RYTAC · Role of YAP/TAZ on Circulating Tumour Cells
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2021-06-01 → 2023-05-31
- EU contribution
- €191,149
- Participants
- 1
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
Role of YAP/TAZ on Circulating Tumour Cells
The metastatic spread of cancer is achieved by the haematogenous dissemination of circulating tumour cells (CTCs). However, the temporal dynamics that dictate the generation of metastasis-competent CTCs are largely uncharacterized and it is often assumed that CTCs are constantly shed from growing tumours. The goal of this MSCA fellowship was to determine the factors controlling the generation of CTCs. By analysing samples from breast cancer patients and mouse models, I made the ground-breaking discovery that CTCs do not shed from the tumours constantly throughout the day, but instead their intravasation follows a precise oscillation pattern with increased number observed during the rest phase of the circadian rhythm (night for humans, day for rodents). I also demonstrated that rest-phase CTCs are highly prone to metastasize, whereas CTCs generated during the active phase are devoid of metastatic ability. Furthermore, single cell RNA analysis revealed a marked upregulation of mitotic genes exclusively during the rest phase in both patients and mouse models. Finally, I identified that the circadian rhythm regulated hormones, melatonin, testosterone, glucocorticoids and insulin play a key role in the generation of CTCs. Together, the results of this MSCA fellowship leaded to following model of how circadian rhythm regulates metastasis: the daily oscillation of the circadian rhythm regulated hormones melatonin, testosterone, glucocorticoids and insulin regulate the proliferation status of the primary tumour. During the rest phase of the circadian rhythm the primary tumours are more proliferative and this results in increased intravasation and high numbers of CTCs that are more prone to successfully establish metastasis. These results make significant contributions to the field of cancer research as they provide a new rationale for time-controlled interrogation and treatment of metastasis-prone cancers and therefore have the the potential to improve patient outcomes, decrease the cancer-related mortality rates and reduce the burden of cancer on society.
Data: CORDIS, © European Union
Project 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.
Original text from CORDIS.
Participants
- EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH · ZuerichCoordinatorSwitzerland
Links
Data: CORDIS, © European Union