Qi-En Wang Lab
The Qi-En Wang Lab is focused on cancer stem cell biology, DNA repair and chemotherapy resistance. It is particularly interested in investigating the impact of DNA damage responses on the tumor relapse and the development of acquired therapeutic resistance in ovarian cancer, as well as how the cancer stem cell population is maintained in the epithelial ovarian tumor.
Active Research Projects
- Deciphering the mechanism underlying tumor relapse and cisplatin resistance in ovarian cancer
Tumor relapse and acquired chemotherapy resistance are two major factors leading to the high mortality of epithelial ovarian cancer (EOC) patients. It has become increasingly evident that ovarian cancers contain subpopulations of cancer stem cells (CSCs) with enhanced tumorigenicity and chemoresistance. These CSCs are believed to be responsible for treatment failure and tumor relapse. However, it is still unclear how CSCs survive DNA-damaging agent treatment and how the tumor regenerated by the surviving CSCs develops chemoresistance. Error-prone translesion DNA synthesis (TLS), a DNA damage tolerance mechanism that bypasses DNA damage during replication, has been suggested to mediate acquired chemoresistance. Recent studies in Dr. Wang's laboratory have revealed that ovarian CSCs show elevated expression of TLS polymerase η (Polη); we also demonstrated that Polη is critical to the survival of ovarian CSCs following cisplatin treatment. We are currently seeking to understand how enhanced Polη-mediated TLS in CSCs contributes to tumor relapse and the development of acquired cisplatin-resistance after initial cisplatin treatment. This project is currently being supported by a NCI R01 grant (CA211175).
- Understanding the maintenance of CSC population in tumors
Given that CSCs are believed to be responsible for tumor progression and treatment failure, eradication of CSCs will be an effective way to improve the therapeutic efficacy. Recent studies in the lab have revealed a suppressed extracellular signal-regulated kinase (ERK) signaling, an extremely high expression of miR-328-3p (termed miR-328), and a reduced expression of DNA damage-binding protein 2 (DDB2) in ovarian CSCs. We have also elucidated their relationship, e.g., ERK inhibition can elevate the cellular level of miR-328, and miR-328 can directly target DDB2. Most importantly, we have demonstrated that high miR-328 level and low DDB2 levels are critical to the maintenance of the CSC population in EOC cell lines. Based on this scientific premise, we are seeking to demonstrate that ERK-miR-328-DDB2 axis plays a critical role in EOC progression by regulating the maintenance of CSC populations.
- Deciphering the mechanism underlying PARP inhibitor resistance in BRCA-deficient ovarian cancer
Poly (ADP-ribose) polymerase (PARP) inhibitors are an exciting and promising new class of anticancer drugs. PARP inhibitors (PARPi) selectively kill BRCA1/2-deficient cancer cells because the deficiency in BRCA1/2 leads to the impaired homologous recombination (HR) repair, which is unable to repair PARPi-induced DNA double strand breaks (DSBs). However, only a fraction of BRCA1/2 mutation carriers responded to PARPi, and even those who responded subsequently developed resistance and relapsed. Thus, a strategy to overcome the PARPi resistance of BRCA1/2-deficient cancers is much needed to improve this promising targeted therapy. One of the mechanisms underlying acquired PARPi resistance is the restoration of DNA repair capability, including treatment-induced reverse mutation in the defective BRCA1/2 gene. We have found that PARPi can induce ALDH1A1, which is able to enhance DNA repair capacity in BRCA2 deficient cells. We are currently investigating the mechanism underlying ALDH1A1-mediated DNA repair in ovarian cancer cells.
Dayong Wu, PhD – Research Associate 2
Tejinder Pal, PhD – Postdoctoral Researcher
Xuetao Bai, PhD – Postdoctoral Researcher
Na Li, MSc – Research Assistant 1
Shurui Cai – Graduate Research Associate
Ananya Banerjee – Visiting Scholar
Kousalya Lavudi – Visiting Scholar
Gordon Xie – Student Research Assistant