Abstract
During tumorigenesis, pathways that promote the epithelial-to-mesenchymal transition (EMT) can both facilitate metastasis and endow tumor cells with cancer stem cell properties. To gain a greater understanding of how these properties are interlinked in cancers we used Drosophila epithelial tumor models, which are driven by orthologues of human oncogenes (activated alleles of Ras and Notch) in cooperation with the loss of the cell polarity regulator, scribbled (scrib). Within these tumors, both invasive, mesenchymal-like cell morphology and continual tumor overgrowth, are dependent upon Jun N-terminal kinase (JNK) activity. To identify JNK-dependent changes within the tumors we used a comparative microarray analysis to define a JNK gene signature common to both Ras and Notch-driven tumors. Amongst the JNK-dependent changes was a significant enrichment for BTB-Zinc Finger (ZF) domain genes, including chronologically inappropriate morphogenesis (chinmo). chinmo was upregulated by JNK within the tumors, and overexpression of chinmo with either RasV12 or Nintra was sufficient to promote JNK-independent epithelial tumor formation in the eye/antennal disc, and, in cooperation with RasV12, promote tumor formation in the adult midgut epithelium. Chinmo primes cells for oncogene-mediated transformation through blocking differentiation in the eye disc, and promoting an escargot-expressing stem or enteroblast cell state in the adult midgut. BTB-ZF genes are also required for Ras and Notch-driven overgrowth of scrib mutant tissue, since, although loss of chinmo alone did not significantly impede tumor development, when loss of chinmo was combined with loss of a functionally related BTB-ZF gene, abrupt, tumor overgrowth was significantly reduced. abrupt is not a JNK-induced gene, however, Abrupt is present in JNK-positive tumor cells, consistent with a JNK-associated oncogenic role. As some mammalian BTB-ZF proteins are also highly oncogenic, our work suggests that EMT-promoting signals in human cancers could similarly utilize networks of these proteins to promote cancer stem cell states.
Highlights
The Epithelial-to-mesenchymal transition (EMT), a developmental process involved in morphogenesis, organogenesis and wound healing, can be coopted by epithelial cancer cells to gain metastatic potential
The expression of nearly 1000 genes was altered by the expression of bskDN in either Ras or Notch-driven tumors, and less than half of these changes were shared between the two tumor types, indicating that Jun N-terminal kinase (JNK) signaling elicits unique tumorigenic expression profiles depending upon the cooperating oncogenic signal
Of the 399 JNK-regulated probe sets shared between Ras and Notch-driven tumors, we hypothesized that these had the potential to provide key insights into JNK’s oncogenic activity, and to prioritize these targets, we considered that the expression of the critical oncogenic regulators would not just be altered by bskDN, but would be normalized to close to wild type levels
Summary
The Epithelial-to-mesenchymal transition (EMT), a developmental process involved in morphogenesis, organogenesis and wound healing (reviewed in [1]), can be coopted by epithelial cancer cells to gain metastatic potential (reviewed in [2]). Triggers driving the induction of EMTs during tumorigenesis are beginning to be elucidated, and can include heterotypic interactions between tumor and associated stromal cells as a result of localized inflammation [4,5,6]. Cytokines such as IL-6 can promote an EMT and endow tumor cells with cancer stem cell properties [7], and TGFβ, which has well-established roles in the induction of EMT, can cooperate with TNF to induce EMT, stemness and tumorigenicity [8]. Deciphering the complex interrelationship that exists between the EMT and self-renewal pathways in cancer cells is a major challenge and will require the use of powerful model systems to tease out the separate and interconnected aspects of these two key developmental properties
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