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

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

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.

Data: CORDIS, © European Union