Project Funding Details

Renal Cell Carcinomas (RCCs) are the seventh most common site for tumour in the world, with more than 140,000 deaths annually. RCCs are heterogenous with different molecular and histological classifications. The most common are clear-cell, papillary and chromophobe RCCs. Metabolic reprogramming is a central feature of these types of cancers, as testified by the numerous mutations within genes regulating cellular metabolism both in sporadic and hereditary forms of RCC. Modelling RCC in the mouse has been challenging, as inactivation of key cancer drivers in the kidney only results in cyst formation. We have inactivated the Tsc1 gene, a master regulator of mTORC1 which is upregulated in the majority of RCCs, in a restricted segment of the renal tubule. Mice develop cysts which progressively transform into papillae, cystadenomas and carcinomas with full penetrance within three months of life. We have shown that constitutive activation of mTORC1 results in profound metabolic alterations including downregulation of the TCA cycle enzyme fumarate hydratase, and consequently accumulation of the oncometabolite fumarate (Drusian et al, Cell Reports, 2018). In preliminary studies, we now intercrossed the mice with a transgenic line (mT/mG) which results in cells turning green when the Tsc1 gene is inactivated. scRNAseq of these kidneys reveal the co-existance of progressively transforming cells, having clear signatures of papillary RCC. We also identify progressively increasing metabolic alterations; we identify markers for each population; and we identify one enzyme which is upregulated and a promising target for therapy. Based on these new evidences we have outlined in this grant proposal three broad workpackages: WP#1. Complete the characterization of the progressive transformative events in RCC. WP#2. Exploratory identification and validation of targets for therapy. WP#3. Translating the results to the human condition. WP#1. We will use spatial transcriptomics and metabolomics as well as cell isolation to complete the characterization of the progressive cancerous lesions and to study the role of non-cell autonomous changes occurring in the tumor microenvironment. WP#2. We will test inhibitors of a first candidate for therapy and perform a robust high content screening to identify new vulnerabilities in these cancers. WP#3. We will validate some of our findings and markers identification into human samples, optimize the animal models as to be able to observe metastatic cancer and work towards definition of the cell of origin of pRCC. - We expect to be able to define the trajectory of events occurring from a normal epithelium to the gradual transformation into carcinoma. - We will also identify new vulnerabilities in these cancers and test novel therapeutic targeted approaches to defeat the transforming cells. - We expect to identify novel markers for these cancers in humans, and possibly to identify the cell of origin of papillary RCC. Our results will allow to shed new light on a specific subtype of renal cancer, papillary RCC which is poorly defined. In addition, the results will likely be relevant for other RCCs and possibly for other types of cancer.