Throughout the development and life of an animal, many of its cells die and are removed to make space for new tissues. A group of proteins called caspases play a key role in this cell death process. Chemotherapy and radiotherapy work as cancer treatments because they damage dividing cancer cells to such an extent that caspases are turned on and kill those cells. Unfortunately the tumor occasionally grows back after the treatment, partly because caspases also help to produce signals that boost the growth of any surviving cancer cells.

Pérez, Lindblad and Bergmann have now used the fruit fly Drosophila to investigate how caspases encourage tumor cells to grow and spread. The fruit flies all carried a mutation in a gene called Ras, which is often mutated in human cancers. Using a combination of genetic and biochemical experiments Pérez, Lindblad and Bergmann found that mutant Ras prevents cells with active caspases from dying. Instead, the caspases redirect their activity and help cancer cells to produce small chemicals called reactive oxygen species. These chemicals can play many different roles in cancers, but in this setting they attract immune cells to the site of the tumor. The immune cells in turn send other signals back to the cancer cells, which further activate the caspases. Overall, this self-perpetuating signaling loop between the cancer cells and the surrounding immune cells helps the tumors to grow.

Future work toward developing new cancer treatments will need to work on ways of enhancing the cell-killing properties of caspases while inhibiting their ability to help tumors to grow. Further experiments will also be needed to find out exactly how the mutant Ras gene protects tumor cells from death.

Larval imaginal discs in Drosophila are single-cell layered sacs of epithelial cells that develop into the adult appendages such as eyes and wings, and are frequently used as genetic models for growth control and tumor development. Maintenance of apical-basal polarity of epithelial cells is critical for suppression of neoplastic tumor development (Elsum et al., 2012; Bergstralh and St Johnston, 2012; Martin-Belmonte and Perez-Moreno, 2011). Mutations in genes encoding components of the Scribble complex including scribble (scrib), lethal giant larvae (lgl) and discs large (dlg) disrupt apical-basal polarity in epithelial cells which can trigger malignant neoplastic tumor growth (Bergstralh and St Johnston, 2012; Elsum et al., 2012; Bilder et al., 2000; Gateff, 1978; Bilder and Perrimon, 2000). Drosophila larvae entirely mutant for scrib fail to respond to stop signals of growth, fail to pupariate and continue to grow as larvae (Gateff, 1994; Wodarz, 2000). They die as giant larvae with severely overgrown imaginal discs.

However, scrib mutant cells (clones) in otherwise wild-type imaginal discs are eliminated by cell competition mediated by neighboring wild-type cells (Brumby and Richardson, 2003; Menéndez et al., 2010; Igaki et al., 2009; Uhlirova et al., 2005; Ohsawa et al., 2011; Leong et al., 2009; Chen et al., 2012; Vaughen and Igaki, 2016). Mechanistically, in response to cell competition, Eiger, the Tumor Necrosis Factor alpha (TNFα)-like ligand in Drosophila, triggers Jun N-terminal kinase (JNK) activation and apoptosis in scrib mutant cells (Igaki et al., 2009; Brumby and Richardson, 2003; Uhlirova et al., 2005; Cordero et al., 2010; Ohsawa et al., 2011; Leong et al., 2009; Igaki et al., 2006; Chen et al., 2012). This tumor-suppressing function is dependent on Eiger and JNK through induction of apoptosis. Inhibition of Eiger or JNK restores the growth potential of scrib mutant cells which can then form large tumor masses in imaginal discs (Brumby and Richardson, 2003; Igaki et al., 2009; Uhlirova et al., 2005; Chen et al., 2012).

However, if additional oncogenic mutations such as Ras^V12 are introduced into scrib mutant cells (referred to a scrib^−/− Ras^V12), they can unleash their full malignant potential (Brumby and Richardson, 2003; Pagliarini and Xu, 2003). scrib^−/− Ras^V12 mosaic eye/antennal imaginal discs display all neoplastic features observed in human tumors including unrestricted growth, failure to differentiate, tissue invasion and organismal lethality (Pagliarini and Xu, 2003; Brumby and Richardson, 2003). scrib^−/− Ras^V12 clones occupy a large portion of the mosaic disc and trigger multi-layered overgrowth of the entire disc compared to wild-type controls (Figure 1H,I). scrib^−/− Ras^V12 mutant cells also invade other tissues, most notably the ventral nerve cord (VNC) in the brain (Figure 1H,I) (Pagliarini and Xu, 2003). The scrib^−/− Ras^V12 condition in ey-FLP-induced eye imaginal disc mosaics is 100% lethal. 95% of ey-FLP-induced scrib^−/− Ras^V12 mosaic animals die as larvae; the remaining animals die during pupal stages.

