Role of ZEB factors in macrophages in atherosclerosis and ovarian cancer
[eng] Macrophages polarization from an inflammatory to a tolerogenic state occurs in both physiological and pathological, and this reprogramming is key in the development of several diseases as different as atherosclerosis or cancer. The results presented in this dissertation indicate that a) ZEB1 e...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2021 |
| País: | España |
| Institución: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/179898 |
| Acceso en línea: | https://hdl.handle.net/2445/179898 http://hdl.handle.net/10803/672363 |
| Access Level: | acceso abierto |
| Palabra clave: | Macròfags Arterioesclerosi Oncologia Macrophages Arteriosclerosis Oncology |
| Sumario: | [eng] Macrophages polarization from an inflammatory to a tolerogenic state occurs in both physiological and pathological, and this reprogramming is key in the development of several diseases as different as atherosclerosis or cancer. The results presented in this dissertation indicate that a) ZEB1 expression in macrophages inhibits atherosclerotic plaque formation and b) ZEB1 expression in macrophages promotes ovarian cancer tumor progression while ZEB2 expression inhibits it. ZEB1 inhibits lipid accumulation in macrophages through increased cholesterol efflux thus protecting mice from atherogenesis. Accordingly, Zeb1∆Mac mice fed with pro-atherogenic diet have a higher plaque size and higher lipid content compared to Zeb1WT counterparts. Mechanistically, ZEB1 is required for the activation of the AMPK-LXRα-ABCA1/G1 pathway, which is critical for cholesterol efflux and anti-inflammatory switch in macrophages. Besides, ZEB1 is a mediator of macrophage activation by ox-LDL through p65. In regard to ovarian cancer, we show that ZEB1 and ZEB2 in TAMs have an opposite role in ovarian cancer initiation and progression. Expression of ZEB1 in TAMs promotes tumorigenesis and ZEB2 inhibits it. Zeb1∆Mac TAMs exhibited lower adhesion with tumor cells and increased phagocytosis while Zeb2∆Mac TAMs have increased PD-1 and promote PD-L1 overexpression in ID8 cells. Moreover, ZEB1 expression in TAMs stimulates stem-like characteristics in ID8 cancer cells while ZEB2 inhibits this phenotype thus promoting enhanced survival in tumor-bearing Zeb1∆Mac mice and decreased survival in Zeb2∆Mac counterparts. These results established ZEB1 as a protector of the cardiovascular system from atherosclerosis development. On the other hand, ZEB1 and ZEB2 are tumor-promoting and tumor-repressor factors in ovarian cancer, respectively, through their regulating of the functions of the TAMs. Altogether, the present dissertation sets ZEB1 and ZEB2 in macrophages as a potential therapeutic target in both pathologies. |
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