Blebs promote cell survival by assembling oncogenic signalling hubs

Area of Science:

• Cell Biology
• Cancer Research
• Molecular Signaling

Background:

• Cell survival typically requires adhesion to a substrate, with detachment leading to anoikis (programmed cell death).
• Cancer cells often acquire anoikis resistance, a critical step for metastasis, by adopting rounded morphologies and forming plasma membrane blebs.
• The precise function of blebs in non-migratory contexts, particularly in anoikis resistance, remains underexplored.

Purpose of the Study:

• To investigate the role of plasma membrane blebs in conferring anoikis resistance.
• To elucidate the molecular mechanisms by which blebs promote cell survival in detached states.
• To explore the therapeutic potential of targeting bleb-mediated signaling in cancer.

Main Methods:

• Three-dimensional imaging and manipulation of cell morphological states.
• Analysis of signaling pathway activation (ERK, PI3K, MAPK) in response to blebbing.
• Investigating the role of septin proteins and mutant NRAS in bleb-associated signaling hubs.
• Pharmacological inhibition of blebs and septins in detached cancer cells and fibroblasts.
• Assessing the impact of BRAF and MEK inhibition on bleb-dependent survival.

Main Results:

• Blebbing induces the formation of signaling hubs at the plasma membrane, recruiting septins to scaffold active mutant NRAS and its effectors.
• These signaling hubs activate ERK and PI3K pathways, promoting pro-survival signaling.
• Inhibition of blebs or septins in detached cells leads to NRAS mislocalization, reduced MAPK/PI3K activity, and cell death.
• BRAF-mutated melanoma cells become sensitive to bleb/septin inhibition upon combined BRAF and MEK blockade.
• Fibroblasts engineered to bleb exhibit anoikis resistance similar to cancer cells, even without oncogenic mutations.

Conclusions:

• Plasma membrane blebs function as signaling organelles that confer anoikis resistance by organizing pro-survival pathways.
• Blebbing is essential for the oncogenic function of mutant NRAS.
• Targeting bleb-mediated signaling presents a potential therapeutic strategy for cancers, particularly in combination therapies.
• Blebs can confer anoikis resistance independently of oncogenic mutations, highlighting their fundamental role in cell survival.