Project description
Molecular players of cancer metastasis
Cancer cells have the remarkable ability to travel through the blood stream or the lymphatic system to distant tissues and cause metastases. Clusters of circulating tumour cells (CTCs) are usually responsible for metastasis formation, but little is known on how their size impacts their metastatic potential. The EU-funded RYTAC project will investigate the dynamics of CTC clusters and especially the role of the YAP and TAZ proteins, transcriptional coactivators with opposing roles in various cellular functions. Researchers will delineate the localisation of these proteins in CTC clusters and its association with metastatic lesions. Project findings will have a significant impact on the clinical management of cancer and the design of targeted treatments.
Objective
Metastasis is the leading cause of all cancer-related deaths. Circulating Tumour Cells (CTCs) are cancer cells that shed off the primary tumour, enter into blood vessels and through the blood circulation are transferred to distant organs, whereby they establish new metastatic lesions. CTCs are detected as single cells and/or clusters of cells with clusters being more metastasis-prone than single CTCs. CTC clusters have different sizes varying from 2- to 50-cells. However, it still remains unknown if the different size of CTCs has an impact on their metastatic potential and what factors regulate their size. To elucidate the molecular dynamics of clustered CTC formation, we performed RNA-seq analysis in cells from primary tumours and CTCs and identified the YAP/TAZ gene signature to be upregulated in CTCs. YAP/TAZ is an interesting molecular node, as its function depends on its subcellular localisation. Junctional localised YAP/TAZ inhibits cancer cell dissemination by supporting the maintenance of cell-cell adhesions, while nuclear YAP/TAZ induces a genetic program that promotes cancer progression. We hypothesised that YAP/TAZ could play a critical role on CTC biology, regulating the size and metastatic potential of CTCs. Thus, the aim of this fellowship is to determine the impact of the size of clustered CTCs on establishing metastatic lesions and provide mechanistic insight on the role of YAP/TAZ. More specifically, I will determine: 1) the localisation of YAP/TAZ in CTCs from mouse models and patients with breast cancer, 2) if YAP/TAZ affects the size of clustered CTCs in breast cancer mouse models, 3) if YAP/TAZ localisation affects the metastatic potential of CTC clusters of variable sizes and 4) signals regulating the nucleocytoplasmic shuttling of YAP/TAZ in CTCs. Hence, this research could be the foundation for developing novel anticancer therapies and an improved patient stratification system.
Fields of science
Programme(s)
Funding Scheme
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinator
8092 Zuerich
Switzerland