Size-control Mechanisms in Development & Tumorigenesis

To understand the developmental functions of tumor suppressors, we have been performing genetic screens to identify overgrowth mutations in mosaic flies. Interestingly, all the identified mutations also deregulate organ and organism size, suggesting that tumorigenesis might reflect an impairment of organ size control. Three classes of mutations have been isolated.

Mutations in the first class, comprised of genes such as lats (also known as wts), cause dramatic overproliferation, resulting in tumorous growth of mutant cells in mosaic animals and enlarged organs in homozygous mutants. Mice deficient for Lats1 develop soft-tissue sarcomas and ovarian stromal cell tumors, indicating a critical role for Lats in mammalian tumorigenesis. 

Analyses of LATS proteins revealed that they are a novel family of negative cyclin-dependent kinase (CDK) regulators and also regulate the cytoskeleton by modulating activities of molecules such as LIMK1 and CDC2. 

Mutations in the second class of genes, such as slimb, cause patterned outgrowths in mosaic animals and alter organ size by affecting signals that regulate pattern formation.

Mutations in the third class, such as the Drosophila homologs of the human tumor suppressors, PTEN, TSC1, and TSC2, cause overgrowth of mutant clones in mosaic animals largely by increasing cell size. Size control mechanisms could be critical targets for evolutionary events to alter organism size, and also for disease processes such as tumorigenesis that require increases in tissue size. 

Tuberous sclerosis complex (TSC) is a genetic disease characterized by hamartomas in multiple organs including brain, kidneys, lungs, heart, eyes, and skin. TSC is a common cause of epilepsy and autism and is also the cause of lymphangiomyomatosis (LAM), a rare lung disease. However, the functions of the two TSC genes are unknown. 

Our findings thatDrosophila Tsc1 and Tsc2 function together in the insulin/PI3K/PTEN/Akt pathway downstream of Akt and upstream of S6K, and that TSC defects can be alleviated by reducing S6K activity, have now been confirmed in other animals and human patients. This has helped lead to the initiation of clinical trials in the US, England, and Germany.

We are also working with the Rothberg Institute to develop novel therapeutics for TSC patients. Given that the pathway is mutated in a large number of cancers and is involved in insulin signaling, the therapeutic implications of results from such trials will go beyond the TSC and LAM patient population.

Further characterization of these tumor growth-promotion mutations will likely lead to the identification of new tumor suppressors and mechanisms regulating growth.