Using patient-led genetics to identify new therapeutic targets in metastatic cholangiocarcinoma

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Cholangiocarcinoma (CCA) includes a heterogeneous group of malignancies that can emerge at every point of the biliary tree. Incidence (~5:100,000) is rising worldwide and CCA already represents the second most frequent primary liver tumour and ~3% of all gastrointestinal cancers. Noteworthy, a 37% increase in deaths were registered in Europe in the past two decades, which makes CCA a major health, social and economic burden. CCA is generally asymptomatic in early stages and is commonly diagnosed in advanced phases, when the majority of patients have metastatic disease. This circumstance extremely compromises the potential curative options mainly based on surgery or liver transplantation and clearly impacts on all the health systems worldwide. Moreover, the high risk of tumour recurrence and the elevated chemoresistance of CCAs contribute to poor prognosis. The first line chemotherapy includes the combination of gemcitabine and cisplatin, which is palliative and solely increases patients overall survival in 12 months. The etiopathogenesis of CCA remains largely unknown. At the molecular level, CCA is a genetically heterogeneous disease and whilst a small number of driver-mutations have been found, one-third of patients do not contain therapeutically actionable mutations and for the remaining two-thirds that do, targeted therapies against these mutations have limited efficacy. The proposed work will examine the molecular basis of metastatic CCA and determine how genetic diversity in CCA sculpts a diverse tumour microenvironment. Using whole exome sequencing candidate "metastatic driver" mutations in CCA patient-derived circulating tumour cells (CTC) will be identified. An innovative in vivo CRISPR screening method to generate primary tumours containing mutations in "metastatic drivers" in the mouse will be performed, and the potential of these drivers to initiate CCA metastasis in vivo will be assessed. We will use the information here to identify how distinct mutations affect the interactions between cancer cells and the tumour microenvironment, and ultimately allow a tumour to become permissive to metastasis. This work should substantially increase our understanding of the functional genetics in CCA, as well as the likely identification of novel target pathways for future therapeutic development in metastatic CCA with diverse genomic profiles. Furthermore, it is expected to identify broadly applicable principles of metastasis that can be tested in other cancers. Ultimately, by understanding how genetic changes interact to shape the architecture of a tumour, we will be better placed to modulate these processes for therapeutic benefit.