Targeting cholesterol impairs cell invasion of all breast cancer types
Abstract Background Breast cancer clinical outcome relies on its intrinsic molecular subtype and mortality is almost exclusively due to metastasis, whose mechanism remains unclear. We recently revealed the specific contribution of plasma membrane cholesterol to the invasion of malignant MCF10CAIa bu...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2024-01-01
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| Series: | Cancer Cell International |
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| Online Access: | https://doi.org/10.1186/s12935-023-03206-z |
| _version_ | 1797355485042573312 |
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| author | Mauriane Maja Marie Verfaillie Patrick Van Der Smissen Patrick Henriet Christophe E. Pierreux Nor Eddine Sounni Donatienne Tyteca |
| author_facet | Mauriane Maja Marie Verfaillie Patrick Van Der Smissen Patrick Henriet Christophe E. Pierreux Nor Eddine Sounni Donatienne Tyteca |
| author_sort | Mauriane Maja |
| collection | DOAJ |
| description | Abstract Background Breast cancer clinical outcome relies on its intrinsic molecular subtype and mortality is almost exclusively due to metastasis, whose mechanism remains unclear. We recently revealed the specific contribution of plasma membrane cholesterol to the invasion of malignant MCF10CAIa but not premalignant MCF10AT and normal MCF10A cell lines in 2D, through invadopodia formation and extracellular matrix (ECM) degradation. In the present study, we address the impact of breast cancer subtypes, mutations and aggressiveness on cholesterol implication in breast cancer cell invasion and 3D spheroid invasion and growth. Methods We used nine breast cancer cell lines grouped in four subtypes matching breast tumor classification. Four of these cell lines were also used to generate 3D spheroids. These cell lines were compared for cell invasion in 2D and 3D, spheroid growth in 3D, gelatin degradation, cortactin expression, activation and subcellular distribution as well as cell surface cholesterol distribution and lipid droplets. The effect of plasma membrane cholesterol depletion on all these parameters was determined in parallel and systematically compared with the impact of global matrix metalloproteinase (MMP) inhibition. Results The six invasive cell lines in 2D were sensitive to partial cholesterol depletion, independently of their subtype, aggressiveness or mutation. Nevertheless, the effect was stronger in the three cell lines able to degrade gelatin. 3D spheroid invasion was also reduced after cholesterol depletion in all breast cancer subtypes tested. Notably, targeting cholesterol was more powerful than MMP inhibition in reducing invasion in both 2D and 3D culture models. Moreover, cholesterol depletion in the six invasive cell lines impaired cortactin distribution in the perinuclear region where invadopodia localized. Breast cancer cell line aggressiveness relied on cholesterol-enriched domains at the ECM-free side and intracellular lipid droplets. Furthermore, the three gelatin-degrading cell lines were characterized by increased cholesterol-enriched submicrometric domains at their ECM-contact side. Conclusion Together, our data suggest cell surface cholesterol combined with lipid droplet labeling as a breast cancer cell aggressiveness marker. They also open the way to test other cholesterol-targeting drugs in more complex models to further evaluate whether cholesterol could represent a strategy in breast cancer therapy. |
| first_indexed | 2024-03-08T14:11:50Z |
| format | Article |
| id | doaj.art-148eabf81f0749c89915c407fde3ee39 |
| institution | Directory Open Access Journal |
| issn | 1475-2867 |
| language | English |
| last_indexed | 2024-03-08T14:11:50Z |
| publishDate | 2024-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Cancer Cell International |
