Cell crowding activates pro-invasive mechanotransduction pathway in high-grade DCIS via TRPV4 inhibition and cell volume reduction

Authors

Xiangning Bu, Department of Anatomy and Cell Biology, School of Medicine and Health Sciences, George Washington University, Washington, DC, United States.
Nathanael Ashby, Department of Anatomy and Cell Biology, School of Medicine and Health Sciences, George Washington University, Washington, DC, United States.
Teresa Vitali, Department of Anatomy and Cell Biology, School of Medicine and Health Sciences, George Washington University, Washington, DC, United States.
Sulgi Lee, Department of Anatomy and Cell Biology, School of Medicine and Health Sciences, George Washington University, Washington, DC, United States.
Ananya Gottumukkala, Department of Anatomy and Cell Biology, School of Medicine and Health Sciences, George Washington University, Washington, DC, United States.
Kangsun Yun, Department of Anatomy and Cell Biology, School of Medicine and Health Sciences, George Washington University, Washington, DC, United States.
Sana Tabbara, Department of Pathology, George Washington Medical Faculty Associates, Washington, DC, United States.
Patricia Latham, Department of Pathology, George Washington Medical Faculty Associates, Washington, DC, United States.
Christine Teal, Department of Surgery, George Washington Medical Faculty Associates, Washington, DC, United States.
Inhee Chung, Department of Anatomy and Cell Biology, School of Medicine and Health Sciences, George Washington University, Washington, DC, United States.

Document Type

Journal Article

Publication Date

4-21-2025

Journal

eLife

Volume

13

DOI

10.7554/eLife.100490

Keywords

DCIS; TRPV4; calcium homeostasis; cancer biology; cell biology; cell volume; human; mechanotransduction; trafficking

Abstract

Cell crowding is a common microenvironmental factor influencing various disease processes, but its role in promoting cell invasiveness remains unclear. This study investigates the biomechanical changes induced by cell crowding, focusing on pro-invasive cell volume reduction in ductal carcinoma in situ (DCIS). Crowding specifically enhanced invasiveness in high-grade DCIS cells through significant volume reduction compared to hyperplasia-mimicking or normal cells. Mass spectrometry revealed that crowding selectively relocated ion channels, including TRPV4, to the plasma membrane in high-grade DCIS cells. TRPV4 inhibition triggered by crowding decreased intracellular calcium levels, reduced cell volume, and increased invasion and motility. During this process, TRPV4 membrane relocation primed the channel for later activation, compensating for calcium loss. Analyses of patient-derived breast cancer tissues confirmed that plasma membrane-associated TRPV4 is specific to high-grade DCIS and indicates the presence of a pro-invasive cell volume reduction mechanotransduction pathway. Hyperosmotic conditions and pharmacologic TRPV4 inhibition mimicked crowding-induced effects, while TRPV4 activation reversed them. Silencing TRPV4 diminished mechanotransduction in high-grade DCIS cells, reducing calcium depletion, volume reduction, and motility. This study uncovers a novel pro-invasive mechanotransduction pathway driven by cell crowding and identifies TRPV4 as a potential biomarker for predicting invasion risk in DCIS patients.

APA Citation

Bu, Xiangning; Ashby, Nathanael; Vitali, Teresa; Lee, Sulgi; Gottumukkala, Ananya; Yun, Kangsun; Tabbara, Sana; Latham, Patricia; Teal, Christine; and Chung, Inhee, "Cell crowding activates pro-invasive mechanotransduction pathway in high-grade DCIS via TRPV4 inhibition and cell volume reduction" (2025). GW Authored Works. Paper 7022.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/7022

Department

Anatomy and Regenerative Biology