to guide efficient PSC durotaxis.<\/jats:p>","DOI":"10.1242\/jcs.263846","type":"journal-article","created":{"date-parts":[[2025,2,28]],"date-time":"2025-02-28T10:36:37Z","timestamp":1740738997000},"source":"Crossref","is-referenced-by-count":15,"title":["Piezo1-induced durotaxis of pancreatic stellate cells depends on TRPC1 and TRPV4 channels"],"prefix":"10.1242","volume":"138","author":[{"given":"Ilka","family":"Budde","sequence":"first","affiliation":[{"name":", University of M\u00fcnster 1 Institute of Physiology II , Robert-Koch Str. 27B, 48149 M\u00fcnster ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e9","family":"Schlichting","sequence":"additional","affiliation":[{"name":", University of M\u00fcnster 2 Institute for Analysis and Numerics , Einsteinstr. 62, 48149 M\u00fcnster ,","place":["Germany"]},{"name":", University of Ulm 3 Institute of Applied Analysis , Helmholtzstra\u00dfe 18, 89081 Ulm ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Ing","sequence":"additional","affiliation":[{"name":", University of M\u00fcnster 1 Institute of Physiology II , Robert-Koch Str. 27B, 48149 M\u00fcnster ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Schimmelpfennig","sequence":"additional","affiliation":[{"name":", University of M\u00fcnster 1 Institute of Physiology II , Robert-Koch Str. 27B, 48149 M\u00fcnster ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Kuntze","sequence":"additional","affiliation":[{"name":", University of M\u00fcnster 1 Institute of Physiology II , Robert-Koch Str. 27B, 48149 M\u00fcnster ,","place":["Germany"]},{"name":", University of Ulm 3 Institute of Applied Analysis , Helmholtzstra\u00dfe 18, 89081 Ulm ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benedikt","family":"Fels","sequence":"additional","affiliation":[{"name":", University of M\u00fcnster 1 Institute of Physiology II , Robert-Koch Str. 27B, 48149 M\u00fcnster ,","place":["Germany"]},{"name":", University of M\u00fcnster 4 Gerhard-Domagk-Institute of Pathology , 48149 M\u00fcnster ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joelle M.-J.","family":"Romac","sequence":"additional","affiliation":[{"name":"University of L\u00fcbeck 5 Institute of Physiology, , 23562 L\u00fcbeck ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandip M.","family":"Swain","sequence":"additional","affiliation":[{"name":"University of L\u00fcbeck 5 Institute of Physiology, , 23562 L\u00fcbeck ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodger A.","family":"Liddle","sequence":"additional","affiliation":[{"name":"University of L\u00fcbeck 5 Institute of Physiology, , 23562 L\u00fcbeck ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Stevens","sequence":"additional","affiliation":[{"name":", University of M\u00fcnster 2 Institute for Analysis and Numerics , Einsteinstr. 62, 48149 M\u00fcnster ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albrecht","family":"Schwab","sequence":"additional","affiliation":[{"name":", University of M\u00fcnster 1 Institute of Physiology II , Robert-Koch Str. 27B, 48149 M\u00fcnster ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7057-4761","authenticated-orcid":false,"given":"Zolt\u00e1n","family":"Peth\u0151","sequence":"additional","affiliation":[{"name":", University of M\u00fcnster 1 Institute of Physiology II , Robert-Koch Str. 27B, 48149 M\u00fcnster ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2025,4,25]]},"reference":[{"key":"2025042516231637800_JCS263846C1","doi-asserted-by":"publisher","first-page":"1120","DOI":"10.1039\/c5ib00040h","article-title":"Human breast cancer invasion and aggression correlates with ECM stiffening and immune cell infiltration","volume":"7","author":"Acerbi","year":"2015","journal-title":"Integr. 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