Prostate cancer is the most diagnosed cancer and the leading cause of cancer death in men worldwide. Although nearly all patients respond
to androgen deprivation therapy, most patients progress to castration-resistant prostate cancer with high rates of metastasis and mortality. Over the past decade, large-scale cancer genome studies have uncovered emerging genetic alterations in advanced prostate cancer. It is vital to identify and characterize genetic determinants that drive prostate cancer development, metastatic progression, and resistance to therapy. The Zhao Laboratory focuses on functional genomics of prostate cancer, with a special interest in the crosstalk between cancer cells and immune components in the tumor microenvironment and metastatic niche. Using state-of-the-art mouse modeling systems and single-cell multi-omics, our major research directions include:
- Characterizing the genetic determinants that drive prostate cancer development, metastatic progression, and therapy resistance
- Identifying genetic alterations involving myeloid cell remodeling in the tumor microenvironment and metastatic niche
- Developing biomarker-driven immunotherapies and combinatorial strategies for personalized cancer care
Characterizing the genetic determinants that drive prostate cancer development, metastatic progression, and therapy resistance
Genetically engineered mouse models (GEMMs) produce spontaneous tumors in immunocompetent mice, offering unique systems for studying tumor development, metastatic progression, and tumor-host interactions. Our team utilizes the GEMMs to investigate the role of emerging tumor suppressor genes and oncogenes in prostate cancer progression and response to therapies. Our laboratory has established and characterized several GEMMs to mimic different genetic subtypes of prostate cancer. Combined with high-throughput multi-omics technology and in-depth mechanistic studies, these GEMMs enable us to uncover novel functions of hotspot genetic alterations, alone or in combination, in different stages of prostate cancer. Besides, we generate syngeneic cell lines and 3D tumor organoids from these GEMMs, which provide unique tools to study tumorigenesis, cancer cell-immune cell interaction, and drug response.
Identifying genetic alterations involving myeloid cell remodeling in the tumor microenvironment and metastatic niche
Immunosuppressive myeloid cells, including tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs), contribute to progression and therapy resistance in prostate cancer. Understanding the crosstalk between cancer cells and myeloid components in the tumor microenvironment and metastatic niche facilitates the development of effective therapeutics for advanced prostate cancer. Combining our state-of-the-art mouse modeling systems and single-cell-based immunoprofiling, we aim to deconvolute how genetic alterations in cancer cells influence the abundance, phenotype, and functions of myeloid cells in prostate tumors and metastatic diseases.
Developing biomarker-driven immunotherapies and combinatorial strategies for personalized cancer care
Checkpoint immunotherapy only showed modest anti-tumor activities in advanced prostate cancer, partially due to lack of T cell infiltration, low mutational burden, and presence of suppressive immunocytes. To improve the efficacy of immunotherapy in prostate cancer, it is equally important to explore combinatorial strategies and identify the molecular subtypes that better respond to certain immunotherapy. Taking advantage of our unique preclinical mouse models, we determine the impact of oncogenic alterations on immune checkpoint signaling and the efficacies of checkpoint immunotherapy in prostate cancer. By elucidating in-depth mechanisms and conducting pre-clinical trials, we aim to develop biomarker-driven combinatorial immunotherapy for men with lethal prostate cancer.