Stem Cell Biology: Major Accomplishments

Recent studies in Dr. Ruth Lehmann’s laboratory reveal that RhoL, a GTPase homologue expressed in hemocytes, the Drosophila immune cell progenitors, is a new regulator of invasion, adhesion, and Rap1 localization during immune cell transmigration. Rap1 GTPase activates integrin affinity and thereby allows for the transmigration of immune cells through an endothelial barrier. The authors find that RhoL mediates integrin adhesion caused by Drosophila Rap1 overexpression and moves Rap1 away from a concentration in the cytoplasm to the leading edge during invasive migration (Siekhaus et al. Nat Cell Biol 12, 2010).

Studies in the Aifantis lab focusing on T-cell acute lymphoblastic leukemia (T-ALL) have shown that the suppression of IkB kinase (IKK) expression can affect the survival of human T-ALL cells and in vivo maintenance of the disease. These data suggest that this may be an approach to treating the disease. The authors show that Hes1, a transcriptional repressor and a Notch target, is responsible for IkB kinase (IKK) activation in T-ALL. Hes1 works via repression of deubiquitinase CYLD, the expression of which is suppressed in primary T-ALL (Espinosa et al. Cancer Cell 18, 2010). Furthermore, Dr. Aifantis’ lab has found that the Notch pathway can play both tumor-promoting and tumor-suppressive roles within the same tissue. Notch-inactivating mutations result in aberrant accumulation of granulocyte/monocyte progenitors, extramedullary hematopoiesis, and the induction of chronic myelomonocytic leukemia-like disease. Notch pathway-dependent Hes1 regulation is responsible for suppression of the myelomonocytic-specific gene signature (Klinakis et al. Nature 473, 2011).

Studies in the Barcellos-Hoff Lab have shown that the irradiated microenvironment can affect the latency and the molecular signatures of tumors. The lab’s recent paper published in Cancer Cell found that tumors in irradiated hosts illustrate TGFb-mediated tumor acceleration, and the tumors are predominantly estrogen receptor-negative -- a TGFB-independent effect linked to mammary stem cell activity (Nguyen et al. Cancer Cell 19, 2011).

Research in the Fishell Lab has shown that a specific subset of cortical interneurons, which arise from the caudal ganglionic eminence within the ventral telencephalon and are reelin- and calretinin-positive, require neural activity before postnatal day 3 for correct migration. In their recent Nature paper, the authors show that after postnatal day 3, glutamate-mediated activity controls the axonal and dendritic development of these interneurons. Furthermore, the engulfment and cell motility 1 gene (Elmo1) is selectively expressed in this population of interneurons and is necessary and sufficient for their activity-dependent migration (De Marco Garcia et al. Nature 472, 2011).

Research by Dr. Mayumi Ito’s group has identified Wnt signaling as a key pathway in linking melanocyte stem cell (McSC) and epithelial stem cell (EpSC) activity during hair follicle regeneration. Wnt signaling is essential for coordinated actions of these two stem cell populations and is thus critical for hair pigmentation. Wnt activation in McSCs drives their differentiation into pigment-producing melanocytes. In EpSCs, Wnt signaling dictates hair follicle formation and regulates McSC proliferation during hair regeneration (Rabbani et al. Cell 145, 2011).

A recent study in Dr. Eva Hernando’s laboratory has shown a correlation between microRNAs and the metastatic potential of human melanomas, the deadliest form of skin cancer. In their recent paper in Cancer Cell, the authors illustrate that increased levels of miR-30b/d are associated with advanced stage melanomas, greater risk for metastasis, and reduced patient survival. The authors also show that ectopic over expression of miR-30b/d suppresses the function of the GalNAc transferase GALNT7 and results in increased synthesis of the immunosuppressive cytokine IL-10, leading to increased melanoma metastases. Silencing of the miRNAs in tumor cells, on the other hand, led to suppression of metastatic melanoma. This work identifies a critical role of miRNAs in melanoma metastasis and provides clinical insight into a possible mechanism of screening human melanomas for miRNA expression to evaluate for metastasis potential and tumor severity. (Gaziel-Sovran, et al. Cancer Cell 21, 2011)

Recent studies in the laboratory of Dr. Eva Hernando illustrate that anti-miR-182 treatment in a mouse model of melanoma liver metastasis leads to a lower burden of metastases compared with controls, and suggest a promising therapeutic strategy for metastatic melanoma. miR-182 is a pro-metastatic miRNA that is frequently overexpressed in melanoma. Anti-miR-182 treatment successfully downregulated miR-182 levels, and transcriptional profiling of the tumors revealed an enrichment of genes controlling survival, adhesion, and migration modulated in response to anti-miR182 treatment (Huynh et al. Oncogene 30, 2011).

Studies of murine prostate stem cells in the Wilson lab have revealed a marker of these multipotent cells. Aldehyde dehydrogenase (ALDH) activity was found in a subset of prostate epithelial cells which also expressed antigens found on stem cells of other origins. Cells with high levels of ALDH were shown to have greater prolifereative potential in vitro and were more effective in generating prostatic tissue in vivo, implicating ALDH as a functional marker of prostate progenitor cells (Burger et al. Stem Cells 27, 2009). Dr. Wilson’s lab further found that several of the key transcriptional components that are predicted to be active in the embryonic prostate stem cell niche regulate processes such as self-renewal, lipid metabolism, and cell migration (Blum et al. PLoS One 5, 2010).

Recent findings in the Reinberg lab have shown that Jarid2 associates with PRC2 to stimulate its activity in vitro. Jarid2 also colocalizes with Ezh2, a subunit of PRC2, in embryonic stem (ES) cells. Jarid2 can bind DNA, and its recruitment in ES cells is interdependent with that of PRC2. ES cell differentiation is impaired upon down-regulation of Jarid2 (Li et al. Genes Dev 24, 2010). Furthermore, Dr. Reinberg’s group has shown that Ezh2 interacts with the noncoding RNAs HOTAIR and Xist. Phosphorylation of Ezh2 at residue 345 by cyclin-dependent kinase 1 increased HOTAIR binding to Ezh2, and the T345 domain was important for binding of the 5’ end of Xist (Kaneko et al. Genes Dev 24, 2010).