Whereas the series of genetic events leading to colorectal cancer (CRC) have been well established, the precise functions that these alterations play in tumor progression and how they disrupt intestinal homeostasis remain poorly characterized. Activation of the Wnt/Wg signaling pathway by a mutation in the gene APC is the most common trigger for CRC, inducing benign lesions that progress to carcinomas due to the accumulation of other genetic alterations. Among those, Ras mutations drive tumour progression in CRC, as well as in most epithelial cancers. As mammalian and Drosophila's intestines share many similarities, we decided to explore the alterations induced in the Drosophila midgut by the combined activation of the Wnt signaling pathway with gain of function of Ras signaling in the intestinal stem cells. Here we show that compound Apc-Ras clones, but not clones bearing the individual mutations, expand as aggressive intestinal tumor-like outgrowths. These lesions reproduce many of the human CRC hallmarks such as increased proliferation, blockade of cell differentiation and cell polarity and disrupted organ architecture. This process is followed by expression of tumoral markers present in human lesions. Finally, a metabolic behavioral assay shows that these flies suffer a progressive deterioration in intestinal homeostasis, providing a simple readout that could be used in screens for tumor modifiers or therapeutic compounds. Taken together, our results illustrate the conservation of the mechanisms of CRC tumorigenesis in Drosophila, providing an excellent model system to unravel the events that, upon mutation in Apc and Ras, lead to CRC initiation and progression.

Organ and tissue formation requires a finely tuned temporal and spatial regulation of differentiation programmes. This is necessary to balance sufficient plasticity to undergo morphogenesis with the acquisition of the mature traits needed for physiological activity. Here we addressed this issue by analysing the deposition of the chitinous extracellular matrix of Drosophila, an essential element of the cuticle (skin) and respiratory system (tracheae) in this insect. Chitin deposition requires the activity of the chitin synthase Krotzkopf verkehrt (Kkv). Our data demonstrate that this process equally requires the activity of two other genes, namely expansion (exp) and rebuf (reb). We found that Exp and Reb have interchangeable functions, and in their absence no chitin is produced, in spite of the presence of Kkv. Conversely, when Kkv and Exp/Reb are co-expressed in the ectoderm, they promote chitin deposition, even in tissues normally devoid of this polysaccharide. Therefore, our results indicate that both functions are not only required but also sufficient to trigger chitin accumulation. We show that this mechanism is highly regulated in time and space, ensuring chitin accumulation in the correct tissues and developmental stages. Accordingly, we observed that unregulated chitin deposition disturbs morphogenesis, thus highlighting the need for tight regulation of this process. In summary, here we identify the genetic programme that triggers the timely and spatially regulated deposition of chitin and thus provide new insights into the extracellular matrix maturation required for physiological activity. In this work we studied the maturation of the extracellular matrix during Drosophila embryogenesis. Drosophila deposit a chitin-rich extracellular matrix with key physiological functions, such as the control of organ size and shape, and cuticle formation. Chitin synthesis depends on chitin synthases, and in Drosophila the gene krotzkopf verkehrt (kkv) encodes the main enzyme of this family. Our observations indicate that Kkv alone is not sufficient to induce chitin formation. We have identified another function (which is exerted by the activity of two genes encoding MH2-domain proteins) that are equally required for chitin deposition. The most striking result of our analysis is that the presence of Kkv and the newly identified function is sufficient to trigger chitin deposition in ectodermally-derived tissues, even if they are normally devoid of this polysaccharide. Importantly, we also demonstrate that unregulated chitin deposition (absent, advanced, or ectopic) leads to severe defects in morphogenesis. We show that the temporal and spatial pattern of kkv and the other two genes perfectly recapitulates the deposition of chitin, thereby unveiling a highly co-ordinated mechanism for the acquisition of mature traits.

Hormones play essential roles during development and maintaining homeostasis in adult organisms, regulating a plethora of biological processes. Generally, hormones are secreted by glands and perform a systemic action. Here we show that Juvenile Hormones (JHs), insect sesquiterpenoids synthesized by the corpora allata, are also synthesized by the adult Drosophila gut. This local, gut specific JH activity, is synthesized by and acts on the intestinal stem cell and enteroblast populations, regulating their survival and cellular growth through the JH receptors Gce/Met and the coactivator Tai. Furthermore, we show that this local JH activity is important for damage response and is necessary for intestinal tumor growth driven by activating mutations in Wnt and EGFR/Ras pathways. Together, our results identify JHs as key hormonal regulators of gut homeostasis and open the possibility that analogous hormones may play a similar role in maintaining vertebrate adult intestinal stem cell population and sustaining tumor growth.

The evolutionary perspective of cancer (which origins and dynamics result from evolutionary processes) has gained significant international recognition over the past decade and generated a wave of enthusiasm among researchers. In this context, several authors proposed that insights into evolutionary and adaptation dynamics of cancers can be gained by studying the evolutionary strategies of organisms. Although this reasoning is fundamentally correct, in our opinion, it contains a potential risk of excessive adaptationism, potentially leading to the suggestion of complex adaptations that are unlikely to evolve among cancerous cells. For example, the ability of recognizing related conspecifics and adjusting accordingly behaviors as in certain free‐living species appears unlikely in cancer. Indeed, despite their rapid evolutionary rate, malignant cells are under selective pressures for their altered lifestyle for only few decades. In addition, even though cancer cells can theoretically display highly sophisticated adaptive responses, it would be crucial to determine the frequency of their occurrence in patients with cancer, before therapeutic applications can be considered. Scientists who try to explain oncogenesis will need in the future to critically evaluate the metaphorical comparison of selective processes affecting cancerous cells with those affecting organisms. This approach seems essential for the applications of evolutionary biology to understand the origin of cancers, with prophylactic and therapeutic applications.