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CD44 restricts EGFR mobility to polarize cytoskeletal signalling modules driving bleb-based migration.
Ankita Jha1, Ankit Chandra2, Payam E Farahani3,4
1Cell and Developmental Biology Center, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA. ankita.13jha@gmail.com.
Nature Cell Biology
|July 6, 2026
Summary
Metastatic melanoma cells use stable, polarized leader blebs for efficient migration in confined, low-adhesion spaces. Epidermal Growth Factor Receptor (EGFR) signaling via Phosphoinositide 3-kinase (PI3K) is crucial for maintaining bleb polarity and driving cell movement.
Area of Science:
- Cell Biology
- Biophysics
- Cancer Research
Background:
- Cells migrate differently based on their microenvironment.
- High confinement and low adhesion favor hydrostatic pressure-driven leader blebs for cell migration.
- Metastatic melanoma cells exhibit unique migration patterns in confined spaces.
Purpose of the Study:
- To investigate the molecular mechanisms underlying polarized bleb morphology in metastatic melanoma cells.
- To understand how Epidermal Growth Factor Receptor (EGFR) signaling influences leader bleb stability and polarity.
- To elucidate the role of specific signaling molecules and protein interactions in bleb-based migration.
Main Methods:
- High-resolution live imaging of migrating melanoma cells.
- Molecular perturbations to disrupt signaling pathways (e.g., PI3K inhibition).
- Biosensors to detect signaling molecule activity gradients within blebs.
- Optogenetic tools to manipulate signaling gradients.
- Mathematical modeling to simulate bleb dynamics.
Main Results:
- Epidermal Growth Factor Receptor (EGFR) signaling through Phosphoinositide 3-kinase (PI3K) stabilizes and polarizes leader blebs.
- A gradient of EGFR and PI3K activity was observed, decreasing from rear to front within leader blebs.
- Specific lipid and GTPase distributions (PIP3/Rac1 at rear, PIP2/RhoA at tip) were identified, contrasting with mesenchymal migration.
- CD44 and ERM proteins restrict EGFR mobility at the bleb rear, establishing the signaling gradient.
- Optogenetic disruption of the gradient led to bleb retraction.
Conclusions:
- EGFR-PI3K signaling is essential for maintaining polarized leader blebs in confined, low-adhesion environments.
- A novel signaling gradient mechanism, involving CD44 and ERM proteins, establishes bleb polarity.
- This study defines the biophysical and molecular basis of polarity in bleb-based migration.
- Alternative spatial organization of signaling modules supports distinct cell migration modes.
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