Jean-Paul De La O
Understanding the mechanisms underlying metastatic spread of cancer cells to distant organs is imperative to reducing cancer mortality, as metastatic tumors are usually more aggressive and resistant to therapy then the parental tumor. While breast cancer has an overall low mortality rate, the majority of deaths can be attributed to metastatic disease. Recently, the receptor tyrosine kinase Ron has emerged as a key player in breast cancer metastasis and its expression correlates with very poor outcome in patients with estrogen receptor negative (ER-) basal-like breast cancer, a sub-type of breast cancer that currently has no targeted therapy. Although Ron did not correlate with outcome in ER+ patients independent of their therapy, when solely looking at patients with ER+ tumors that received Tamoxifen therapy, Ron correlated with an overall good outcome and response to therapy. These data suggest that Ron and ER may functionally interact to dictate tumor dynamics and response to therapy. My research aims to uncover the mechanisms by which Ron and ER interact to modulate tumor growth, metastatic spread, and response to Tamoxifen therapy. Ultimately, I want determine whether Ron represents a good therapeutic target and which patient population are most likely to benefit from Ron inhibition, so as to design the most informative clinical trial.
Traditional two-dimensional cell cultures on plastic may poorly represent true cell behavior occurring in its natural three-dimensional environment. For related reasons, current in vitro and in vivo preclinical testing methods of new cancer drugs usually fail to relevantly predict success in clinical trials. The limitations of our current methods are inhibiting our ability to efficiently advance our understanding of cancer biology and develop more effective therapeutics. In an effort to reduce this barrier to progress, I am applying principles of tissue engineering towards the development of better tumor models for both drug testing and the study of cancer biology. More specifically, I am culturing cancer cells in porous polymer microsphere scaffolds to provide a three-dimensional environment. These microsphere cultures are being used to provide a more relevant in vitro model of the tumor microenvironment. Also this approach will be implemented to improve the clinical relevance of in vivo models by offering more control on where and how tumors form within an animal model.
Cancer can emerge when regulation of the cell division cycle goes awry. To better understand this process and potentially exploit targets therapeutically, our lab has focused on identifying novel factors involved in cell cycle control by examining genetic interactions within cell cycle regulatory pathways in the fission yeast Schizosaccharomyces pombe. We've since identified the FAR complex, a putative protein phosphatase 2A (PP2A) protein complex, which, when disrupted, causes profound mitotic and cytokinetic defects. We've identified an orthologous complex in human cells and it too is involved in cell cycle control and interestingly this complex appears to biochemically link centrosomes to the Golgi apparatus during cell cycle progression. The major focus of my research is to discover and understand PP2A targets regulated by the FAR complex and to further elucidate the roles of the Golgi and centrosomes as signaling platforms in cell cycle regulation. More broadly, I'm working to identify additional factors and pathways by developing and refining new screening technologies in S. pombe.
Elevated fatty acid synthesis (lipogenesis) is thought to be a required metabolic adaptation that conveys a growth advantage to a wide variety of cancer cells, but the mechanism and intermediates involved in the activation of this elevated lipogenesis remain to be clearly delineated. Our lab studies PAS kinase, a molecule that acts as both a sensor and signal transducer of cellular nutrient status. Mice lacking PAS kinase fail to develop steatosis or obesity after being fed a high fat diet, indicating that PAS kinase is required for the pathogenic elevation of lipogenesis induced by diet. As such, PASK signaling may also be required for the elevated lipogenesis observed in cancer. To test this, I am characterizing the role of PASK in lipogenesis-driven proliferation in both in vitro and in vivo cancer models.
Improved understandings of the molecular mechanisms that promote metastasis are needed to develop therapies that target this deadly disease. The stages of metastasis closely resemble events that occur during formation of the vertebrate neural crest (NC), and it is therefore not surprising that genes controlling NC development are aberrantly reactivated during metastasis. The AXL receptor tyrosine kinase (RTK) is a potential therapeutic target for cancer treatment because it can promote cancer cell growth, migration and metastasis. Overexpression of AXL is observed in several cancer cell lines including NC-derived neuroblastoma and melanoma. Our studies suggest that AXL is an essential regulator of EMT during both NC development and cancer progression. We are currently using the zebrafish model to determine the critical downstream mediators of AXL and testing whether overexpression of AXL can promote tumor invasion and/or metastasis in zebrafish models of melanoma and neuroblastoma.
