Glycine decarboxylase activity drives non-small cell lung cancer tumor-initiating cells and tumorigenesis.

Identification of the factors critical to the tumor-initiating cell (TIC) state may open new avenues in cancer therapy. Here we show that the metabolic enzyme glycine decarboxylase (GLDC) is critical for TICs in non-small cell lung cancer (NSCLC). TICs from primary NSCLC tumors express high levels of the oncogenic stem cell factor LIN28B and GLDC, which are both required for TIC growth and tumorigenesis. Overexpression of GLDC and other glycine/serine enzymes, but not catalytically inactive GLDC, promotes cellular transformation and tumorigenesis. We found that GLDC induces dramatic changes in glycolysis and glycine/serine metabolism, leading to changes in pyrimidine metabolism to regulate cancer cell proliferation. In the clinic, aberrant activation of GLDC correlates with poorer survival in lung cancer patients, and aberrant GLDC expression is observed in multiple cancer types. This link between glycine metabolism and tumorigenesis may provide novel targets for advancing anticancer therapy.

Induced pluripotent stem cells: a new approach for physiological research.

The generation of induced pluripotent stem (iPS) cells by controlled delivery of reprogramming factors enables the derivation of pluripotent cells from a variety of somatic cell types. Patient-tailored iPS cells remove the major roadblock of immune rejection for clinical applications associated with the use of human embryonic stem (hES) cells. Beside therapeutic issues, iPS cell technology opens the door for broader research on human pluripotent cells because ethical limitations are lifted with iPS cells compared to hES cells. Scientists are now able to generate iPS cells for disease modelling and use them in basic research of physiological and pathophysiological models. In this concise review, we discuss the state of the art in the field of iPS cell induction by cell fusion or defined factors. Techniques to derive pluripotent cells from somatic sources are introduced and discussed, as well as some biological factors that influence the generation of iPS cells. We compare ES and iPS cells to answer the question whether these cells are identical, and we finish with an outlook on clinical research with iPS cells with a focus on cardiovascular medicine.

Efficient endoderm induction from human pluripotent stem cells by logically directing signals controlling lineage bifurcations.

Human pluripotent stem cell (hPSC) differentiation typically yields heterogeneous populations. Knowledge of signals controlling embryonic lineage bifurcations could efficiently yield desired cell types through exclusion of alternate fates. Therefore, we revisited signals driving induction and anterior-posterior patterning of definitive endoderm to generate a coherent roadmap for endoderm differentiation. With striking temporal dynamics, BMP and Wnt initially specified anterior primitive streak (progenitor to endoderm), yet, 24 hr later, suppressed endoderm and induced mesoderm. At lineage bifurcations, cross-repressive signals separated mutually exclusive fates; TGF-ß and BMP/MAPK respectively induced pancreas versus liver from endoderm by suppressing the alternate lineage. We systematically blockaded alternate fates throughout multiple consecutive bifurcations, thereby efficiently differentiating multiple hPSC lines exclusively into endoderm and its derivatives. Comprehensive transcriptional and chromatin mapping of highly pure endodermal populations revealed that endodermal enhancers existed in a surprising diversity of "pre-enhancer" states before activation, reflecting the establishment of a permissive chromatin landscape as a prelude to differentiation.