Microenvironmental signals are thought to dramatically influence the fate of adult stem cells and cancer cells. However, it has been challenging to characterize and harness these forces in order to control the differentiation of normal stem cells in the regenerative medicine setting. Similarly, in the setting of clinical cancer progression, it has been nearly impossible to eradicate residual tumor cells present after optimal surgical or medical therapy, likely due in part to non-cell autonomous signals. We employ a model of adult stem cell plasticity-the spermatogonial stem cells (SSCs) of the testis-to study the role that the microenvironment plays in determining whether stem cells will continue 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. The second project addresses the specific role of the vascular endothelium, as a key component of the microenvironment 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. 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.