Role of YAP/TAZ on Circulating Tumour Cells

Project Information

RYTAC

Grant agreement ID: 101028567

DOI

10.3030/101028567

Project terminated on 31 March 2023

EC signature date 23 March 2021

Start date 1 June 2021

End date 31 May 2023

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 191 149,44

EU contribution

€ 191 149,44

Coordinated by

EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH
Switzerland

Periodic Reporting for period 1 - RYTAC (Role of YAP/TAZ on Circulating Tumour Cells)

Reporting period: 2021-06-01 to 2023-05-31

Summary of the context and overall objectives of the project

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.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

The results from this MSCA postdoctoral fellowship were disseminated in many and different ways.

First, this fellowship resulted in the following publications that include a reference to EU funding in the Acknowledgment sections.:
1. Zoi Diamantopoulou et., The metastatic spread of breast cancer accelerates during sleep. Nature, 2022 (https://doi.org/10.1038/s41586-022-04875-y).
2. Zoi Diamantopoulou et al., A new time dimension in the fight against metastasis. Trends in Cell Biology, 2023 (https://doi.org/10.1016/j.tcb.2023.02.002).


Additionally, the publication was posted in several social media such as the LinkedIn and Twitter account of the ETH.
Furthermore, several scientific journals wrote commentaries about this publication such as:
1. Breast cancer cells are more aggressive during sleep K. Irving, Science 2022
2. More of a nightmare: metastasis accelerates during sleep. I. Bakoyiannis, Lab Animal 2022
3. Dissemination of circulating tumor cells at night: role of sleep or circadian rhythm? Y. Dauvilliers et al., Genome Biology, 2022
4. While the Body Rests, Breast Cancer Spreads More Aggressively. A. Manjarrez, The Scientist, 2022
5. Cancer cells spread affressively during sleep. Ball H and Nagrath S. Nature 2022
6. To sleep, perchance to spread. Dart A. Nature Reviews Cancer, 2022
7. Sleep spreads metastasis. Attwaters M, Nature Cancer, 2022

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

This MSCA postdoctoral fellowship had a strong impact on my career development. Through this prestigious fellowship, I expanded and strengthen my scientific expertise in the cancer metastasis field, focusing particularly on the biology of the Circulating Tumour Cells (CTCs). The in-depth knowledge that I gained during this fellowship enabled me to delve into the intricacies of CTCs, broadening my understanding and contributing to the advancement of this critical area of research. In addition to expanding my scientific expertise, this fellowship enhanced my transferrable skills. I learnt to recognise and tackle challenges and effectively redirecting research projects to achieve successful outcomes without waste of resources. Furthermore, I improved my time management skills and I boosted my daily productivity. The results of these efforts became evident when I published the results of the new project in the prestigious journal, Nature, before the end of the fellowship. Moreover, during this fellowship, I enhanced my leadership skills by supervising the work of one MSc student (Milena Wild) and two PhD students (Ece Su Ildiz and Simran Asawa). Importantly, building upon the success and expertise gained through the MSCA fellowship, I created a unique and competitive research niche and I successfully transitioned to the next phase of my career as a Junior Group Leader position at the prestigious CRUK Beatson Institute. This accomplishment stands as a statement to the impact of the fellowship on my career path.
In parallel with the profound impact on my career development, this fellowship brought significant benefits to society as well. During this fellowship, I made the ground-breaking discovery that the metastatic spread of breast cancer occurs during sleep. By analysing blood samples from breast cancer patients and mouse models, I revealed that the CTCs are not generated constantly throughout the day, but instead their intravasation follows an oscillation pattern with high CTC numbers observed during the rest phase of the circadian rhythm (night for human, day for rodents). These findings have a profound influence on the scientific community, opening new directions in the field of cancer research, advancing our knowledge on the biology of metastasis and bringing us closer in developing effective anti-metastatic therapies. Furthermore, these findings can have the potential to make a strong impact on the civil society if implemented in daily clinical routines. By collecting blood samples at the time of the day of high CTCs numbers, a different prognosis can be established, leading to the administration of more effective therapies that could impact the overall outcomes for cancer patients. Importantly, these results can also have a strong impact on policy making and devising the strategy for developing more accurate cancer prognostic systems. Therefore, the results of this fellowship contribute directly towards the European policy objectives by promoting scientific progress and the well-being of its citizens. The dissemination of these results through press releases, social media and interviews (as detailed in the section below) represents the first step towards reaching the intended audience.
Overall, this MSCA postdoctoral fellowship has had a profound impact on my career development, made significant contributions to the field of cancer research and has the potential to improve patient outcomes, decrease the cancer-related mortality rates and reduce the burden of cancer on society.

Model of how circadian rhythm regulates metastasis