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Cancer Biology

Cancer Biology

Stem cell tumor in fly intestine.

Cell Biology

Cell Biology

PRL-1 staining in fly embryo.

Leslie Saucedo

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 disease (1). 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 two of the approximately 35 genes isolated in the screen. 


In my screen, I identified a relatively unexplored member of the Ras superfamily of GTPases, Rheb (2). 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 2 (2,3). 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 investigating 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 metastasis (4); 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 published the first paper to characterize PRL-1 in a model organism, which can be found here


The main environmental factor that we suspect regulates the function of PRL family members is redox regulation. All PRLs (from fly to human) are predicted to have an active site that would be in a non-accessible conformation under physiologically normal redox conditions (5). Therefore, we are altering the redox state of cells through genetic manipulation of levels of enzymes that regulate oxidation and reduction to see the effects on PRL function. Because recent work has demonstrated that cancer cells require elevated levels of antioxidant activity (6), we have expanded our work to quantify the effects of manipulated redox enzymes on other genes involved in cancer, such as Ras and Src.


I envision my research program to remain primarily centered on elucidating the regulation and function of PRL-1 as well as redox regulation of candidate oncogenes. We appear to be the only fly lab investigating these lines of research and I see us in a prime position to use basic science approaches to contribute significant information the field of human cancer biology.



(1) Fortini 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.

(2) Saucedo 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.

(3) 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.

(4) Bessette DC, Qui D, Pallen CJ. PRL PTPs: mediators and marker of cancer progression. Cancer Metastasis Rev. 2008 Jun;27(2):231-52.

(5) Skinner AL, Vartia AA, Williams TD, Laurence JS. Enzyme activity of phosphatase of regenerating liver is controlled by the redox environment and its C-terminal residues. Biochemistry. 2009 May 26;48(20):4262-72.

(6) Glasauer A, Chandel NS. Targeting antioxidants for cancer therapy. Biochem Pharmacol. 2014 Nov 1;92(1):90-101