"Therapeutic strategies targeting cancer stem cells" Hideyuki Saya

Title:

"Therapeutic strategies targeting cancer stem cells"

Speaker:

Hideyuki Saya
Division of Gene Regulation, Institute for Advanced Medical Research (IAMR)
Keio University School of Medicine, Tokyo  Japan

Abstract:

Cancer stem cells (CSCs) are a subset of tumor cells that are responsible for initiating and maintaining the disease. In the clinical point of view, the most important characteristics of CSCs include their resistance to various therapeutic interventions. However, the underlying mechanisms of the resistance remain unclear.

CD44 has been identified as a cell surface marker associated with cancer stem cells (CSCs) in several types of epithelial tumor. We have recently found that expression of CD44, in particular variant forms of CD44 (CD44v), contributes to the defense against reactive oxygen species (ROS) by promoting the synthesis of reduced gluathione (GSH), a primary intracellular antioxidant. CD44v interacts with and stabilizes xCT, a subunit of a glutamate-cystine transporter, and thereby promotes the uptake of cystine for GSH synthesis (Cancer Cell 2011). Therefore, ablation of CD44 reduced GSH levels and increased ROS levels, leading to suppression of tumor growth and metastasis in both transgenic and xenograft tumor models (Nat Commun 2012; Cancer Res 2013). Our findings reveal a novel function for CD44v in protection of CSCs from high levels of ROS in the tumor microenvironment. Based on these preclinical findings, we are currently conducting clinical trials using an xCT inhibitor for cancer patients having advanced gastric cancer and lung cancer.

We established a mouse osteosarcoma (OS) stem cell through overexpression of c-MYC in bone marrow stromal cells derived from Ink4a/Arf (-/-) mice. In this model, we found that the loss of adipogenic potential is an essential event for OS development (Oncogene 2010). Therefore, our understanding of regulatory mechanisms of adipocyte differentiation would greatly contribute to control OS tumorigenesis. We have recently found a novel regulatory mechanism of adipocyte differentiation, in which regulation of MKL1 by actin cytoskelton dynamics drives adipocyte differentiation mediated by PPARγ, a master transcriptional regulator of adipogenesis (Nat Commun 2014). Based on this concept, we attempted to induce adipocyte differentiation in OS stem cells, which resulted in a significant suppression of tumorigenesis. Induction of trans-differentiation in cancer stem cells by regulating actin cytoskeleton dynamics is a potential approach for some tumor types