Abstract
The phenomenon of how oncogenes and tumor-suppressor mutations can synergize to promote tumor fitness and cancer progression can be studied in relatively simple animal model systems such as Drosophila melanogaster. Almost two decades after the landmark discovery of cooperative oncogenesis between oncogenic RasV12 and the loss of the tumor suppressor scribble in flies, this and other tumor models have provided new concepts and findings in cancer biology that has remarkable parallels and relevance to human cancer. Here we review findings using the RasV12; scrib−/− tumor model and how it has contributed to our understanding of how these initial simple genetic insults cooperate within the tumor cell to set in motion the malignant transformation program leading to tumor growth through cell growth, cell survival and proliferation, dismantling of cell–cell interactions, degradation of basement membrane and spreading to other organs. Recent findings have demonstrated that cooperativity goes beyond cell intrinsic mechanisms as the tumor interacts with the immediate cells of the microenvironment, the immune system and systemic organs to eventually facilitate malignant progression.
Highlights
Mutations in oncogenes and tumor suppressors can synergize over time in order to optimize the tumor fitness within the host, a phenomenon known as cooperative oncogenesis
These findings highlight the importance of genetic cooperation for malignant transformation, the precise mechanisms operating during cooperative oncogenesis remain unclear
We summarize the contribution of the RasV12 ; scrib−/− model to the understanding of cooperative oncogenesis and cancer biology
Summary
Mutations in oncogenes and tumor suppressors can synergize over time in order to optimize the tumor fitness within the host, a phenomenon known as cooperative oncogenesis. A vast number of studies in the wing and eye-antennal discs have revealed several sets of cooperating genes that control tumor formation, growth and survival (reviewed in [6]) Among these cancer models, the cooperation between the Drosophila KRAS homolog oncogene, RasV12 and the loss of the cell polarity tumor suppressor scribble (referred to hereafter as “RasV12 ; scrib−/− ”) has been the most extensively investigated. The cooperation between the Drosophila KRAS homolog oncogene, RasV12 and the loss of the cell polarity tumor suppressor scribble (referred to hereafter as “RasV12 ; scrib−/− ”) has been the most extensively investigated This model recapitulates essential aspects of carcinoma development: loss of epithelial structure and differentiation, sustained proliferation, cytoskeletal remodeling, resistance to cell death, basement membrane degradation, and invasion [7,8,9,10,11]. The study of the genetic interactions between the two drivers of this model for cooperative oncogenesis has rapidly allowed the identification of key downstream signaling pathways and new concepts, which together explain malignancy
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