Bioactive sphingolipid metabolites modulate ovarian cancer cell structural mechanics

Abstract

Cancer progression is associated with an increased deformability of cancer cells and reduced resistance to mechanical forces, enabling motility and invasion. This is important for metastases survival and outgrowth and as such could be a target for chemopreventive strategies. In this study, we determined the differential effects of exogenous sphingolipid metabolites on the elastic modulus of mouse ovarian surface epithelial cells as they transition to cancer. Treatment with ceramide or sphingosine-1-phosphate in non-toxic concentrations decreased the average elastic modulus by 21% (p ≤ 0.001) in transitional and 15% (p ≤ 0.02) in aggressive stages while exerting no appreciable effect on non-malignant cells. In contrast, sphingosine treatment on average increased the elastic modulus by 33% (p ≤ 0.0002) in aggressive cells while not affecting precursor cells. These results indicate that tumor-supporting sphingolipid metabolites act by making cells softer, while the anti-cancer metabolite sphingosine partially reverses the decreased elasticity associated with cancer progression. Thus, sphingosine may be a valid alternative to conventional chemotherapeutics in ovarian cancer prevention or treatment.

Changes in membrane sphingolipid composition modulate dynamics and adhesion of integrin nanoclusters

“…Several studies have indicated that Cer formation directly influences cortical actin remodeling by altering the cell biomechanical properties 67 , enhancing the assembly of complexes inducing actin polymerization 68 , decreasing cell spreading capacity in measle virus infected T cells 69 or directly interfering with the interactions between actin and the ERM proteins 70 71 . Future studies should address whether Cer formation has direct effect on the cortical actin in the monocytes, thus contributing to the altered interactions between LFA-1 and cortical actin observed here.…”

Sphingolipid abnormalities in cancer multidrug resistance: Chicken or egg?

“…As sphingosine was quickly degraded, it was postulated that bioactive metabolites ceramide and SM are responsible [203]. In a mouse ovarian cancer progression model, augmented membrane capacitance, altered cell dielectric properties and lower membrane stiffness (characteristics of advanced cancer cells) were reverted to that of early tumor stage cells by nontoxic sphingosine levels [204, 205]. Finally, sphingolipids lowered incidence of aberrant crypt foci (ACF), which are putative preneoplastic lesions in the colon, suppressed cell proliferation and increased adenoma:carcinoma ratio in colon carcinogen-treated mice when they were fed dairy glycosphingolipids [206] and SM [207, 208] through their diet or SphK1, but not SphK2, was deleted [209].…”

Sub-cellular force microscopy in single normal and cancer cells

“…Different research groups have used this approach to introduce cell biomechanical properties as "label-free" biophysical markers to predict cancer risk, cancer progression from benign to aggressive stages [32], and treatment efficacy [33]. Despite promising results, the current trend in single-cell force microscopy does not provide the most comprehensive and information-rich picture of cell biomechanics.…”