Laboratory of Alexander Nikitin
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Research

 

Our long-term goal is to understand how aberrations in molecular and cellular mechanisms governing tissue development and regeneration may lead to cancer initiation and progression. Our specific areas of interest include understanding the role of stem cell niches in ovarian and prostate carcinogenesis. We are also interested in the establishment of stem cell pathology as a discipline.

The role of stem cell niches in ovarian carcinogenesis. 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 tumor suppressor genes p53 (Trp53) and Rb (Rb1), we demonstrated that OSE-restricted p53 and Rb inactivation leads to epithelial ovarian carcinogenesis in 97% of mice. Importantly, mouse ovarian carcinomas closely resemble human high-grade serous ovarian carcinomas, the most common and deadly type of ovarian carcinomas. Similar to progression in human counterparts, mouse ovarian carcinomas spread intraperitoneally, form ascites, and metastasize to the contralateral ovary, the lung and the liver.

OSE stem cells express ALDH (red) and retain BrdU label (green). Blue, nuclear stain DAPI.

Our studies identified the hilum region of the mouse ovary, the transitional/junction area between OSE, mesothelium and tubal epithelium, as previously unrecognized cancer-prone stem cell niche of the OSE (Flesken-Nikitin et al., 2013). Importantly, cells located in the hilum region easily undergo malignant transformation suggesting that ovarian carcinomas may arise from the stem cell niche located at the junction between OSE and other cell types. Our recent studies suggest that tubal-peritoneal junctions of the uterine (aka Fallopian) tube contain cancer-prone stem cells of the tubal epithelium in humans (Schmoeckel et al., 2017). These findings support the notion 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 (Flesken-Nikitin et al., 2014, Fu et al. 2018). Read more about our ovarian cancer research.

The role of stem cell niches in prostate carcinogenesis. 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 niche. Transformation of the prostate stem cell niche can be also achieved by a combined inactivation of p53 and mir-34 genes (Cheng et al., 2014). However, unlike carcinomas in p53/Rb model, these neoplasms do not have neuroendocrine component. These findings suggest that aberrations of the Rb pathway may be essential for the neuroendocrine differentiation. Our current research is focused on the role of neuroendocrine signaling in normal and neoplastic prostate epithelium.)

Stem cell pathology. Rapid advances in stem cell biology and regenerative medicine have opened new opportunities for better understanding disease pathogenesis and development of new diagnostic, prognostic and treatment approaches. Many stem cell niches are well defined anatomically, thereby allowing their routine pathological evaluation during disease initiation and progression. Evaluation of consequences of genetic manipulations in stem cells, and investigation of the roles of stem cells in regenerative medicine and pathogenesis of various diseases, such as cancer, require significant expertise in pathology for accurate interpretation of novel findings. Therefore, there is an urgent need for developing stem cell pathology as a discipline able to match the rapid advances of stem cell research and regenerative medicine. We define stem cell pathology as an area of pathology which focuses on studying the roles of stem cells in disease pathogenesis, identifies pathological consequences of stem cell transplantation, and evaluates side effects of genetic and epigenetic manipulations of stem cells (Fu et al, 2018). We anticipate that close integration of stem cell pathology with animal modeling and in vivo imaging will significantly accelerate our progress towards understanding the pathogenesis of diseases associated with stem cell niche disorders. An example of such approach is Cornell Stem Cell Modeling and Phenotyping Core with its Cornell Stem Cell Pathology Unit.