Sandra Ryeom, Ph.D.

Associate Professor Of Cancer Biology

My lab has been focused on understanding the role of the vasculature in promoting tumor progression and metastasis. Using mouse models of cancer, primary endothelial cells and molecular and cell biological approaches, we have been investigating the contributions of the calcineurin-NFAT signaling pathway towards activation of the vascular endothelium during tumor angiogenesis leading to tumor progression and metastasis. Calcineurin is a calcium regulated ser/thr phosphatase that regulates a number of physiological processes, most notably in T cells and neurons. Upon activation, calcineurin dephosphorylates members of the NFAT family, triggering their nuclear entry and transactivation of targets including pro-angiogenic genes in endothelial cels. One of the major contributions of my lab to the tumor microenvironment field is the critical importance of the calcineurin-NFAT pathway as an intracellular mediator of vascular endothelial growth factor (VEGF) activation in endothelial cells during pathologic angiogenesis. Anti-angiogenic cancer therapy has been focused primarily on targeting VEGF or its receptors and has been largely unsuccessful. Our work offers intracellular targets downstream of VEGF as possible therapeutic options. 

My lab is also investigating the role of calcineurin-NFAT in endothelial cells in early metastatic sites in the lung and liver and identifying relevant NFAT-dependent targets promoting metastatic colonization and expansion. Further, we have begun to examine the role of the calcineurin-NFAT pathway in stromal cells during metastasis and are investigating the ‘stromagenic switch’ during tumor progression. Similar to the concept of the angiogenic switch when the balance of pro- and anti-angiogenic proteins shift towards a pro-angiogenic phenotype triggering the expansion of blood vessel growth or tumor angiogenesis, it is also becoming evident that stromal cells in the tumor microenvironment become activated to promote tumor growth and metastasis. We will identify cellular and molecular mechanisms by which stromal cells become activated and primed to permit metastatic tumor cell seeding. Further, my lab will also investigate cross-talk between stromal cells and endothelial cells in early metastatic sites and define the contribution of calcineurin-NFAT targets in stromal cells and endothelial cells towards this cross-talk. 

For many years, it has been assumed that endothelial cells from different organs were similar in their activation, regulation and output of secreted factors during tumor growth and metastasis. Studies in our lab indicate that endothelial cells from different organ environments are unique and respond differently to pro-angiogenic factors producing organ specific secretomes. Another area of interest in the lab is to understand the contribution of endothelial cells in different organs towards maintaining stem cells populations. For example, my lab has identified the testicular endothelium as the critical accessory cell in the spermatogonial stem cell niche providing the factors necessary to maintain spermatogonial stem cell identity. We are examining endothelial cells in other organs to understand their contribution in stem cell niches as well as the role of organ specific endothelium in mediating metastatic tropism.