Periodic Reporting for period 4 - INTRAHETEROSEQ (Molecular characterization of the role of intra-tumor heterogeneity in cancer progression and metastasis) Reporting period: 2019-11-01 to 2020-10-31 Summary of the context and overall objectives of the project Cancer is produced by the progressive accumulation of mutations in the DNA of the cells. The characterization of these mutations has been very helpful in the past to identify genes and molecular pathways involved in tumour progression. This knowledge has been successfully used in many cases to design specific treatments that have improved very significantly the treatment of specific tumour types.Besides these improvements, cancer continues causing around 1.7 million deaths in Europe every year, it is estimated that more than 90% are due to the direct or indirect effects of metastasis, secondary tumours produced in different organs from the original primary tumour.Recent experiments have proved that tumours are composed of different cell populations, some of them very minoritory, molecularly distinct from the rest of the tumour and it is hypothesized that are these minority populations the origin of the treatment resistant tumours or the mestastasis.In the present project, we have designed a new experimental strategy in mouse models to identify, separate and study independently those minority populations in order to understand which they have different that allows them to be metastatic. The overall goal is to understand the molecular basis of the metastatic potential in order to improve cancer treatment in patients. Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far During this first period of the project, we have focussed our efforts to develop new molecular tools not available at the beginning of the project. For that we have generated a new modified genetic allele that allow the identification of minority clones inside the mouse tumours. We have tested this allele in vitro and have started the first experiments in vivo. At the same time we have developed and validated a mouse model of pancreatic model which generates pancreatic tumours molecularly and astrologically similar to those observed in human patients. We have seen that these tumours, similarly to what happen in humans, are highly heterogeneous and metastatic, producing metastasis in the same organs (liver and lung) which are frequently affected by human cancer metastasis. Accordingly to these results, we have seen that our mouse models will be useful to study the role of these minority populations in tumour progression and metastasis. 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) In this first period of the project we have generated a new mouse modified allele that significantly improved the labelling of minority clones inside of mouse tumours compared to the previously designed strategies. This will allow us for first time the independent molecular study of these populations. Additionally, we have characterize our pancreatic mouse model beyond the knowledge published until know, describing that the metastatic potential is not dependent in a germinal p53 deficiency and that the tumours are genetically heterogeneous. Therefore, we have confirmed that this mouse model will be useful to study intratumour heterogeneity and its role in tumour progression and metastasis. Project summary.