Figure 1 with 2 supplements see all

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Interestingly, Ras^V12 inhibits the apoptotic activity of JNK and converts the tumor-suppressor function of Eiger and JNK in scrib^−/− cells into a tumor-promoting one in scrib^−/− Ras^V12 cells (Enomoto et al., 2015; Cordero et al., 2010; Uhlirova et al., 2005; Igaki et al., 2006; Uhlirova and Bohmann, 2006). Therefore, the aggressive tumor growth of scrib^−/− Ras^V12 mutant clones becomes dependent on Eiger and JNK (Igaki et al., 2006; Uhlirova and Bohmann, 2006; Brumby et al., 2011). Mechanistically, it is not understood how Ras^V12 promotes this oncogenic switch of Eiger and JNK.

Caspases are Cys-proteases that mediate the mechanistic events of apoptotic cell death (Shalini et al., 2015; Xu et al., 2009; Fuchs and Steller, 2011; Salvesen et al., 2016). They are synthesized as zymogens and depending on the length of their prodomains can be classified into initiator and effector caspases. Initiator caspases such as mammalian Caspase-9 or its Drosophila ortholog Dronc are controlled by upstream signaling events and when activated initiate apoptosis by activating effector caspases such as mammalian Caspase-3 or its Drosophila ortholog DrICE (Fuchs and Steller, 2011; Shalini et al., 2015; Salvesen et al., 2016). Caspases induce apoptosis of many cells to maintain homeostatic conditions, and are also thought to be critical for tumor suppression by eliminating malignant cells.

However, caspases can also have tumor-promoting roles, for example through apoptosis-induced proliferation (AiP), a caspase-driven process by which apoptotic cells produce mitogenic signals for proliferation of neighboring surviving cells (Mollereau et al., 2013) (reviewed in [Fogarty and Bergmann, 2017; Ryoo and Bergmann, 2012]). There are two types of AiP. During ‘genuine’ AiP, apoptotic cells release mitogenic factors before completing the apoptotic program. This type of AiP has been described for regeneration and wound healing both in vertebrates and invertebrates (Tseng et al., 2007; Fan and Bergmann, 2008; Chera et al., 2009; Li et al., 2010). ‘Genuine’ AiP may also be involved in human pathologies such as cancer, and may account for increased cell proliferation and repopulation of tumors following cytotoxic treatments (chemo- or radiotherapy) which induces massive apoptosis (reviewed in [Fogarty and Bergmann, 2017; Ichim and Tait, 2016]). Caspases play significant tumor-promoting roles in these settings (Li et al., 2010; Huang et al., 2011; Donato et al., 2014; Cheng et al., 2015; Zhang et al., 2015; Kurtova et al., 2015).

The second type is ‘undead’ AiP. Here, the apoptosis pathway is induced upstream, but the execution of apoptosis is blocked. In Drosophila, apoptosis inhibition is achieved experimentally by expression of the effector caspase inhibitor p35 which very specifically inhibits DrICE (Hay et al., 1994; Meier et al., 2000; Hawkins et al., 2000). Therefore, because these cells have initiated the apoptotic process and contain active Dronc, but cannot die, they are referred to as ‘undead’. In ‘undead’ cells, non-apoptotic functions of active Dronc can now be examined, one of which is the release of mitogenic signals for induction of AiP which can lead to hyperplastic overgrowth (Wells et al., 2006; Kondo et al., 2006; Huh et al., 2004; Ryoo et al., 2004; Martín et al., 2009; Pérez-Garijo et al., 2009; Pérez-Garijo et al., 2004; Fan et al., 2014; Rudrapatna et al., 2013; Pérez-Garijo et al., 2005). ‘Undead’ states of cells may also be present under pathological conditions. For instance, it has been proposed that Ras^V12 can maintain apoptotic cells in an ‘undead’-like state promoting tumorigenesis (Hirabayashi et al., 2013).

