|Laboratory of Alexander Nikitin|
The long-term goal of our research is to understand how aberrations in molecular and cellular mechanisms governing tissue homeostasis may lead to cancer initiation and progression. Our specific areas of interest include understanding the role of stem cell compartment in carcinogenesis, and studies of the epithelial ovarian cancer pathogenesis. We are also interested in pursuing technology-oriented research based on cross-disciplinary collaborations.
Understanding the role of stem cell compartment in carcinogenesis. A significant body of information exists about contribution of stem cells to hematopoietic malignancies. However, solid neoplasms have been difficult to study (Matoso and Nikitin, 2008, Nafus and Nikitin, 2009, Nikitin et al., 2009, Cheng et al., 2010) . Using prostate epithelium-specific inactivation of p53 and Rb, we have developed a new autochthonous mouse model of metastatic prostate cancer (Zhou et al., 2006). In this model neoplasms exhibit features of both luminal and neuroendocrine differentiation and are marked with multiple signature gene expressions commonly found in human prostate carcinomas. Intriguingly, all malignant neoplasms arise only from the proximal region of prostatic ducts, the compartment highly enriched for prostatic stem/progenitor cells (Zhou et al., 2007). Our observations indicate that synergistic effects of p53 and Rb alterations on prostate carcinogenesis are particularly effective in the context of the stem cell compartment. Further studies are currently addressing specific roles of p53/miR-34 and Rb pathways in development, maintenance and malignant transformation of the prostate stem cell compartment (Cheng et al., 2014). We have also established new models of mammary (Cheng et al., 2010) and soft tissue neoplasia (Choi et al., 2010), which should be very useful for studying the relationship between stem cell biology and malignant transformation. Most recently we have identified a novel cancer-prone stem cell niche of the ovarian surface epithelium (Flesken-Nikitin et al., 2013). These studies are relevant to understanding of epithelial ovarian cancer pathogenesis as described below.
Studies of epithelial ovarian cancer pathogenesis. Epithelial ovarian cancer (EOC) is the 5th leading cancer type among cancer-related deaths in women in the United States. Until recently, available models of EOC were based on either transplantation systems or non-mammalian models such as egg-laying aged hen. Thus, comprehensive evaluation of epithelial ovarian carcinogenesis in the context of immunocompetent mammals was impossible. Due to its symptomless development and few accurate animal models, EOC pathogenesis remains among the least understood of all major cancers.
Our laboratory developed an approach for introduction of defined genetic alterations exclusively into the ovarian surface epithelium (OSE) in situ in time-controlled manner (Flesken-Nikitin et al., 2003). We have taken advantage of the enclosed anatomical location of the mouse ovary within the bursa, which allows for selective exposure of the OSE to inducing agents and established a technique of trans-infundibular intrabursal administration of replication-deficient recombinant adenovirus expressing Cre-recombinase. Using this approach in combination with Cre-loxP mediated gene inactivation in mice with floxed p53 and Rb, we demonstrated that OSE-restricted p53 and Rb inactivation leads to epithelial ovarian carcinogenesis in 97% of mice. Importantly, mouse EOC closely resembles human serous adenocarcinoma of the ovary. Similar to progression in human counterparts, ovarian neoplasms spread intraperitoneally, form ascites, and metastasize to the contralateral ovary, the lung and the liver. Thus, the first genetically defined model of sporadic EOC developing in immunocompetent animal has been established. This model directly proves the capacity of alterations in p53 and Rb-mediated pathways to cause EOC and is particularly useful for modeling of postnatally induced carcinogenesis (Corney et al., 2008).
Using this model we have determined that p53 transcriptionally regulates expression of microRNAs family miR-34 (Corney et al., 2007). MicroRNAs (miRNAs) are a recently discovered class of non-coding RNAs, which control gene expression either by degradation of target mRNAs or by posttranscriptional repression (Corney et al., 2008). Notably, among computationally predicted effectors of miR-34 are Ezh2, Met, cyclin D1, Cdk4, Cdk6, Cdk7, and E2F3, indicating existence of novel mechanisms of p53-mediated regulation. We have reported common downregulation of mir-34 genes in ovarian cancer and shown importance of feed-forward p53/miR-34/Met loop for control of cell motility and invasion (Corney et al., 2010, Hwang et al., 2011a, Hwang et al., 2011b).
In our recent studies we have identified the hilum region of the mouse ovary, the transitional/junction area between OSE, mesothelium and tubal epithelium, as a previously unrecognized stem cell niche of the OSE (Flesken-Nikitin et al., 2013). Importantly, cells located in the hilum region easily undergo malignant transformation suggesting that EOC may arise from the stem cell compartment located at the junction between OSE and other cell types. These findings also suggest that susceptibility of other transitional zones, such as squamo-columnar junctions of the cervix and anus, to malignant transformation may be explained by presence of previously unknown stem cell niches.
Technology-oriented research based on cross-disciplinary collaborations. It is our strong conviction that advances in modern life sciences greatly depend on the development of new technologies resulting from successful interactions among investigators with diverse disciplinary backgrounds. At Cornell University we have been fortunate to set-up a number of collaborations allowing us to apply the cutting edge photonics (Flesken-Nikitin et al., 2005, Williams et al., 2010) and nanofabrication (Flesken-Nikitin et al., 2007, Choi et al., 2007), to such challenging areas of cancer research as molecular imaging and targeting.