Delineating the role of membrane blebs in a hybrid mode of cancer cell invasion in three-dimensional environments

Abstract

The study of cancer cell invasion in 3D environments in vitro has revealed a variety of invasive modes, including amoeboid migration, characterized by primarily round cells that invade in a protease-and adhesion-independent manner. Here, we delineate a contractilitydependent migratory mode of primarily round breast cancer cells that is associated with extensive integrin-mediated extracellular matrix (ECM) reorganization that occurs at membrane blebs, with bleb necks sites of integrin clustering and integrin-dependent ECM alignment. We show that the spatiotemporal distribution of blebs and their utilization for ECM reorganization is mediated by functional β1 integrin receptors and other components of focal adhesions. Taken together, the work presented here characterizes a migratory mode of primarily round cancer cells in complex 3D environments and reveals a fundamentally new function for membrane blebs in cancer cell invasion.

Actin Remodeling Defects Leading to Autoinflammation and Immune Dysregulation

“…The local concentration of the complement system C3 fraction also contributes to this process ( 63 ). However, in 3D environment, the blebbing motility seems the more common migratory strategy of blood cells ( 64 , 65 ). Stop-codon variants of the CDC42 gene has been recently associated with a novel autoinflammatory disease characterized by neonatal-onset of cytopenia, rash, and hemophagocytosis (NOCARH), successfully treated with interleukin-1β inhibition (no.…”

Proteolysis-free cell migration through crowded environments via mechanical worrying

“…4 Although under some conditions amoeboid cells secrete matrix metalloproteinases (MMPs), 18 amoeboid migration is not usually considered a proteolytic migration mode, and so it has been generally assumed that these tunnels were pre-formed by 'helper' cells moving in a mesenchymal manner, a migration mode in which the extracellular matrix (ECM) is degraded via MMPs. 4 Despite the notion that amoeboid cells cannot remodel their environment to generate their own paths and thus would be forced to immobility in a very dense microenvironment, blebbing cells in soft extracellular matrices have been observed to physically manipulate fibers, pushing them out of their way 19 and tugging on them with adhesions, 20 suggesting the possibility of an amoeboid migration mode enabled by matrix remodeling.…”

Blebs Promote Cell Survival by Assembling Oncogenic Signaling Hubs

“…In these poorly attached states, cells often adopt rounded morphologies and form small hemispherical plasma membrane protrusions called blebs [6][7][8][9][10][11][12][13] . Bleb function has long been investigated in the context of amoeboid migration but is far less deeply examined in other scenarios [14][15][16][17][18][19] . Here we show by quantitative subcellular 3D imaging and manipulation of cell morphological states that blebbing triggers the formation of membrane-proximal signaling hubs that initiate signaling cascades leading to anoikis resistance.…”