Mechanistically, we have shown that AiP-mediated hyperplastic overgrowth of ‘undead’ tissue depends on a Dronc-initiated feedback amplification loop which involves reactive oxygen species (ROS) – specifically extracellular ROS produced by the membrane-bound NADPH oxidase Duox –, activation of macrophage-like hemocytes, secretion of Eiger by hemocytes, Eiger-dependent activation of JNK in epithelial disc and further activation of Dronc by JNK (Fogarty et al., 2016) (reviewed by [Diwanji and Bergmann, 2017a; Diwanji and Bergmann, 2017b]). Therefore, similar to the scrib^−/− Ras^V12 case, Eiger and JNK signaling have proliferation- and growth-promoting functions in this ‘undead’ AiP model.

These similarities prompted us to investigate the role of ROS and caspases for tumor growth of scrib^−/− Ras^V12 clones in Drosophila. We report that oncogenic Ras switches the pro-apoptotic activity of caspases into a tumor-promoting one and thereby maintains scrib^−/− Ras^V12 cells in an ‘undead’-like state. Consistently, inhibition of caspases blocks tumor growth and tissue invasion. The tumor-promoting function of apoptotic caspases is dependent on the generation of intra- and extracellular ROS which are required for neoplastic behavior of scrib^−/− Ras^V12 clones. Furthermore, caspase-induced ROS are essential for the recruitment and activation of hemocytes at scrib^−/− Ras^V12 mosaic discs. Hemocytes signal back to tumorous epithelial cells to stimulate JNK signaling which further promotes caspase activity. Thus, these events constitute a feedback amplification loop which is necessary for neoplastic activity of scrib^−/− Ras^V12 cells. This work extends previous models about the conversion of Eiger and JNK signaling from anti-tumor to pro-tumor roles by oncogenic Ras and identifies caspases as essential components of this switch. In conclusion, although apoptotic caspases are usually considered to be tumor suppressors, under certain conditions, for example in the presence of oncogenic Ras^V12 in scrib mutant cells, they can also adopt a tumor-promoting role.

The traditional view of caspases holds that they counter tumorigenesis by eliminating tumor cells and thus mediate a tumor suppressor function (Hanahan and Weinberg, 2000; Hanahan and Weinberg, 2011). This tumor-suppressing function of caspases has been reported in mammalian systems (Asselin-Labat et al., 2011; Ho et al., 2009) and in Drosophila, where, for example, scrib mutant cells undergo caspase-dependent apoptosis in a JNK- and Eiger-dependent manner (Brumby and Richardson, 2003; Igaki et al., 2006; Igaki et al., 2009; Uhlirova et al., 2005). However, more recent work has suggested that caspases and apoptosis in general can also have the opposite, tumor-promoting function, both in flies and in mammals (Cheng et al., 2015; Donato et al., 2014; Huang et al., 2011; Kurtova et al., 2015; Li et al., 2010; Zhang et al., 2015); reviewed by (Ryoo and Bergmann, 2012; Ichim and Tait, 2016; Fogarty and Bergmann, 2017). Furthermore, in Drosophila it was previously shown that oncogenic Ras switches the tumor-suppressing function of JNK and Eiger in scrib^−/− mutant cells to a tumor-promoting one in scrib^−/− Ras^V12 cells (Igaki et al., 2006; Cordero et al., 2010; Uhlirova et al., 2005; Enomoto et al., 2015). Mechanistic details about this oncogenic switch have been largely elusive. Our data presented here imply that a critical step for this oncogenic switch is the conversion of caspase activity by oncogenic Ras.

Consistent with a previous report in different context (Hirabayashi et al., 2013), our results demonstrated that oncogenic Ras can suppress the apoptotic activity of caspases and keeps scrib^−/− Ras^V12 cells in an ‘undead’-like condition. While caspases may still induce apoptosis in a few tumor cells, they now largely promote generation of intra- and extracellular ROS which are required for malignant growth and tissue invasion of surviving neoplastic cells. Evidence that caspases are indeed activated in scrib^−/− Ras^V12 clones is not only provided in this study, but also in a report that showed that small malignant clones (lgl^−/− Ras^V12) undergo caspase-mediated apoptosis and elimination in a similar way as scrib clones (Menéndez et al., 2010). Only when mutant clones have reached a certain size, can they develop malignant tumors despite intrinsic caspase activation (Menéndez et al., 2010; Ballesteros-Arias et al., 2014).

