Probing the microenvironment of stem cells and tumor cells...

We employ models of adult stem cell plasticity­, including the spermatogonial stem cells (SSCs) of the testis, to study the role that the microenvironment plays in determining whether stem cells will continue to self-renew or otherwise differentiate in a lineage-specific manner.  SSCs represent an extreme example of cellular plasticity due to their unique ability, as we have shown, to acquire pluripotency in vitro without the addition of exogenous genes.  The mechanisms of this “switch” in cell state, and, in particular, the positive and negative influences of the microenvironment are under investigation. We have recently identified a novel G protein coupled receptor (GPR125) which has proven useful as a marker of undifferentiated spermatogonia in both mouse and humans. The function of GPR125 is also being scrutinized using GPR125-deficient mice and other novel molecular tools. The second major line of inquiry addresses the specific role of the vascular endothelium, as a key component of the microenvironment (or niche) in vivo, in maintenance of adult stem cells and cancer cells.  We recently demonstrated that human endothelial cells support tumor cell survival and clonagenic growth.  These studies were enabled by the discovery of the adenoviral E4ORF1 gene which confers a pro-survival but non-transformed status upon primary endothelial cells which can then be studied in the absence of serum or most exogenous growth factors.  Genetic and chemical screens are being employed to identify extrinsic factors that abrogate lineage commitment of stem cells or block the supportive effects of vascular endothelium on the tumor.