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: Non-coding sequences constitutes 98% of human genome. However the functions of non-coding sequences in cancer are large unknown. Non-coding RNAs, including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), represent novel classes of gene regulators. It is estimated that they control almost every genetic pathway and they are increasingly implicated in cancer development and metastasis.
Combining a miRNA expression library in a cell-based assay, Huang laboratory identified miR-373 and 520c as promoters of tumor migration, invasion and metastasis. Using bioinformatics and proteomics approaches, Huang laboratory also found a long non-coding RNA, treRNA, regulates metastasis at the translational step. Huang laboratory is currently using forward genetic screens to identify novel non-coding RNAs that regulate tumor development and metastasis.
Cancer Biomarker: The mortality rates are high in patients with late-stage solid tumors. Lack of biomarkers with high specificity and sensitivity is a major factor in the failure of cancer early diagnosis in the clinics. The Huang laboratory is currently using next generation sequencing technology to identify and validate circulating biomarkers in clinical samples. The molecules identified from this unbiased approach can serve as biomarkers for early diagnosis and disease progression monitoring.
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.