Our data suggest that JNK activity acts both upstream and downstream of caspases and ROS generation in scrib^−/− Ras^V12 mutant clones (Figure 5). It is possible that initially, when the scrib^−/− Ras^V12 mutant cells form, a cell competition signal triggers JNK activation in scrib^−/− Ras^V12 cells, similar to the events in scrib^−/−-only mutant cells (Figure 6). In both scrib^−/− and scrib^−/− Ras^V12 mutant cells, this JNK activity results in caspase activation (Figures 3 and 5A). However, due to the anti-apoptotic activity of Ras^V12, caspases induce only very little apoptosis in scrib Ras^V12 clones (Figure 3). Therefore, although caspases are active, most scrib^−/− Ras^V12 cells do not die and thus are in an ‘undead’-like state. Caspases now promote the generation of extracellular ROS through activation of NADPH oxidase Duox. These ROS recruit and activate hemocytes (Figure 4). It is known that hemocytes can release Eiger (Cordero et al., 2010; Parisi et al., 2014; Fogarty et al., 2016) which signals through its receptor Grindelwald (Andersen et al., 2015) for further stimulation of JNK activity in scrib^−/− Ras^V12 cells. Thus, we postulate that JNK, caspases, ROS, hemocytes and Eiger constitute an amplification loop (Figure 6) which may be necessary for tumor initiation.

Figure 6

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Evidence of an amplification loop is provided by the mutual dependence of caspases, ROS and JNK (Figure 5; Figure 3—figure supplement 1). Similar amplification loops have been described in apoptotic and ‘undead’ cells (Wells et al., 2006; Shlevkov and Morata, 2012; Fogarty et al., 2016). This amplification loop ensures persistent oncogenic signaling in scrib^−/− Ras^V12 cells. This is in striking contrast to scrib^−/− mutant cells alone in which JNK signaling triggers linear caspase activation and apoptosis (Brumby and Richardson, 2003; Igaki et al., 2006; Igaki et al., 2009; Uhlirova et al., 2005). In later stages of tumorigenesis, the amplification loop may have reached full strength and promotes malignant growth and invasion of scrib^−/− Ras^V12 cells (Figure 6). Amplification loops have also been observed in other neoplastic tumor models in Drosophila. For example, intestinal stem cell tumors form in response to an amplification loop (Chen et al., 2016). In a glycolytic tumor model, ROS are also part of a amplification loop that facilitates metabolic reprogramming (Wang et al., 2016). Thus, it is possible that tumorigenesis in general depends on amplification loops to sustain oncogenic signaling.

There are similarities and differences in the amplification loops of the ‘undead’ hyperplastic AiP model and the neoplastic scrib^−/− Ras^V12 tumor model. In both models, caspases, ROS, hemocytes and JNK are required for growth. However, regarding caspases, the ‘undead’ AiP model only involves the initiator caspase Dronc for growth (in fact, effector caspases are inhibited by P35 in this model) (Fan et al., 2014; Huh et al., 2004; Pérez-Garijo et al., 2004; Pérez-Garijo et al., 2009; Ryoo et al., 2004). In contrast, the neoplastic scrib^−/− Ras^V12 model requires both initiator (Dronc) and effector (DrICE) caspases. Inhibition of either suppresses malignant growth and invasion. Another interesting difference is the differential involvement of ROS. While only extracellular ROS are essential in the ‘undead’ AiP model, neoplastic growth of scrib^−/− Ras^V12 cells requires both intra- and extracellular ROS. Mitochondria are the likely source of intracellular ROS because expression of mitochondrial SOD2 can suppress tumor growth and invasion of scrib^−/− Ras^V12 tumors (Figure 1N). It is unclear if these two populations of ROS are dependent or independent of each other. Recently, it was shown in endothelial cells that Nox-derived ROS can trigger an increase in mitochondrially-derived ROS and loss of mitochondrial membrane potential suggesting a dependence of mitochondrial ROS from Nox-generated ROS (Shafique et al., 2017). However, alternatively, it is also possible that intra- and extracellular ROS are produced independently by caspase activity, and both are separately required for neoplastic transformation.

