ICC 2021

Mauriane Maja

Mauriane Maja, Speaker at Cancer Congress
de Duve Institute, UCLouvain, Belgium
Title : Role of Membrane Cholesterol in Breast Cancer Cell Invasion

Abstract:

Breast cancer mortality is almost exclusively due to metastatic disease. Better molecular characterization of the primary tumor is therefore crucial for a good prediction of the clinical outcome. Breast cancer cells are characterized by aberrant lipid accumulation and metabolism. However, how those changes influence plasma membrane biophysical properties and cell invasion is not understood. Taking benefit from our expertise in membrane lipid imaging and biophysics, the goal of the present study is to evaluate whether and how plasma membrane cholesterol composition and distribution contribute to breast cancer cell invasion.
Using the malignant MCF10CAIa, the pre-malignant MCF10AT and the normal human mammary epithelial MCF10A cells which offer the same background, we showed that, as compared to normal and premalignant cells, malignant cells exhibit (i) a decreased cytocortex stiffness, (ii) an increased plasma membrane stiffness, (iii) a higher cholesterol content at the cell dorsal face and its distribution in submicrometric lipid domains, and (iv) a higher matrix metalloprotease (MMP)-dependent capacity of oriented invasion through Matrigel towards serum. To explore the potential involvement of cholesterol in cell invasion, cells were partially cholesterol-depleted with methyl-β-cyclodextrin (mβCD). We found a specific inhibition of oriented invasion in the malignant cells, in perfect correlation with the residual cholesterol content. Furthermore, while cholesterol depletion similarly decreased the plasma membrane stiffness of the 3 cell lines, it differentially modulated the cell cholesterol surface distribution in domains and cell:cell contacts in the malignant cells vs the premalignant and normal cells. Moreover, F-actin-enriched cortactin-positive invadopodia structures were specifically found at the ventral surface of malignant cells grown on fibronectin-coated coverslips and cholesterol depletion decreased their abundance and size. Cholesterol depletion also inhibited extracellular matrix degradation, as evidenced by the decreased size and abundance of fluorescent gelatin degradation areas. The level of inhibition was similar to the one observed upon inhibition of MMP activity by GM6001 whereas the combination of mβCD and GM6001 abrogated the effect of drugs alone, suggesting same mechanism of action/target.
Altogether, our data suggest the specific dependence of malignant MCF10CAIa cells to cholesterol surface distribution for invadopodia outgrowth, extracellular matrix degradation and cell invasion. Such dependence was similarly observed for MDA-MB-231, another invasive breast cancer cell line. Our research provides new clues for the understanding of the molecular events underlying cellular mechanisms in breast cancer, a crucial step before the development of novel therapies based on targeting cholesterol in cancer cells to increase sensitivity to chemotherapeutic agents and consequently defeat multidrug resistance.

Biography:

Mauriane Maja studied Biomedical Sciences at the Université Catholique de Louvain, Belgium and graduated as MS in 2018. After a research internship at iTeos Therapeutics where she participated in the development of a new generation of highly differentiated immune-oncology therapeutics, she decided to start a PhD at the de Duve Institute under the supervision of Prof. D. Tyteca (CELL Unit). For the last three years, she has been focusing on the role of plasma membrane lipids in breast cancer cell migration and invasion. She has published a first research article in Advanced Science

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