Abstract
During development, the behaviour of cells is tightly regulated ensuring optimal functioning of healthy epithelial tissues. Epithelial cells thus establish well organized intercellular junctions, apico/basal polarity, cytoskeletal architecture, and integrate regulatory and homeostatic inputs relayed by dedicated signalling pathways. Alterations in these processes are most often associated with cancer.My lab is interested in deciphering the mechanisms in which junctional and polarity alterations are able to induce tumorigenesis. Scaffold proteins represent important regulators of these different processes, and alterations to several key epithelial scaffolds have been linked to cancer. Recent work in the team identified Magi, a member of the MAGUK family, as a regulator of E-Caherin-based Adherens Junctions during eye development in Drosophila. The main goal of my thesis was to study the function of MAGI1, the most abundant MAGI family member in human tissues, during cancer, and more specifically its roles in luminal A Breast Cancer cells. Using mainly loss-of-function approaches, we were able to identify a tumour suppressive function of MAGI1 in luminal BCa cells both in vitro cellular assays as well as in xenografted nude mice. Moreover, this work revealed that MAGI1 inhibits an AMOTL2/P38 signalling axis that is activated upon MAGI1 loss and then responsible for the enhanced tumorigenicity phenotype obtained. Interestingly, the loss of MAGI1 induced increased myosin activity, increased compressive behaviours, and associated elevated plasma membrane tension, which we propose to be one of the activator of P38 downstream of MAGI1 loss. Strikingly, even though cells lacking MAGI1 showed increased tumorigenicity, the activity of the YAP onco-protein is lowered in MAGI1-deficient luminal breast cancer cells, suggesting that the relationship between YAP and tumorigenesis could be more complex than commonly assumed.The study of Hippo pathway regulations is indeed a major axis of the team. A secondary objective of my thesis was thus to explore the involvement of YAP/TAZ and of the Hippo pathway during Oxaliplatin exposure in colon cancer cells. As first line chemotherapy along with 5 Fluorouracil, it is important to understand the mechanism of action of Oxaliplatin beyond its major role as inducer of deleterious DNA double strand breaks. HCT116 colon cancer cells treated with relatively modest doses of Oxaliplatin (at IC50), featured a translocation of YAP/TAZ to the nucleus accompanied with increased YAP/TAZ-mediated transcription, as judged by qPCR and RNA-Seq. This effect was coupled with a re-organization of the actin cytoskeleton inside the cell upon the treatment, and many genes affected by oxaliplatin treatment were actin regulators (including several that are also potential YAP/TAZ targets). This study involves YAP/TAZ in HCT116 response to Oxaliplatin treatment, and we propose that it leads to actin re-organization.