Research interests in the Wang laboratory involve three major areas: (1) Hematopoietic Stem Cell (HSC) Biology-to determine the role of the ROS-p38 MAPK pathway in HSC self-renewal and ex vivo expansion; (2) Experimental Cancer Therapeutics aimed at developing novel therapeutic strategies to overcome the radiation resistance in cancer treatment; and (3) Cancer Stem Cell (CSC) Biology-to determine the role of CSCs in cancer development, therapy response and tumor relapse.
2012 Department Christmas Party: Aimin Yang, Gavin Yong Wang, Lu Wang
Role of the ROS-P38 MAPK Pathway in HSC Self-Renewal & Ex Vivo Expansion
The use of umbilical cord blood (CB) as a source of HSCs for transplantation therapy is rapidly expanding, particularly for the treatment of acute myeloid leukemia. However, CB-derived HSCs are of limited use in adults because the number of HSCs available in CB is not sufficient; thus, ex vivo expansion of HSCs is needed to bridge this gap in availability. Activation of p38 mitogen-activated protein kinase (p38 MAPK or p38) has been implicated in the pathogenesis of a variety of hematopoietic disorders, including Franconi anemia (FA) and myelodysplastic syndromes (MDS). More interestingly, inhibition of p38 has been shown to improve the function of HSCs and hematopoietic progenitor cells (HPCs) in FA and MDS patients and to rescue p38 activation-mediated premature exhaustion of HSCs in FoxO3 knockout mice. However, the role of the ROS-p38 MAPK pathway in the regulation of human HSC self-renewal and ex vivo expansion is unclear. The long-term goal of this project is to develop a novel and innovative approach to increase CB HSC expansion by targeting the ROS-p38 MAPK pathway. The outcome of this study will provide novel insights into the role of the ROS-p38 pathway in the regulation of HSC self-renewal and ex vivo expansion. More importantly, this study may lead to the discovery of novel molecular targets of the ROS-p38 pathway for intervention to improve the ex vivo expansion of CB HSCs.
Ionizing Radiation-Induced Premature Senescence in Lung Cancer Treatment
Radiotherapy is used in over 50 percent of patients during the course of cancer treatment both as a curative modality and for palliation. However, radioresistance is a major obstacle to the success of radiotherapy and contributes significantly to treatment failure and tumor relapse. Lung cancer is the leading cause of cancer deaths in the United States and worldwide. Even with current advanced treatment, the 5-year overall survival rate is less than 16 percent and has not changed appreciably over many decades. This poor prognosis emphasizes the urgent need for the discovery and development of novel radiosensitizers that can be used clinically to improve the efficacy of lung cancer radiotherapy. Our recent studies demonstrate that the tumor cell killing effect of ionizing radiation (IR) is associated with the induction of premature senescence but not apoptosis in non-small cell lung cancer (NSCLC) cells, suggesting an important role of senescence induction in lung cancer radiotherapy. Most recently, we have identified a small molecule compound that can induce premature senescence in NSCLC cells. Given the importance of senescence induction in cancer prevention and treatment, we hypothesize that this small molecule inducer of senescence could be exploited as a novel radiosensitizer to improve the efficacy of radiotherapy for lung cancer treatment. Both in vitro cellular and preclinical animal models are being utilized to test this novel hypothesis in the lab.
Ionizing radiation induces premature senescence in H460 lung cancer cells in a dose-dependent manner. Senescence-associated β-glactosidase (SA-β -gal) staining and BrdU incorporation assays were employed to determine senescent cells in irradiated lung cancer cells.
Targeting CSCs for Cancer Treatment
Therapy-resistance and tumor recurrence is a major obstacle to the success of cancer treatment. Cancer stem cells (CSCs), also called tumor-initiating cells (TICs), have the unique capacity to divide asymmetrically, producing one stem cell (self-renewal) and one progenitor cell that is able to generate heterogeneous lineages of the cancer cells that comprise tumors. As few as 200 of such CSCs were able to form tumors when xenotransplanted into NOD/SCID mice, whereas tens of thousands of other tumor cells could not. Given the high tumorigenic potential of CSCs, it is suggested that the inability of current cancer therapies to efficiently eradicate CSCs might be the primary cause of therapy-resistance, metastasis, tumor recurrence and treatment failure. Therefore, there is a critical need for the discovery and development of novel anticancer agents that can effectively eliminate CSCs in the course of cancer treatment. Toward this aim, we have identified a small molecule A2512, which selectively depletes the CD44+/CD24-/low stem cell subpopulation in breast cancer cells. Ongoing studies in the lab are focusing on determining the mechanisms by which A2512 inhibits CSC self-renewal and evaluating its potential to eradicate CSCs in tumor tissues using xenotransplanted tumor models.