Spatiotemporal regulation of metastatic breast cancer cell fate

forthcoming

Breast cancer is the most common malignancy in women with globally over 600’000 deaths per year. While cancer diagnosis before metastasis is often associated with a favourable prognosis, due to surgical and new therapeutic approaches, once metastasis is initiated, the survival rates decline significantly. However, the understanding of this last and most detrimental phase of cancer remains at a low resolution, reflected by the lack of metastasis-targeted therapeutic options. In fact, most of the studies have focused on the understanding of primary tumour states and their relationship to metastasis. Recently, it has emerged, however, that secondary seeding from metastatic deposits to new sites plays a role in cancer spread. We made an unexpected discovery that the cancer cells metastasised to different sites display dramatically distinct molecular and functional properties, thereby having diverse impacts on cancer progression. This highlights a previously underappreciated role of secondary seeding and emphasises the need to study metastasis at a higher resolution. Indeed, metastasis is an evolutionary process that occurs across various organs and timescales, yet its spatiotemporal progression is a black box. To this end, we will use cutting-edge technologies such as evolving barcodes and niche-labelling systems and state-of-the-art in vivo models to identify 1) different spatiotemporally controlled metastatic behaviours, together with 2) the associated alterations in the metastatic niche and 3) specific niche-cancer crosstalk that guides the cancer expansion and metastatic properties. This project will create a first spatiotemporal cellular model of metastasis, which will reveal how the metastatic behaviour at different sites is shaped during metastatic progression. Our research has a long-term ambition to design new therapeutic approaches informed by the metastatic profile and temporal biomarkers in patients.