Kidney cancer is among the 10 most frequently diagnosed cancers and its incidence is rising1. Clear cell Renal Cell Cancer (ccRCC), the most common subtype accounts for 75% of all cases.
The Cancer Genome Atlas has defined the mutational landscape of ccRCC and have identified loss of the short arm of chromosome 3 and mutations in the VHL gene as the most common alteration in kidney cancer cells. This is followed by mutations of other genes, like PBRM1, SETD2 and BAP1. Tracking Renal Cell Cancer Evolution through therapy (TRACERx Renal) is a multi-center, longitudinal cohort study and evaluates how heterogeneous tumours are and how they have evolved over time. TRACERx has identified 7 subtypes of how tumours evolve and these associate with the clinical behaviour of ccRCC. Tumours with low heterogeneity rapidly progressed to multiple tissue sites. Tumours with high ITH showed attenuated progression, and metastatic capacity evolved gradually, starting with a solitary metastasis. Given these regarding the evolutionary subtypes and their association with clinical behaviour, understanding of the functional bases of these patterns is of major interest. Therefore, more faithful in vivo and in vitro models are necessary.
Beside the intrinsic changes in tumour cells, the tumour microenvironment (TME) can have both tumour-promoting and suppressive functions and impact tumour progression. ccRCCs are highly immune infiltrated but in contrast to other solid cancer this is associated with worse prognosis for the patient. The majority of infiltrating immune cells are T cells, some of which show an exhausted phenotype, characterized by upregulation of inhibitory receptors, including PD-1 and CTLA-4, which have also been exploited as therapeutic targets. In advanced and metastatic tumours, infiltration of immunosuppressive macrophages has been described. The importance of the TME is further underlined by the fact that most approved therapies of ccRCC target the TME, either the immune compartments or targeting the blood vessel system. Molecular markers for therapy response are still missing, highlighting the ongoing need understand the underlying mechanisms of therapy response for each evolutionary subtype.
The objectives of this project are:
1. Refine the ordering and clonal resolution in selected cases of the TRACERx Renal Study by micro-biopsy profiling (WP1).
2. Characterise the predictability of evolutionary trajectories will be addressed through repeated passaging of tumour PDOs followed by targeted panel sequencing to detect enrichment of mutations and changes in the clonal composition of organoids (WP2).
3. Analyse the metastatic capacity for metastatic drivers in the context of each evolutionary subtype and define the number of metastatic sites (WP3).
4. Characterise the response rates to immune checkpoint inhibition in PDO co-cultures for each evolutionary subtype (WP4).
5. Test the repeatability of the evolutionary trajectories through experimental manipulation of the genotype combination and sequence in normal kidney organoids (WP5).
