# Mechanosensation in tumorigenesis and metastasis

> **NIH NIH F30** · YALE UNIVERSITY · 2020 · $30,330

## Abstract

Project Summary/Abstract
Tumors continuously interact with their surroundings, using mechanosensitive proteins to detect and respond to
the microenvironment. PIEZO1 is a mechanosensing ion channel that is activated by cell membrane tension. In
epithelial monolayers, PIEZO1 is required for live cell extrusion in areas of overcrowding, while promoting
proliferation in response to cell stretching or low cell density. PIEZO1 relocalizes from the plasma membrane to
the cytoplasm with increasing cell density, suggesting that its dichotomous effects on proliferation or extrusion
are dictated by its localization. Of note, breast cancer cells have been shown to express functional PIEZO1
channels. However, studies to date have not interrogated the function or localization of PIEZO1 in three-
dimensional (3D) systems, and the relevance of PIEZO1-mediated proliferation and extrusion for cancer
progression is unclear. In my preliminary work, I have found that high PIEZO1 expression is associated with
poorer overall survival in meta-analysis of breast cancer cohorts, even when controlling for tumor grade or
molecular subtype. In addition, I have found that PIEZO1 is more highly expressed in metastases compared to
primary breast tumors, and across diverse cancer types, I observed that PIEZO1 expression is associated with
focal adhesion, integrin signaling, and cell motility pathways. Collectively, these findings implicate PIEZO1 as a
mechanosensor that promotes cancer progression by relocalizing in response to microenvironmental stimuli to
drive the proliferation or extrusion of tumor cells. I hypothesize that PIEZO1 is a dynamic sensor of mechanical
forces in 3D systems, driving breast cancer tumorigenesis and metastasis. My first aim is to assess the effect
of cell density and substrate stiffness on PIEZO1 localization in developing breast cancer spheroids. To
accomplish this, I will generate MCF-7 human breast cancer cell lines expressing GFP-tagged endogenous
PIEZO1 (PIEZO1-GFP), as well as H2B-mCherry and LifeAct-tagBFP2 reporters. I will utilize live confocal
imaging to quantify the cellular localization of PIEZO1 as MCF-7 cells proliferate to form spheroids in 3D culture.
Additionally, I will assess PIEZO1 localization in MCF-7 spheroids grown in environments of varying stiffness.
My second aim is to interrogate the effect of PIEZO1 loss on breast cancer progression. To do so, I have
generated PIEZO1-knockout (KO) MCF-7 cells and Piezo1-KO E0771 murine breast cancer cells. I will assess
the spheroid forming ability of KO vs. control MCF-7 cells grown in 3D culture. I will also orthotopically inject KO
vs. control E0771 cells into mice to compare their tumorigenic and metastatic capacity. Building on my
preliminary computational work, I will further investigate whether PIEZO1-KO leads to aberrations in focal
adhesion-integrin signaling in breast cancer spheroids. If successful, this project will establish that PIEZO1
dynamically localizes in response to m...

## Key facts

- **NIH application ID:** 9991253
- **Project number:** 1F30CA250249-01
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Ryan D Chow
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $30,330
- **Award type:** 1
- **Project period:** 2020-03-16 → 2023-03-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9991253

## Citation

> US National Institutes of Health, RePORTER application 9991253, Mechanosensation in tumorigenesis and metastasis (1F30CA250249-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9991253. Licensed CC0.

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