| spelling | doaj.art-148eabf81f0749c89915c407fde3ee392024-01-14T12:37:13ZengBMCCancer Cell International1475-28672024-01-0124111810.1186/s12935-023-03206-zTargeting cholesterol impairs cell invasion of all breast cancer typesMauriane Maja0Marie Verfaillie1Patrick Van Der Smissen2Patrick Henriet3Christophe E. Pierreux4Nor Eddine Sounni5Donatienne Tyteca6CELL Unit and PICT Imaging Platform, de Duve Institute, UCLouvainCELL Unit and PICT Imaging Platform, de Duve Institute, UCLouvainCELL Unit and PICT Imaging Platform, de Duve Institute, UCLouvainCELL Unit and PICT Imaging Platform, de Duve Institute, UCLouvainCELL Unit and PICT Imaging Platform, de Duve Institute, UCLouvainLaboratory of Tumor and Development Biology, GIGA-Cancer, University of LiègeCELL Unit and PICT Imaging Platform, de Duve Institute, UCLouvainAbstract Background Breast cancer clinical outcome relies on its intrinsic molecular subtype and mortality is almost exclusively due to metastasis, whose mechanism remains unclear. We recently revealed the specific contribution of plasma membrane cholesterol to the invasion of malignant MCF10CAIa but not premalignant MCF10AT and normal MCF10A cell lines in 2D, through invadopodia formation and extracellular matrix (ECM) degradation. In the present study, we address the impact of breast cancer subtypes, mutations and aggressiveness on cholesterol implication in breast cancer cell invasion and 3D spheroid invasion and growth. Methods We used nine breast cancer cell lines grouped in four subtypes matching breast tumor classification. Four of these cell lines were also used to generate 3D spheroids. These cell lines were compared for cell invasion in 2D and 3D, spheroid growth in 3D, gelatin degradation, cortactin expression, activation and subcellular distribution as well as cell surface cholesterol distribution and lipid droplets. The effect of plasma membrane cholesterol depletion on all these parameters was determined in parallel and systematically compared with the impact of global matrix metalloproteinase (MMP) inhibition. Results The six invasive cell lines in 2D were sensitive to partial cholesterol depletion, independently of their subtype, aggressiveness or mutation. Nevertheless, the effect was stronger in the three cell lines able to degrade gelatin. 3D spheroid invasion was also reduced after cholesterol depletion in all breast cancer subtypes tested. Notably, targeting cholesterol was more powerful than MMP inhibition in reducing invasion in both 2D and 3D culture models. Moreover, cholesterol depletion in the six invasive cell lines impaired cortactin distribution in the perinuclear region where invadopodia localized. Breast cancer cell line aggressiveness relied on cholesterol-enriched domains at the ECM-free side and intracellular lipid droplets. Furthermore, the three gelatin-degrading cell lines were characterized by increased cholesterol-enriched submicrometric domains at their ECM-contact side. Conclusion Together, our data suggest cell surface cholesterol combined with lipid droplet labeling as a breast cancer cell aggressiveness marker. They also open the way to test other cholesterol-targeting drugs in more complex models to further evaluate whether cholesterol could represent a strategy in breast cancer therapy.https://doi.org/10.1186/s12935-023-03206-zCholesterol submicrometric domainsBreast cancer cell linesMatrigel invasion3D spheroid growth3D spheroid invasionLipid droplets |
| spellingShingle | Mauriane Maja Marie Verfaillie Patrick Van Der Smissen Patrick Henriet Christophe E. Pierreux Nor Eddine Sounni Donatienne Tyteca Targeting cholesterol impairs cell invasion of all breast cancer types Cancer Cell International Cholesterol submicrometric domains Breast cancer cell lines Matrigel invasion 3D spheroid growth 3D spheroid invasion Lipid droplets |
| title | Targeting cholesterol impairs cell invasion of all breast cancer types |
| title_full | Targeting cholesterol impairs cell invasion of all breast cancer types |
| title_fullStr | Targeting cholesterol impairs cell invasion of all breast cancer types |
| title_full_unstemmed | Targeting cholesterol impairs cell invasion of all breast cancer types |
| title_short | Targeting cholesterol impairs cell invasion of all breast cancer types |
| title_sort | targeting cholesterol impairs cell invasion of all breast cancer types |
| topic | Cholesterol submicrometric domains Breast cancer cell lines Matrigel invasion 3D spheroid growth 3D spheroid invasion Lipid droplets |
| url | https://doi.org/10.1186/s12935-023-03206-z |
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