The role of Piezo1 mechanotransduction in high-grade serous ovarian cancer: Insights from an in vitro model of collective detachment.

Autor: Micek HM; Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI 53705, USA., Yang N; Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA., Dutta M; Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI 53705, USA., Rosenstock L; Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI 53705, USA., Ma Y; Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI 53705, USA., Hielsberg C; Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI 53705, USA., McCord M; Department of Mechanical Engineering, University of Wisconsin-Madison, Madison, WI 53705, USA.; Biophysics Program, University of Wisconsin-Madison, Madison, WI 53705, USA., Notbohm J; Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI 53705, USA.; Department of Mechanical Engineering, University of Wisconsin-Madison, Madison, WI 53705, USA.; Biophysics Program, University of Wisconsin-Madison, Madison, WI 53705, USA.; University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA., McGregor S; Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.; University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA., Kreeger PK; Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI 53705, USA.; Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.; University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.
Jazyk: angličtina
Zdroj: Science advances [Sci Adv] 2024 Apr 26; Vol. 10 (17), pp. eadl4463. Date of Electronic Publication: 2024 Apr 26.
DOI: 10.1126/sciadv.adl4463
Abstrakt: Slowing peritoneal spread in high-grade serous ovarian cancer (HGSOC) would improve patient prognosis and quality of life. HGSOC spreads when single cells and spheroids detach, float through the peritoneal fluid and take over new sites, with spheroids thought to be more aggressive than single cells. Using our in vitro model of spheroid collective detachment, we determine that increased substrate stiffness led to the detachment of more spheroids. We identified a mechanism where Piezo1 activity increased MMP-1/MMP-10, decreased collagen I and fibronectin, and increased spheroid detachment. Piezo1 expression was confirmed in omental masses from patients with stage III/IV HGSOC. Using OV90 and CRISPR-modified PIEZO1 -/- OV90 in a mouse xenograft model, we determined that while both genotypes efficiently took over the omentum, loss of Piezo1 significantly decreased ascitic volume, tumor spheroids in the ascites, and the number of macroscopic tumors in the mesentery. These results support that slowing collective detachment may benefit patients and identify Piezo1 as a potential therapeutic target.
Databáze: MEDLINE
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