Keywords: MicroRNA biology, Cancer Research, Lung cancer, Cancer genomics, Oncogene mechanism, Oncogenic signaling, Cancer cell metabolism, Cancer drugs, CRISPR-based gene targeting, exosome, extracellular vesicles.
I. Lung Cancer Signaling, MicroRNA, and Metabolism
Oncogenes activated via gene amplification have a proven track record of being amenable to drug discovery. We and others discovered a recurrent amplified region in lung cancer genomes. This amplicon contains the TTF-1 gene (thyroid transcription factor 1 or known as NKX2-1) which is essential for lung development and morphogenesis. We mapped the interconnection between TTF-1 and microRNAs to uncover novel entry points to investigate TTF-1-linked lung biology and discovered the two types of microRNAs interacting with TTF-1 - miR-365 that regulates TTF-1 and miR-33a that is regulated by TTF-1. Since miR-33a is a known regulator of cholesterol metabolism (CM), our finding suggests that TTF-1 may modulate CM in the lung. This represents a novel research direction regarding TTF-1 and we are actively pursuing it.
II. Cancer Secretome and Exosome
How a cell lineage gene such as TTF-1 may reprogram the function of secretome is poorly understood. To this end, we discovered that TTF-1 confers an antiangiogenic function to the secretome of lung cancer epithelial cells. This antiangiogenic activity is derived from TTF-1-promoted secretion of GM-CSF from the lung cancer epithelial cells which in turn induces endothelial cells to release the antiangiogenic soluble VEGF receptor 1. In view of this finding, we surmise that the exosomal cargo content in the secretome may also be subject to TTF-1 regulation. Indeed, we have shown that VEGF is a direct transcriptional target of TTF-1 and the exosomal VEGF cargo level is increased in the TTF-1+ lung cancer cells, suggesting that TTF-1 may reprogram the exosomal cargo content. We are interested in quantifying the extent of the TTF-1-dependent exosomal cargo reprogramming and the associated biological consequences.
Dr. David Mu received Ph.D. in Chemistry from the University of California at Berkeley under the guidance of Professor Judith P. Klinman. Subsequently, he conducted postdoctoral research in the laboratory of Professor Aziz Sancar at the University of North Carolina at Chapel Hill. His postdoctoral research of human Nucleotide Excision Repair mechanism attracted support from the Damon Runyon Cancer Research Fund. Following postdoctoral training, he joined the Cancer Genomics Division of Tularik Inc., using genomic tools to find novel cancer genes for drug discovery. Out of his desire to pursue research of his interest, he later returned to academia by joining the Cancer Genome Center of the Cold Spring Harbor Laboratory (CSHL), extending his cancer genomics research specifically in the realm of lung cancers. His research at CSHL culminated in the discovery of a recurrent lung cancer amplicon at 14q13 in which three genes (TTF-1, NKX2-8, and PAX9) are coamplified. Currently, Dr. Mu is dissecting the signaling mechanism of the amplified lung oncogenes at 14q13 by probing how the microRNA network is intertwined with the amplified lung oncogenes. In addition, he has a separate line of research that searches for new uses of old medications. Due to his past work experience in the biotech sector, he is keen in translating his scientific studies into practices that improve people's life.