Pharmacological targeting of membrane rigidity: implications on cancer cell migration and invasion

Abstract

The invasive potential of cancer cells strongly depends on cellular stiffness, a physical quantity that is not only regulated by the mechanical impact of the cytoskeleton but also influenced by the membrane rigidity. To analyze the specific role of membrane rigidity in cancer progression, we treated cancer cells with the Acetyl-CoA carboxylase inhibitor Soraphen A and revealed an alteration of the phospholipidome via mass spectrometry. Migration, invasion, and cell death assays were employed to relate this alteration to functional consequences, and a decrease of migration and invasion without significant impact on cell death has been recorded. Fourier fluctuation analysis of giant plasma membrane vesicles showed that Soraphen A increases membrane rigidity of carcinoma cell membranes. Mechanical measurements of the creep deformation response of whole intact cells were performed using the optical stretcher. The increase in membrane rigidity was observed in one cell line without changing the creep deformation response indicating no restructuring of the cytoskeleton. These data indicate that the increase of membrane rigidity alone is sufficient to inhibit invasiveness of cancer cells, thus disclosing the eminent role of membrane rigidity in migratory processes.

Optical stretching in continuous flows

“…We designed the setup in a minimalistic approach to change as few parameters as possible to keep the systems comparable. In this regard, we used the same lasers, optical fibers, and reservoirs as in previous studies concerning cancer research [4,8,39,59,60], various research questions of single cell rheology [38,40,41,61,62], and the principle of the Optical Stretcher as an optical rheometer for living cells [36,37,50]. The microfluidic surroundings have been adopted as far as possible, keeping the channel dimensions and path lengths, as well as flow velocities and pressure in the same order of magnitude.…”

“…This non-invasive high throughput measurement is fully automatized and has led to valuable insights for cancer research. It has been utilized in the analysis of primary cancer samples [3,4], cell line models for the malignant transformation [2] and the influence of drugs and other interferences with the metabolism of cancer cells [8,[37][38][39] and has even led to the development of the completely novel approach of thermorheology of living cells [40,41]. The possibility to measure several hundred cells within hours gives a huge statistical advantage that balances out the broad distribution of properties in biological specimen.…”

Are cancer cells really softer than normal cells?

“…Softening of the plasma membrane was also reported recently in breast and cervical cancer cells using fluctuation analysis of membrane blebs or of giant plasma membrane vesicles (Händel et al., ). Conversely a pharmacological inhibitor that increases membrane rigidity also decreases invasiveness of a mammary carcinoma cell line (Braig et al., ). Interestingly, thermal noise is not the only source of membrane shape fluctuations and active non‐equilibrium energy‐dependent forces are thought to enhance such fluctuations (Tuvia et al., ; Manneville et al., ; Betz et al., ; Boss et al., ; ).…”

Anti-metastatic functions of type 1 interferons: Foundation for the adjuvant therapy of cancer

“…These reports suggest that IFN1 and IFNAR interaction affects the actin-cytoskeleton organization (perhaps contributing to IFN1-mediated inhibition of cell proliferation and cell migration). Increasing the rigidity of the plasma membrane with reagents, such as the Acetyl-CoA carboxylase inhibitor Soraphen A, has been shown to diminish cancer cell migration and invasion [82]. In the case when cancer cells evolve to suppress IFN1 signaling, treatment with reagents to increase membrane rigidity may increase cancer cell death in circulation.…”