Dr. Thiele leads a research program which develops novel therapies for children with solid tumors using state-of-the-art biologic and genomic analyses of tumors and normal counterparts. She pioneered studies using retinoids to “target” the MYCN oncogene and control tumor growth. These led to clinical studies which showed that retinoids improved outcomes for children with high-risk neuroblastoma.
Her section has developed pre-clinical models and genetically engineered mice (GEMs) to study mechanisms of neuroblastoma tumorigenesis and assess novel therapeutic interventions. Ongoing studies are aimed at understanding epigenetic/chromatin based mechansims to re-program and differentiate neuroblastoma tumor cells.
Cell and Molecular Biology Section
Every year approximately 700 cases of neuroblastoma (NB) and 210 cases of Ewings' sarcoma (EWS) are diagnosed in children less than 20 years of age. Half will fail conventional therapy. Despite the progress made in the development of clinical/genetic-based staging systems for NB and EWS the prognosis for patients with unfavorable disease remains dismal. The focus of the Cell and Molecular Biology Section has been to develop a comprehensive understanding of the biology of peripheral neuroectodermal tumors cells. We do so by developing in vitro and in vivo modeling systems that will enable genetic interrogation of the biologic systems of tumor cells and their normal counterparts. The insights gained from these studies serve as a platform for the development of novel therapies for the treatment of children with these diseases.
A number of genetic alterations have been identified in neuroblastoma tumors which are thought to contribute to tumorigenicity. Despite these genetic alterations, retinoids (derivatives of Vitamin A) are capable of arresting cell growth, inducing differentiation and suppressing tumorigenicity. Thus by activating alternative intracellular signaling programs we may be able to bypass genetic defects and restore growth control and induction of differentiation.
Project I: The BDNF/TrkB/PI3-Kinase/AKT Pathway Is Important in the Survival and Metastatic Capability of NB Tumor Cells. The specific aims of this project are:
- To identify and characterize the molecular mechanisms mediating these processes; and
- To evaluate the therapeutic potential of targeting downstream signaling intermediaries of the PI3-Kinase/AKT pathway to enhance chemosensitivity and inhibit metastasis and angiogenesis.
Project II: Clinical, Histopathologic and Genetic Evidence Indicates that Alterations in the Regulation of Normal Development Contribute to NB Tumorigenesis. The specific aims of this project are:
- To identify and characterize NB tumor-initiating cells/cancer stem cells;
- To identify the epigenetic pathways dysregulated in NB by using chemical and siRNA screens to identify comounds that target these epigenetic pathways; and
- To study the epigenetic mechanisms regulating NB differentiation by using chemical and small molecule screens to identify agents that stimulate differentiation.
CBMS Research Data
CHLA-LAN-5 neuroblastoma cell growth in vitro - Note neuroblastoma cells are motile and clumps of cells aggregate. Cells continue to proliferate until the entire bottom of the flask is confluent.
CHLA-LAN-5 neuroblastoma cells treated with retinoic acid in vitro. - Note neuroblastoma cells growing in clumps, disperse and begin to extend short extensions. By 48hrs cells have ceased to proliferate and the extension of processes increases. Subsequently cells begin to re-aggregate and the clumps are tethered to each other and the bottom of the flask by longer neuritic-like extensions. In a “tug-of-war” like fashion the clumps of cells move around the flask and aggregate into even larger balls of cells.
The CMBS Section 2014
Essential role of the zinc finger transcription factor Casz1 for mammalian cardiac morphogenesis and development.J. Biol. Chem. 289: 29801-29816, 2014. [ Journal Article ]
- Cancer Res. 72: 315-324, 2012. [ Journal Article ]
Genetic and pharmacologic identification of Akt as a mediator of brain-derived neurotrophic factor/TrkB rescue of neuroblastoma cells from chemotherapy-induced cell death.Cancer Res. 65: 2070-2075, 2005. [ Journal Article ]
CASZ1, a candidate tumor-suppressor gene, suppresses neuroblastoma tumor growth through reprogramming gene expression.Cell Death Differ. 18: 1174-1183, 2011. [ Journal Article ]
Decreased expression of N-myc precedes retinoic acid-induced morphological differentiation of human neuroblastoma.Nature. 313: 404-406, 1985. [ Journal Article ]
Dr. Thiele received her Ph.D. in Microbiology and Immunology from the University of California, Los Angeles. She completed her postdoctoral research as a Cancer Research Institute and a Damon Runyon-Walter Winchell Fellow at the NCI. Dr. Thiele was one of the founding editors of Cell Death & Differentiation, and has served on the editorial boards of Cell Death & Differentiation, Cancer Research and Molecular Cancer Therapeutics. Dr. Thiele was Chair of the AACR Women in Cancer Research and has a long-standing interest in developing programs so that young scientific investigators can realize their potential. As the Chief of the Cell and Molecular Biology Section in the Pediatric Oncology Branch, Dr. Thiele's scientific interest is in the field of cancer biology with a special emphasis on pediatric neuroectodermal tumors and neuronal development. She has been involved in the organization of the Advances in Neuroblastoma Research Association (ANRA). Her research strives to understand molecular mechanisms involved in the pathogenesis of neuroblastoma tumors and utilizes insights gleaned from these studies to develop novel therapeutic strategies for pediatric tumors.
|Fidelia Acevedo||Program Assistant|
|Deblina Banerjee, Ph.D.||Postdoctoral Fellow (Visiting)|
|Norris Lam. B.S.||Postbaccalaureate Fellow|
|Kenneth Lieuw||Research Collaborator|
|Zhihui Liu Ph.D.||Staff Scientist|
|Ming Sun Ph.D.||Postdoctoral Fellow (Visiting)|
|Veronica Veschi, M.D., Ph.D.||Predoctoral Fellow (Visiting)|
|Man Xu Ph.D.||Postdoctoral Fellow (Visiting)|
- A Problem of Disordered Development (CCR connections, Vol. 4, No. 2, 2010)
- Camera on Cancer Research: Unraveling the Molecular Mechanisms of Neuroblastoma
2011 FARE Awards
- Doo-Yi Oh – Retinoids (RA) Relieve EZH2- mediated Epigenetic Suppression of Neuroblastoma (NB) Differentiation
- Shuang Yan, MD, PhD – Neuroblastoma Tumor Initiating Cells Express CD22 Making Them Susceptible to HA22 anti-CD22 Immunotoxin-induced Cell Death
Advances In Neuroblastoma Research 2010 – Best Abstracts
- Ryan Virden – Identification and Analysis of Critical Domains in the Neuroblastoma Tumor Suppressor Gene CASZ1
- Chunxi Wang – EZH2 Mediates Epigenetic Silencing of Candidate Neuroblastoma Tumor Suppressor Gene CASZ1
- Zhihui Liu, PhD – Haploinsufficiency of Candidate Tumor Suppressor Gene CASZ1 Blocks Embryonic Stem Cell Neurogenesis
2010 NCI Director’s Intramural Innovation Awards
- Zhihui Liu, PhD – Genetic Screen of Candidate Tumor Suppressor Genes for Neural Crest-derived Tumors
A collage of our lab staff
The section at Great Falls
Our section singing Christmas Carols