SUNGKYUNKWAN UNIVERSITY SCHOOL OF MEDICINE

1. Mechanisms underlying a broad cancer protection in Down syndrome individuals.
Many studies have shown that the Down syndrome population is protected against cancer. To understand the molecular mechanisms responsible for this cancer protection, our recent studies have focused on the Down syndrome candidate region-1 (DSCR1) gene. Dscr1 is located on chromosome 21 and is an endogenous inhibitor of calcineurin, a serine/threonine phosphatase that plays an important role in the activation of immune cells and endothelial cells by mitogenic signals via NFAT activation. We recently demonstrated that DSCR1 restrains the growth of implanted tumors in mice by suppressing tumor angiogenesis through the attenuation of the VEGF-Calcineurin-NFAT pathway in endothelial cells. Our data indicate that the cancer protection observed in the Down’s syndrome population is due, in part, to the inhibition of angiogenesis by DSCR1. Of interest, accumulating evidence suggests that increased NFAT transcriptional activity contributes to both the initiation and progression of tumors via cancer cell autonomous functions. These observations implicate a possible role for DSCR1 in tumor initiation as well as tumor angiogenesis, contributing to the significantly reduced cancer incidence observed in the Down’s syndrome population. To test this hypothesis, we are exploring the role of DSCR1 as a tumor suppressor in spontaneous lung and pancreatic tumor progression utilizing an oncogenic K-rasG12D conditional knockin mouse model and transgenic mouse models of Down syndrome and DSCR1 trisomy . In addition, we are also determining whether either trisomy 21 or DSCR1 trisomy attenuates angiogenic phenotypes of tumor-associated fibroblasts and bone marrow-derived cells.

2. Study for the roles mTOR-mediated protein synthesis pathway in the control of tumor angiogenesis.
Tumor angiogenesis, the growth of new capillary blood vessels into tumors, is essential for tumor expansion and has been targeted for cancer treatment. However, the therapeutic intervention of tumor angiogenesis has shown only limited success in the clinic due to both evasive and intrinsic resistance to therapy. Thus, to develop successful anti-angiogenic strategies for cancer treatment, it is necessary to fully understand the molecular mechanisms underlying tumor angiogenesis by elucidating signaling networks determining the angiogenic phenotype of endothelial cells, major cell players in the angiogenic process.
Accumulating evidence indicates that the mammalian target of rapamycin (mTOR) kinase, a master regulator of protein synthesis that couples sensing of environmental stimuli such as nutrient and mitogens to cell growth and metabolism, is implicated in tumor angiogenesis through the control of angiogenic behavior of endothelial cells. However, in spite of the emerging role of mTOR-mediated translational regulation in tumor angiogenesis and the possibility of mTOR signaling pathway as a promising target for anti-angiogenic therapy, the signaling networks downstream of mTOR in endothelial cell proliferation and migration is still poorly understood and remains to be further elucidated.
To elucidate the downstream signaling of mTOR in endothelial cells and thus validate mTOR-mediated protein synthesis pathway as a potential target for anti-angiogenic therapy, we are addressing the roles of 40S ribosomal protein S6 kinase 1 and 2 (S6K1 and S6K2), major downstream effectors of mTOR signaling pathway, in tumor angiogenesis in vivo utilizing mice deficient for either S6K1 or S6K2. In addition, we will determine the roles of S6K1 and S6K2 in regulating the angiogenic phenotype of endothelial cells and the underlying mechanisms by monitoring translational alterations in primary endothelial cells from S6K1- and S6K2-null mice upon exposure to angiogenic stimuli using ribosome profiling and mass spectrometry. Furthermore, we are also exploring the impact of S6K1 and S6K2 loss in tumor associated fibroblasts (TAFs) and bone marrow-derived cells (BMDCs) on tumor angiogenesis based on the fact that components other than endothelial cells in tumor microenvironment also participate in the regulation of tumor angiogenesis. These studies will explore the novel roles of translational regulatory pathway in tumor angiogenesis and may have future implications for their therapeutic application for novel cancer treatment.