Insertional mutagenesis to identify molecular mechanisms of breast cancer dormancy and metastasis

Informations projet

PB_dormancy

N° de convention de subvention: 838472

DOI

10.3030/838472

Projet clôturé

Date de signature de la CE 5 Avril 2019

Date de début 1 Mars 2020

Date de fin 28 Février 2022

Financé au titre de

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Coût total

€ 172 932,48

Contribution de l’UE

€ 172 932,48

Coordonné par

FUNDACION PUBLICA ANDALUZA PROGRESO Y SALUD M.P.
Spain

Periodic Reporting for period 1 - PB_dormancy (Insertional mutagenesis to identify molecular mechanisms of breast cancer dormancy and metastasis)

Période du rapport: 2020-03-01 au 2022-02-28

Résumé du contexte et des objectifs généraux du projet

Metastatic disease is the leading cause of cancer deaths, yet our understanding of this process and therapeutic choices are limited. Although most breast cancer patients do not present with metastases at diagnosis, a significant number succumb to disseminated disease years after the treatment of the primary tumour. Disseminated tumour cells have frequently been observed at early stages of breast cancer suggesting that late disease recurrence may result from tumour cells that have remained dormant for decades. These surviving cells may lay dormant or be triggered to proliferate and establish metastatic lesions after a variable period of time. The mechanisms through which dormant tumour cells survive in the cancer patients for long periods of time are unknown for the most part and therefore, the therapeutic choices against these specific tumour cells are virtually inexistent. Along the same line, our knowledge of the mechanisms that trigger the “awaking” of these cells to form a metastasis that threaten the live of the patients are also limited. The_PB-dormancy project focuses on the study of the molecular mechanisms participating in the maintenance of tumour dormancy and the transition to a proliferative state to form a metastasis, aiming to gain insights into these processes with the overall objective to design new therapeutic approaches that improve the quality of life and life expectancy of cancer patients.
The overall objective of the action was to identify genes that regulate breast cancer cell dormancy and the dormant-to-proliferative switch and to develop biotools for the study of BC cell dormancy and metastasis. To achieve this objective, we propose two well-defined specific Aims:
- Aim 1: Discover and functionally validate gene(s) that are critically involved in maintaining the dormant state of breast cancer cells at metastatic sites or that activate the dormant-to proliferative switch
- Aim 2: Generate new and improved in vitro and in vivo model systems to study breast cancer cell dormancy and metastasis.
Aim 1 and Aim 2 have been completed throughout the action and, therefore, we now count on new breast cancer dormancy model systems to further investigate the molecular mechanisms governing tumor cell dormancy and metastasis. In addition, we have identified a new molecular mechanism involving the regulation of a process termed ‘autophagy”, which is essential for the survival of dormant breast cancer cells.
Being breast cancer the most incident cancer in women worldwide and the second cause of death because of cancer, improving the treatment of this disease has an invaluable societal and economical importance for Europe and the rest of the world.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

The PB_dormancy project has been successfully implemented and has come into fruition during the grant period, which corresponds to the last 24 months (March 2020-February 2022), although the reporting period matches the highest restriction period imposed by the COVID-19 pandemics Major experimental objectives of the research plan have been fulfilled as we have generated and validated new in vivo and in vitro model systems to study breast cancer dormancy, which we are extensively using to further develop the main research line in which I have focused my career as an independent researcher. In addition, we have functionally validated the role of our two genes of interest in the maintenance of breast cancer cell dormancy and the dormant-to-proliferative switch and continue working in this line to further characterize the molecular signaling pathways governing tumor cell dormancy and the translation of this information into the clinical practice. In the frame of this research project, we have initiated a formal collaboration with the Department of Pathology and the Department of Oncology of the University Hospital of Jaen to evaluate the expression of our markers of interest in breast cancer tissue samples from defined clinical cases.
With respect to the training and the Personal Career Development Plan that has been developed in the frame of this grant, I have reached scientific independence through the securement of a tenure-track position in the University of Granada. By the end of the MSCA-IF grant I have recruited and contracted through specific funding granted to this end, a laboratory assistant and a PhD student, who form part of the emerging research team which I now direct as a Principal Investigator. Therefore, through the completion of the research program and training plan presented in the PB_dormancy application to the MSCA-IF call, I have fulfilled not only my research goals but also my mid-term career goals.
Finally, regarding the “proposed measures to exploit and disseminate the project results” it is worth to mention the extraordinary difficulties that have had to be overcome to complete this part of the action because of the COVID19 pandemic. Despite these difficulties, I have participated as a speaker in the 2020 (virtual) and 2021 (on-site) editions of the European Researcher’s night, delivering outreach conferences in the European Corner. I have also participated as a speaker in informal outreach meetings and talks about the scientific career with high school students in the “Café con Ciencia” activity organized by the host institution (FPS) and participated in science activities with primary school students. Lastly, I have collaborated with local press media to divulgate “how a scientist career is made”.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

One of the major milestones of the PB_dormancy project has been the generation of three new cell lines which differ in their dormant phenotype. In addition, we have generated a new genetic-engineered mouse model which will also serve as an invaluable tool for the advancement of our understanding of the molecular mechanisms regulating tumor dormancy and metastasis. Given the extreme scarcity of tumor dormancy models available to the scientific community, these new in vitro and in vivo models are extremely valuable. These new tools are being tested and validated in our laboratory through an experimental approach that aims to investigate the role of specific markers in the activation of autophagy, a known survival mechanism in dormant tumor cells, and the invasion capacity of cells which have undergone the dormant-to-proliferative transition. Both the new model systems generated, as well as the new data obtained regarding the regulation of autophagy and invasion in disseminated tumor cells are of utmost importance to the advancement and improvement of breast cancer therapy and the therapy of other cancer types. Given the very high incidence of the neoplastic diseases, both inside and outside Europe, improving the clinical outcome of cancer patients has a deep social impact but also a deep economic impact, as the amount of economic resources devoted to cancer healthcare is enormous, but the benefit in terms of wellbeing is moderate.

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