Haotian Zhao, PhD, Lab
Primary Research Focus
The Zhao lab is focused on the study of brain cancers in children. As the significance of neuro-developmental pathways in childhood brain tumors are better understood, it has become apparent that many processes underlying normal brain development are disrupted and contribute to the development of childhood brain tumors. Knowledge of the genetic, molecular and cellular mechanisms of normal brain development is pivotal in the understanding of pediatric brain tumor development. Strategies targeting these abnormalities in developmental signaling pathways may potentially bring dramatic changes in the way we treat childhood brain tumors and significantly improve the outcome of children with these diseases.
Behind the research
Current research interests in the lab include:
Medulloblastoma Metastasis. WWe are limited in our ability to recognize and treat highly lethal forms of medulloblastoma (MB) because of an incomplete understanding of the biological mechanisms that regulate cellular proliferation, differentiation, and survival, the disruption of which allows pathological expansion of progressive or recurring tumors in primary organ and metastatic sites. MB is the most common malignant pediatric brain tumor that arises from the cerebellum. MB tends to undergo leptomeningeal dissemination (LMD) via spread through the cerebrospinal fluid (CSF) to the leptomeninges and subarachnoid space that cover the brain and spinal cord. Due to the risk of metastatic dissemination in MBs and associated poor prognosis, cranio-spinal radiation and chemotherapy are necessary, which invariably causes debilitating cognitive and neuroendocrine sequelae. Despite marked improvement in the survival of MB patients, approximately one third fails to respond and develop fatal tumor recurrence, which is usually accompanied by leptomeningeal metastasis. Innovative targeted therapies for metastatic and recurrent MBs are in great need that could more effectively manage these complications with reduced adverse effects. Accomplishment of this goal requires a detailed understanding of the mechanisms of MB metastasis and relapse. We generated novel animal models of MB that develop leptomeningeal metastasis, recapitulating key characteristics of human disease. We have developed bioluminescence assays to detect tumors in asymptomatic mice to facilitate non-invasive diagnosis of tumor development. Study of these novel animal models will advance our knowledge regarding MB metastasis and recurrence that is critical for the development of effective new diagnostics and therapies.
Choroid Plexus Tumor. Choroid plexus (CP) neoplasms represent rare primary brain tumors found predominantly in children. These tumors are believed to originate from CP epithelium, which differentiate from roof plate progenitors to form the CP, a specialized tissue that produces cerebrospinal fluid in each ventricle of the brain. While CP papillomas (CPP) are benign, CP carcinomas (CPC) are malignant. Surgery is generally curative; however, clinical outcomes for patients with incompletely resected tumors, recurrent tumors, metastatic spread, or CPCs, can be devastating. Notch signaling, tumor protein p53 (TP53) mutations, recurrent genomic and epigenetic changes have been described. Elucidating CP tumor biology is essential for developing effective new therapies. Accurate preclinical models are crucial for gaining knowledge regarding the molecular mechanims of CP tumors and evaluating potential therapeutics. By inducing sustained expression of the intracellular domain of Notch 1 (NICD1), we developed animal models of CP tumors that recapitulate properties of human CP tumors with NOTCH activation. Study of our extensive and novel animal models will help to define molecular and cellular mechanisms of CP tumors, evaluate new clinically available therapeutic strategies for CP tumors, and validate novel potential therapeutic targets in CP tumors.
May 2017 Dr. Haotian Zhao published a research article in Cancer Research explaining how Notch signaling influences leptomeningeal metastasis of medullosblastoma, the most common pediatric brain malignancy. "ATOH1 promotes leptomeningeal dissemination and metastasis of Sonic Hedgehog subgroup medulloblastomas."
November 2016, Katie Grausam, a PhD candidate in the Zhao laboratory, received a travel award from the University of South Dakota Center for Brain and Behavior Research.
November 2016, The Zhao laboratory gave two oral presentations at the 2016 meeting for the Society for Neuro-Oncology in Scottsdale, AZ. Dr. Zhao's presentation was entitled “Suppression of molecular circuit of multi-ciliate differentiation is critical for choroid plexus carcinoma development”. Katie Grausam, a graduate student in the Zhao laboratory, gave a talk entitled “Targeted therapy for leptomeningeal metastasis of medulloblastoma.”
October 2016, Dr. Zhao received funding from the Matthew Larson Foundation for a Medical Research Grant entitled "Molecular and cellular mechanisms of choroid plexus tumors."