The Huang laboratory is developing and applying high-throughput technologies to functional genomics and cancer research. These technologies allow us to systemically study the functions of genes in the human genome and their roles in tumor development. The laboratory is using these technologies to study tumor metastasis, identify novel chemotherapy drug targets, and improve the efficacy of cancer treatment.
Tumor Growth and Metastasis: Cancer affects approximately one in three individuals. The deaths of most cancer patients are the result of metastasis. The process of metastasis is a complex, multi-step, poorly understood process: it involves tumor growth, invasion, survival in the blood stream or lymphatics, avoidance of immune surveillance, extravasation, and growth at a distant site. Most studies have focused on the formation of tumors, primarily because of the ease with which many tumor cells can be grown. However, relatively little is known about the mutations that affect tumor invasion and metastatic spread.
The Huang laboratory is applying functional genomics technologies to in vivo animal models to identify genes that control metastasis process and understand the mechanisms of tumor invasion and dissemination. Such genes may make excellent anti-cancer drug targets, because their disruption results in the inability of tumors to grow or spread.
Non-coding RNA and Tumor Development: MicroRNAs (miRNAs) are single-stranded noncoding RNAs of ~22 nucleotides and represent a novel class of gene regulators. They function as negative gene regulators by binding to 3’ untranslated regions (3’UTR) of target messenger RNAs (mRNAs) and suppressing their translation or promoting their degradation. It is estimated that each miRNA controls hundreds of gene targets and as a group they regulate 30% of human genes and almost every genetic pathway.
MicroRNAs play important roles in processes as diverse as normal development and cellular homeostasis. Recent evidence suggests that they can function as oncogenes or tumor suppressors. Combining a miRNA expression library in a cell-based assay, Huang laboratory recently identified miR-373 and 520c as promoters of tumor migration, invasion and metastasis. Huang laboratory is currently using forward genetic screens to identify novel non-coding RNAs including miRNAs that regulate tumor development and metastasis.
Selective Chemotherapy: Cancer chemotherapy drugs have traditionally targeted the aberrant proliferation of tumor cells. The mechanisms of action of these drugs include DNA damaging agents, mitotic arrest agents, antimetabolic agents and steroid signaling inhibitors. Unfortunately these small molecules are not specific to tumor cells and cause severe side effects.
Over the past decade, some genetic lesions that are involved in cancer development have been identified and have prompted the development of selective small molecule and antibodies that target the causative proteins in cancers. However, these agents are limited to the treatment of few types of cancer. In order to find targets for the next generation of cancer selective chemotherapy, it will be necessary to use a variety of recent developed new technologies such as RNAi and chemical genetics.
The Huang laboratory is using array-format high throughput technologies to systemically identify genetic molecules and signaling pathways that, when disrupted, either by small molecules or RNAi, lead to tumor cell death but have no effect on normal cells. These studies will lead to new drug targets and chemotherapies that may be effective in the treatment of a broad spectrum of tumors. The small molecules found in this screen may also be more selective than conventional chemotherapy drugs and have fewer side effects.