Elucidate the Context-Dependent Tumorigenic Functions of Human ERBB Receptors in Drosophila 

張夆昌1, 陳俊宏2, 高智飛1

1Department of Biological Science and Technology, National Yang Ming Chiao Tung University

2National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes 

Genetic alterations of ERBB receptors have been shown to promote the initiation and progression of cancers. However, the prevalence of copy number amplification and missense mutations of individual ERBB receptors vary between cancer types. It remains elusive whether the genetic alterations of ERBB receptors are the authentic tumor drivers in specific cancers and whether the oncogenic effects of ectopic expression/mutation of ERBB receptors depend on the cellular/genetic contexts of the affected tissues. Using Drosophila as an in vivo tumor model, we characterize the oncogenic competence and the required downstream signaling pathways of each human ERBB receptor when ectopically expressed in specific tissue/cell types. We find that the oncogenic phenotypes induced by ectopic expression of ERBB receptors vary between tissue types. When ectopically expressed in glia, hERBB2 is capable to induce dramatic overgrowth which displays aspects of tumor-like malignancy, while hEGFR is only capable to induce benign overgrowth. Mechanistically, we found that STAT signaling is upregulated in hERBB2 activated-glial cells but not in hEGFR-activated glial cells, and upregulation of STAT signaling is essential for the proliferation and invasion of hERBB2-activated glial cells. Our findings provide insight into the molecular function of human ERBB receptors in driving tumor formation in glial cells.