I have been enjoying the dynamic and challenging nature of cancer research, which drives me to do something that is new and important at each stage of my academic career. I was trained as a virologist with emphasis on viral entry and infectivity. After my first postdoctoral training at NIAID/NIH, I decided to take a challenge to study cancer biology in Dr. Donehower’s laboratory where the first p53 knockout mouse was generated. My initial work contributed to an important Nature research article concerning the role of p53 on organismal aging (Tyner S et al., Nature 2001). Soon after, I determined that Wip1 phosphatase is a master inhibitor in the DNA damage response, leading to preclinical and clinical studies of Wip1 inhibitors in cancer treatment (Lu X et al., Mol Cell 2004; Lu X et al., Genes & Dev 2005; Lu X et al., Cancer Cell 2007). My current research is focused on the following fields:
Cancer Genomics and targeted therapy - Genomic instability is one of the most pervasive characteristics of cancer cells. In my laboratory, we have been studying DNA damage response and cancer genomic alterations (translocation, amplification, and deletion). My recent work revealed that frequent heterozygous deletion of the p53 gene often encompasses a neighboring essential gene, POLR2A, rendering cancer cells vulnerable to further suppression of POLR2A (Liu Y et al., Nature 2015; Li Y et al., Nature Communications 2018). In collaboration with physician and bioengineering scientists, we are now developing antibody-drug conjugates that specifically target human cancers with chr17p loss . Through bioinformatics analysis of human cancer genomes and experimental validation, we have also identified therapeutic vulnerabilities in many types of human cancer (Liu Y et al, JCI 2018; Liu Y et al, Nature Communications 2018).
Nanodrugs for cancer therapy - My laboratory has been collaborating with biomedical engineering scientists to develop nanoscale biomaterials to safely and effectively deliver anticancer drugs. We have synthesized dual (temperature and pH) responsive polymeric nanoparticles with a core-shell morphology to co-encapsulate both hydrophilic and hydrophilic drugs for targeting tumors and the drug resistance mechanisms of cancer (Zhang W et al., ACS Nano 2010; Rao W et al., ACS Nano 2015). Moreover, we have been working on combined cancer treatment of chemo, photodynamic, and photothermal therapies (Wang H et al., Nature Communications 2015; Wang H et al., Advanced Materials 2016; Agarwal P et al., ACS Nano 2017; Wang H et al., Nature Communications 2018, Liu Y et al., Nature Communications 2018, Xu J et al., Nature Nanotechnology 2019).
Cancer omics and cancer immunology- We are interested to identify cancer gene signatures and tumor microenvironment that impact the infiltration of tumor-associated lymphocytes. Somatic mutations can give rise to neoantigens that are capable of eliciting potent T cell responses driven by current immunotherapies. However, mutations or aberrant gene expression in tumors can also induce resistance to immunotherapies. Clinical databases including cancer genomics, RNA-seq, proteomics, and tumor imaging are now analyzed to identify potential cancer gene signatures that are responsible for tumor-infiltration of cytotoxic lymphocyte. In vitro cytotoxicity assays, tumor organoid models, and in vivo tumor models (syngeneic tumor models and humanized mouse models) will be applied to determine the essential genes for tumor-associated lymphocyte penetration.
My laboratory will continue these efforts in understanding cancer biology, identifying novel drug targets and therapies, and developing new cancer drugs using innovative nanoscale biomaterials.