Updated: December 2012
I define myself as a cell biologist. My specific research focus within cell biology is to understand the mechanisms that allow for unregulated cell growth; a basic hallmark of cancer. Cancer has long been understood to be a genetic disease. To date, there are over 100 genes implicated in promoting cancer when mutated. In particular, I use fruit flies (Drosophila melanogaster) as a model for the underlying genetic changes that subvert the normal biology of cell growth and division. We share a lot more with fruit flies than one would guess from a superficial glance – including over 2/3rds of the genes known to play a direct role in human disease1. Most of the “rules” governing cellular growth and division have been highly conserved throughout evolution, allowing researchers to genetically manipulate fruit flies until an approximation of cancer arises. In attempt to identify novel genes that could contribute to unregulated cellular growth, I performed an unbiased, genetic screen during my postdoctoral work. Ongoing projects in my lab focus on three of the approximately 35 genes isolated in the screen.
In my screen, I identified a relatively unexplored member of the Ras superfamily of GTPases, Rheb2. Increased levels of Rheb in fruit flies leads to a remarkable increase in cell size and also causes cells to accumulate in the G2 phase of the cell cycle (indicating that they cannot enter mitosis). Rheb overexpression phenotypes most closely resemble those caused by hyperactivation of insulin signaling. Genetic and biochemical tests indicated that Rheb is a downstream effector of insulin signaling, and functionally inhibited by the human tumor suppressor, Tuberous Sclerosis 22,3,4. Because Tuberous Sclerosis is inactivated in some human tumors, it seems likely that Rheb activity would be elevated, and thus Rheb directly contributes to the overgrowth of these tumors. Ongoing research in the lab has explored why Rheb (and Insulin signaling) allow both cells and tissues to become enlarged. Interestingly, we have found that if we force cells that overexpress Rheb through mitosis (using co-overexpression of a rate-limiting protein, called String), there is a reduction in tissue size, although cell size remains enlarged. Preliminary data indicates the tissue size reduction is due to apoptosis. We hypothesize that there may be a cell counting mechanism that is dependent on cells passing through mitosis. This line of experimentation indicates that for some tumors (ie “large cell”), increasing cell division might trigger a mechanism to actually reduce tumor volume.
The majority of the research students in the laboratory have devoted their effort to a protein called PRL-1 (Phosphatase in Regenerating Liver-1). Since isolating it in my genetic screen, its human homologue has become a “biomarker” for colon cancer metastasis5; that is high levels of expression in human tumors significantly correlate with the ability of new tumors arising at a second site. The current data on human PRLs (there are three family members) includes contradictory findings and no clear mechanism(s) of how PRLs could contribute to cancer. We have found that PRL-1 actually functions to inhibit cell division in normal cells, suggesting that other genetic or environmental events are needed to convert PRL-1 function. We have recently published the first paper to characterize PRL-1 in a model organism, which can be found here. Main projects in the lab involve examining PRL-1 function in cancerous environments (i.e. addition of oncogenes or removal of tumor suppressors), examining PRL-1 function while manipulating its subcellular distribution and lastly, using genetic interaction tests to place PRL-1 in a signaling pathway similar to what we accomplished with Rheb.
I envision my research program to remain primarily centered on elucidating the function(s) of PRL-1 over the next several years. We appear to be the only fly lab investigating PRL-1 and I see us in a prime position to significantly inform the field of human cancer biology.
1Fortini ME, Skupski MP, Boguski MS, Hariharan IK. A survey of human disease gene counterparts in the Drosophila genome. J Cell Biol. 2000 150(2): F23-30.
2Saucedo LJ, Gao X, Chiarelli DA, Li L, Pan D, Edgar BA. Rheb promotes cell growth as a component of the insulin/TOR signalling network. Nat Cell Biol. 2003 Jun;5(6):566-71.
3Stocker H, Radimerski T, Schindelholz B, Wittwer F, Belawat P, Daram P, Breuer S, Thomas G, Hafen E. Rheb is an essential regulator of S6K in controlling cell growth in Drosophila. Nat Cell Biol. 2003 Jun;5(6):559-65.
4 Zhang Y, Gao X, Saucedo LJ, Ru B, Edgar BA, Pan D. Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins. Nat Cell Biol. 2003 Jun;5(6):578-81.
5Stephens BJ, Han H, Gokhale V, Von Hoff DD. PRL phosphatases as potential molecular targets in cancer. Mol Cancer Ther. 2005 Nov;4(11):1653-61.