Abstract
Can hyperactivation of a few key signaling effectors be the underlying reason for the majority of epithelial cancers despite different driver mutations? Here, to address this question, we use the Drosophila model, which allows analysis of gene expression from tumors with known initiating mutations. Furthermore, its simplified signaling pathways have numerous well characterized targets we can use as pathway readouts. In Drosophila tumor models, changes in the activities of three pathways, Jun N-terminal Kinase (JNK), Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT), and Hippo, mediated by AP-1 factors, Stat92E, and Yorkie, are reported frequently. We hypothesized this may indicate that these three pathways are commonly deregulated in tumors. To assess this, we mined the available transcriptomic data and evaluated the activity levels of eight pathways in various tumor models. Indeed, at least two out of our three suspects contribute to tumor development in all Drosophila cancer models assessed, despite different initiating mutations or tissues of origin. Surprisingly, we found that Notch signaling is also globally activated in all models examined. We propose that these four pathways, JNK, JAK/STAT, Hippo, and Notch, are paid special attention and assayed for systematically in existing and newly developed models.
Highlights
Many components and signaling mechanisms of other pathways involved in cancer, such as Wnt (Wingless in Drosophila), Bone Morphogenetic Protein (BMP), Notch (N), Epidermal Growth Factor Receptor (EGFR)/Ras, Insulin, Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT), and Jun N-terminal kinase (JNK), were delineated using fly genetics [12,13,14,15,16,17,18,19,20]
The JNK, JAK/STAT, and Hippo signaling pathways were very frequently mentioned, leading us to question if their co-activation is truly a common feature underlying development of diverse tumors, or a bias in the assays used
To determine if a specific subset of pathways is consistently activated across diverse tumor types, creating a common tumorigenic signaling state, we performed a meta-analysis using available transcriptomic datasets of Drosophila tumors
Summary
Drosophila imaginal discs, larval precursors of adult epithelial tissues, are outstanding models of epithelial tumorigenesis. In 2005, the Cagan Lab published a Drosophila model of multiple endocrine neoplasia type 2 (MEN2) They used an active form of the Ret-kinase found in patients and expressed it constitutively in larval eye discs [21]. This model was utilized to map downstream effectors and for pharmacological screening, leading to an effective, Food and Drug Administration-approved treatment for the disease within 6 years of the initial publication [22,23]. We set out to determine whether these three pathways, or others, are commonly deregulated in Drosophila tumors of different initiating mutations
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