Furthermore, while we mostly focused from the point-of-view of ‘undead’ AiP, it is also possible that ‘genuine’ AiP contributes to the tumor growth in scrib^−/− Ras^V12. Consistent with this notion is the observation that there are a few apoptotic cells in scrib^−/− Ras^V12 mutant clones (Figure 3E’,F). Genuinely apoptotic cells can also produce ROS in Drosophila imaginal discs (Santabárbara-Ruiz et al., 2015). Therefore, it is tempting to speculate that some of the differences between the ‘undead’ AiP model and the scrib^−/− Ras^V12 model are due to a combination of ‘undead’ and ‘genuine’ AiP in scrib^−/− Ras^V12. This may explain the differences in caspase requirement, the differences in ROS production and the different outcomes of growth – hyperplastic vs. neoplastic – between the ‘undead’ AiP and the scrib^−/− Ras^V12 tumor models. Future work will address this important question.

Another important question for future studies will be to address how Ras^V12 switches the activity of caspases from tumor-suppressors to tumor-promoters. A known target of survival signaling by Ras^V12 is the pro-apoptotic gene Hid which acts upstream of caspase activation (Bergmann et al., 1998; Kurada and White, 1998). Because Eiger and JNK can induce expression of hid (Moreno et al., 2002), it is possible that Hid activity is inhibited by oncogenic Ras. However, while we do not exclude this possibility, it alone may not be sufficient to explain the altered caspase activity because inhibition of hid would result in loss of caspase activity. However, caspases are still active in scrib^−/− Ras^V12 mutant cells (Figure 3B,D) and they are also able to induce apoptosis at least in a small amount of mutant cells (Figure 3E,F). Therefore, it is possible that Ras^V12 modifies caspase activity in a different manner – directly or indirectly – for non-apoptotic ROS generation.

Oncogenic Ras is mediating many steps in the tumorigenic process of scrib^−/− Ras^V12 tissue. It changes the transcriptome of these cells and modifies the downstream activities of JNK (Atkins et al., 2016; Külshammer et al., 2015). However, as shown in this work, a critical step mediated by Ras^V12 is the modification of caspase activity – directly or indirectly – in the early stage of tumorigenesis in a way that the cells survive. At present it is unclear if the caspase-modulating activity of Ras^V12 is dependent on transcription. There may not be enough time for a transcriptional response by the cell to escape the apoptotic activity of caspases. Consistently, work by others has suggested that changes in the transcriptome alone does not fully explain the neoplastic phenotype of scrib^−/− Ras^V12 cells and that other potentially non-transcriptional processes are involved (Atkins et al., 2016). Modification of caspase activity may be one of these non-transcriptional processes.

Non-apoptotic functions of caspases have been reported (Shalini et al., 2015; Fogarty and Bergmann, 2017; Mukherjee and Williams, 2017; Nakajima and Kuranaga, 2017). However, it is largely unknown how cells survive in the presence of activated caspases during non-apoptotic processes. It is possible that a reduction of caspase activity below a certain apoptotic threshold is sufficient for survival. Other models include changes in the subcellular localization of caspases or interaction with modifying factors such as Tango7 (D'Brot et al., 2013). Interesting in this respect is a recent study which showed that mitochondrially-derived SCSβ restricts caspase activity for spermatid maturation in the Drosophila testis (Aram et al., 2016). Since mitochondria release apoptotic signaling molecules such as cytochrome c and Smac during apoptosis (Fuchs and Steller, 2011), it may also be possible that they release signals such as SCSβ or related factors which modulate the activity of caspases for non-apoptotic functions. More work is necessary to address these essential questions for understanding of tumor initiation and progression.

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Author details

1. Ernesto Pérez

   Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, United States

   Present address

   Department of Biology, Austin College, Sherman, United States

   Contribution

   Conceptualization, Formal analysis, Supervision, Funding acquisition, Writing—original draft, Writing—review and editing

   Contributed equally with

   Jillian L Lindblad

   Competing interests

   No competing interests declared

2. Jillian L Lindblad

   Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Investigation, Writing—original draft

   Contributed equally with

   Ernesto Pérez

   Competing interests

   No competing interests declared

3. Andreas Bergmann

   Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, United States

   Contribution

   Data curation, Formal analysis, Investigation

   For correspondence

   andreas.bergmann@umassmed.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-9134-871X

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