C83
Defects in cell polarity underlie tuberous sclerosis-associated renal cell carcinoma
Cleo Bonnet1, Christopher von Ruhland2, Rebecca Harris1, Richard Sandford3, Jeremy Cheadle1
1Cardiff University, Institute of Medical Genetics, Cardiff, UK, 2Cardiff University, Medical Microscopy Sciences, Cardiff, UK, 3University of Cambridge, Department of Medical Genetics, Cambridge, UK
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by mutations in either TSC1, encoding hamartin, or TSC2, encoding tuberin. TSC is associated with a number of different kidney tumours including renal cell carcinoma (RCC). We have engineered Tsc1+/- mice which develop renal cysts that progress into RCCs. Although hamartin and tuberin have been shown to play a role in the mTOR pathway, we have found that many cysts from Tsc1+/- and Tsc2+/- mice do not show activation of mTOR (as assessed by pS6 staining), suggesting that an mTOR-independent pathway may be involved in tumour initiation. The primary cilium is a key organelle that modulates the planar cell polarity (PCP) pathway and defects in the structure/function of this organelle, with subsequent dysregulation of PCP, underlies numerous disorders associated with cystic kidneys such as polycystic kidney disease (PKD). We have crossed Tsc1+/- and Tsc2+/- mice with Pkd1+/- mice and shown that the double heterozygous animals have significantly more cysts as compared to the single heterozygotes suggesting a functional co-operation between their gene products. We have found that hamartin and tuberin help maintain the length of primary cilia in normal renal tubule cells and epithelial cells lining cysts and this is modulated by Pkd1-haploinsufficiency. The lengthening of developing renal tubules is tightly coordinated by the mitotic orientation of dividing cells along the tubule axis. We have found that dividing tubule cells in Tsc1+/- and Tsc2+/- mice have aberrant mitotic orientations, suggesting that defects in cell polarity underlie tumour formation in TSC.
