Yorkie dependent transcriptional network promotes tumor growth.
Studies in Drosophila and other tumor models have revealed cancer promoting signaling interactions and transcriptional addictions in tumors cells. The Hippo pathway effector, Yorkie (Yki) is a key mediator of such interactions and presents an attractive opportunity to study transcriptional dependencies in cancer cells. The RasV12 scrib-/- tumor mosaic model is well-established and shows activation of oncogenic Ras in the background of impaired apical-basal polarity. This model is widely used study molecular mechanisms and signaling events downstream of the oncogenic Ras and Ras-mediated Yorkie (Yki) activation in RasV12, scrib-/- tumor cells. Previously, we have shown that in RasV12, scrib-/- cells Wingless (Wg), Caspases (e.g., the initiator caspase Dronc) and JNK are activated to promote tumorigenesis through their non-apoptotic roles. Amongst these, Wg/Wnt pathway is known to act via canonical and non-canonical pathways during development and cancer, and interact with Yki to promote cancer growth. Genetic epistasis showed that Wg acts upstream of Caspases, JNK and Yki, and downregulation of Wg reduced tumor growth by downregulation of Caspases, JNK and Yki reporters. Our goal is to further understand how the two evolutionarily conserved signaling pathways i.e., Hippo and Wingless crosstalk and interact with each other to regulate tumor growth. To understand this intricate wiring of Wingless-Yorkie during tumor growth and invasion, we will use the RasV12, scrib-/- tumor model in Drosophila imaginal discs. Preliminary data showed that wg transcriptional reporters are upregulated in RasV12, scrib-/- cells, suggesting that increased accumulation of Wg may be due to increased transcription. In other contexts, wg is shown as a transcriptional target of Yki. Therefore, we will test for (a) the effects of Yorkie protein, the main effector molecule of Hippo pathway, on wg transcription and expression of other Wg pathway components by reporter assays, and qRT-PCR- based approaches, and (b) feedback interactions that promote tumorigenesis using genetic epistasis-, and immunohistochemistry-based approaches. Here, we present our progress on the organization of the molecular network involving Wingless and Yorkie.
Madhuri Kango-Singh, Amit Singh
Primary Advisor's Department
Stander Symposium project, College of Arts and Sciences
United Nations Sustainable Development Goals
Good Health and Well-Being
"Yorkie dependent transcriptional network promotes tumor growth." (2022). Stander Symposium Projects. 2436.