My research has centered on identification of novel cancer cell-intrinsic and -extrinsic factors critical for tumor initiation, progression, metastasis and recurrence.  The long-term vision is to utilize this fundamental mechanistic research to facilitate the development of precision cancer medicine.  I specifically focus on ovarian cancer (OC) and breast cancer (BC).  My team has demonstrated that MEX3A, an RNA-binding/E3 ligase dual-function protein, is crucial for OC tumorigenesis.  MEX3A-mediated p53 protein degradation prevented ferroptosis and enhanced tumorigenesis of OC expressing wild type (wt) p53 [Wang et al, Cancer Research, 2023].  We also found a cell adhesion molecule, Desmoglein2 (DSG2), whose dynamic repression and de-repression in response to changing levels of oxygen allowed BC cells to detach from hypoxic primary tumor, invade in circulation and later colonize in oxygen rich distal organs [Chang et al, PNAS, 2021].  I have also made major contributions in understanding the functions of circadian core clock genes, such as PERIOD2 (PER2), in BC initiation and progression [Yu et al, BBA-GRM, 2018; Hwang-Verslues et al, PNAS, 2013].  Recently, my laboratory found that PER2 controls ROS homeostasis and HO-1 (Heme oxygenase-1, HMOX1) expression in OC cells. Loss of PER2 drove epithelial-like OC cells to undergo EMT and increased cisplatin resistance [Preprint DOI: 10.21203/rs.3.rs-5242949/v1].  

Ongoing Research — OC heterogeneity, metabolism, organotropic metastasis and drug resistance.

OC is the deadliest gynecological cancer due to its high heterogeneity, metastasis, chemoresistance and recurrence.  Unfortunately, the underlying mechanisms crucial for OC malignancy remain elusive.  High grade serous ovarian carcinoma (HGSOC) is the most prevalent subtype and has been the most studied.  Ovarian clear cell carcinoma (OCCC) is the second most prevalent subtype.  OCCC incidence rate is particularly high, and rising, in Asian populations, but it remains less understood.  HGSOC is more aggressive than other subtypes, has greater genomic instability, expresses mutated (mut) p53 and BRCA1/2, and easily develops resistance to the standard OC chemotherapy.  In contrast, OCCC has wt p53 and low BRCA mutation frequency.  While OCCC may not be as aggressive in early stage, it generally has higher metastasis and worse prognosis in advanced stages compared to HGSOC.  Numerous treatment strategies have been evaluated for OCCC, but the overall efficacy and subtype selectivity are low.  Developing combinations of targeted therapy and immunotherapy tailored to specific OC subtypes is promising but requires understanding of cancer cell intrinsic mechanisms and tumor microenvironment (TME) interactions that is still lacking for HGSOC and OCCC.  The goal of our ongoing research is to develop such understanding of HGSOC and OCCC tumorigenesis, metastasis and TME interactions, with focus on the role of MEX3A and BMAL2, a circadian gene that we recently found to have a prominent role in both HGSOC and OCCC.