I am post-doctoral fellow in the lab of Dr. Chris Ireland and recently received my PhD from the University of South Florida under the guidance of Dr. Bill Baker. We investigate the oceans for sources of bioactive molecules as marine natural products (NP) have long been recognized as a source of potent and selective anticancer agents. We are conducting collaborative studies utilizing computational chemistry, NP chemistry and cancer biology. The goal of our research is to identify marine natural products capable of disrupting NER through interaction with the XPA-binding pocket of ERCC1. Source organisms will be selected using structure-based in silico docking against the structure of the XPA-binding site of ERCC1 and based on a preliminary screen of a diverse library of purified marine NPs. We will perform in vitro screening using a mechanism-based assay on a targeted fraction library in order to elicit large scale extraction of organisms exhibiting activity, isolation, and structure determination of the active compounds will be carried out. Susceptibility of resistant cell lines to cotreatment with cisplatin and NER disruptors will be determined to gauge the role of NER in cisplatin-resistance in those cell lines. The end result will be lead compounds capable of reverting NER-mediated resistance ready for testing in animal models.
Recent advances in biomolecular-profiling technologies have the potential to explain the biological underpinnings of disease in unprecedented ways. However, to take advantage of this potential, sophisticated analytic techniques are necessary to evaluate the vast quantities of resulting data. Methods are needed to combine evidence across disparate technology platforms such that common downstream analytic techniques can be used to draw biomedical inferences. Additionally, effective methods are needed to associate gene-level data with biological pathway information, potentially enabling pharmacology researchers to target complex diseases, such as cancer, in a modular fashion. The main focus of my research is to use my computational/analytic background to develop bioinformatics techniques that meet the above objectives and most importantly that lead to advances in patient care.
Jonathan Van Vranken
It is becoming increasingly clear that mitochondria lie at the center of most age- related human disease including neurodegeneration, metabolic disorders, and cancer. Recent reports have provided a clear link between mitochondrial dysfunction, specifically of succinate dehydrogenase (SDH), and the incidence of two rare head and neck cancers—paraganglioma and pheochromotycoma—and wild-type gastrointestinal stromal tumors. Current models suggest that loss of SDH activity results in the accumulation of succinate which can leak into the cytosol and inhibit the prolyl-hydroxylase domain containing proteins (PHD) that normally target hypoxia-inducible factor 1 (HIF-1) for degradation. Thus, the cell experiences a state of pseudo-hypoxia. Irrespective of the precise mechanism of tumorigenesis, it is clear that deficiencies in the activity of SDH cause the cancers described above. In total, there are six known SDH-associated genes that, when mutated, cause cancer (SDHAF2, SDHAF1, SDHD, SDHC, SDHB, and SDHA). However, our lab has seen instances in which individuals present with paraganglioma, pheochromocytoma, or WT-GIST without a mutation in any of the known SDH-associated tumor suppressor genes despite a complete absence of SDH activity within the tumors. Thus, there must be additional factors involved in the pathogenesis of these cancers. On the basis of previously published examples, we predict they will be involved in SDH activity/assembly. It is my goal to identify these novel factors and further characterize their function in the context of the eukaryotic cell. Furthermore, I am interested in using the various SDH-associated tumor suppressor genes to better understand the unique role that succinate accumulation plays in the development of cancer.
Yuxia (Lisa) Zhang
Nuclear receptor and transcriptional repressor small heterodimer partner (SHP, NROB2) is a multifunctional regulator of genes critical to liver metabolism. Recent studies from my laboratory provide the first evidence that SHP functions as a tumor suppressor in the development of hepatocellular carcinoma (HCC). Deleting the SHP gene promotes spontaneous hepatoma formation in mice. SHP expression is also markedly diminished in human HCC specimens due to its promoter hypermethylation. On the other hand, SHP exerts a potent pro-apoptotic effect via antagonizing the anti-apoptotic function of Bcl-2. DNA methylation mediated-gene silencing is catalyzed by three DNA methyltransferases (Dnmt1, Dnmt3a and Dnmt3b). Despite evidence for their critical role in carcinogenesis, the mechanism of how the expression of Dnmts is transcriptionally regulated remains largely unknown. My research focuses on defining the molecular mechanism for transcriptional repression of the Dnmt genes by SHP in order to better understand how SHP regulates DNA methylation in hepatocarcinogenesis and further identifying novel tumor suppressors that regulate the development and progression of HCC.