- Email: [email protected]
Tumor Models: Tumor–Stroma Interactions Drive Neoplastic Transformation in Drosophila
Current Biology Vol 24 No 14 R658
assembled into a fabulous biological contraption. References 1. Smith, C.L., Varoqueaux, F., Kittelmann, M., Azzam, R.N., Cooper, B., Winters, C.A., Eitel, M., Fasshauer, D., and Reese, T.S. (2014). Novel cell types, neurosecretory cells, and body plan of the early-diverging metazoan Trichoplax adhaerens. Curr. Biol. 24, 1565–1572. 2. Srivastava, M., Simakov, O., Chapman, J., Fahey, B., Gauthier, M.E.A., Mitros, T., Richards, G.S., Conaco, C., Dacre, M., Hellsten, U., et al. (2010). The Amphimedon queenslandica genome and the evolution of animal complexity. Nature 466, 720–726. 3. Riesgo, A., Farrar, N., Windsor, P.J., Giribet, G., and Leys, S.P. (2014). The analysis of eight
transcriptomes from all poriferan classes reveals surprising genetic complexity in sponges. Mol. Biol. Evol. 31, 1102–1120. 4. Ryan, J.F., Pang, K., Schnitzler, C.E., Nguyen, A.-D., Moreland, R.T., Simmons, D.K., Koch, B.J., Francis, W.R., Havlak, P., et al.; NISC Comparative Sequencing Program (2013). The genome of the ctenophore Mnemiopsis leidyi and its implications for cell type evolution. Science 342, 1242592. 5. Moroz, L.L., Kocot, K.M., Citarella, M.R., Dosung, S., Norekian, T.P., Povolotskaya, I.S., Grigorenko, A.P., Dailey, C., Berezikov, E., Buckley, K.M., et al. (2014). The ctenophore genome and the evolutionary origins of neural systems. Nature 510, 109–114. 6. Srivastava, M., Begovic, E., Chapman, J., Putnam, N.H., Hellsten, U., Kawashima, T., Kuo, A., Mitros, T., Salamov, A., Carpenter, M.L., et al. (2008). The Trichoplax genome and
Tumor Models: Tumor–Stroma Interactions Drive Neoplastic Transformation in Drosophila Stromal cells play a supportive role in the initiation and progression of carcinomas. A new study in Drosophila implicates mesenchymal cells in supporting EGF receptor-driven tumor growth and cellular transformation of epithelial tissues. Marco Mila´n Carcinomas, malignant neoplasms of epithelial origin, are the most common form of human cancer. Mesenchymal cells in the stroma regulate the expression and remodeling of the extracellular matrix (ECM) and produce growth factors that support the survival and proliferation of epithelial transformed cells. As they reported recently in Current Biology, Herranz et al. [1] have used the genetic model species Drosophila to dissect the underlying molecular and cellular mechanisms driving tumor–stroma interactions. This work underscores the contribution of resident mesenchymal cells in promoting the neoplastic transformation of EGF-receptor-expressing epithelial cells and identifies Dpp and Wingless as the signaling molecules driving growth of these two cell populations. EGF-receptor gene amplification has been reported in a wide range of carcinomas, and mutations that activate the small G protein Ras are found in 20–25% of all human tumors. However, neither EGF-receptor overexpression nor the presence of activated Ras is sufficient to drive malignant transformation, and
additional oncogenic mutations are required for disease progression. In this regard, the imaginal primordia of Drosophila — monolayered epithelia within the feeding larvae that grow one-thousand fold in cell number and tissue size — have been used to identify new molecular elements that cooperate with these two oncogenes in driving tumor growth, epithelial transformation, basement membrane degradation, and invasive behavior [2–5]. Mutations that affect the Scribbled–Disc Large–Lgl cell polarity complex or those causing mitochondrial dysfunction, or overexpression of certain miRNAs, cooperate with EGF receptor/Ras dysregulation in promoting tumorigenesis. In all these cases, tumorigenesis relies on a JNK-dependent transcriptional program that regulates the invasion of transformed cells, drives the expression of the mitogenic molecules responsible for tumor growth, and induces the expression of matrix metalloproteins (MMPs) involved in basement membrane degradation, a prerequisite for tissue invasiveness [6,7]. The work of Herranz et al. [1] stems from the observation that depletion of the Polycomb group epigenetic silencer Pipsqueak, a BTB-containing
the nature of placozoans. Nature 454, 955–960. 7. Hobson, R.J., Liu, Q., Watanabe, S., and Jorgensen, E.M. (2011). Complexin maintains vesicles in the primed state in C. elegans. Curr. Biol. 21, 106–113. 8. Feuda, R., Hamilton, S.C., McInerney, J.O., and Pisani, D. (2012). Metazoan opsin evolution reveals a simple route to animal vision. Proc. Natl. Acad. Sci. USA 109, 18868–18872.
Dept. of Biology, University of Utah, Howard Hughes Medical Institute, Salt Lake City, UT, USA. E-mail: [email protected]
http://dx.doi.org/10.1016/j.cub.2014.06.036
nuclear protein [8], cooperates with EGF receptor to elicit malignant neoplastic growth of imaginal primordia. The multilayered tumor induces the expression of MMP1 and the consequent degradation of the basement membrane and becomes highly metastatic, as transformed cells are found in distant internal organs such as the gut and malphigian tubules. Remarkably, Pipsqueak behaves as a tumor-promoting gene in a Drosophila Notch-driven epithelial tumor model [9]. This observation thus reinforces the context-dependent tumor suppressor or tumor-promoting roles of many cancer genes. As is often the case, the initial observation made by Herranz et al. [1] that allowed the identification of a mesenchymal cell population supporting EGF-receptor-driven tumor growth was unexpected, but a key finding. During the characterization of the oncogenic cooperation between EGF receptor and Pipsqueak, GFP-positive EGF-receptor-expressing cells were found to intermingle with ‘‘groups of cells not expressing GFP’’ (Figure 1). Further functional characterization of this population indicated that the GFP-negative cells are resident myoblasts that proliferate in response to Dpp — a member of the TGF-b superfamily — produced by the tumor. Thus, those myoblasts abutting the transformed cell population showed strong activation of the Dpp pathway and elevated mitotic activity. Genetically elegant experiments performed by Herranz et al. [1] demonstrated that the proliferative myoblast population plays a major role in driving neoplastic tumor growth. Thus, selective ablation of the myoblasts
Dispatch R659
organized as organs, as they consist of transformed and stromal cells that interact to promote growth and to shape the tumor. These results highlight that the differences between invertebrate and mammalian tumors are, in fact, fewer than what was originally believed. References
Figure 1. Tumor–stroma interactions in Drosophila epithelial tumors. A sketch depicting the spatial organization of epithelial (green) and mesenchymal (red) cells during normal development and in a neoplastic tumor. EGF receptor-expressing (green nuclei) transformed epithelial cells induce the expression of the mitogenic molecules Wingless and Dpp, which drive proliferation of epithelial and mesenchymal cells, respectively. The expression of Perlecan by the transformed cells is thought to potentiate Dpp signaling in mesenchymal cells. These cells support tumor growth and are required for epithelial transformation.
by the expression of the pro-apoptotic gene reaper, depletion of the Dpp signaling molecule in the transformed cell population, or blockade of the Dpp signaling transduction pathway in the myoblast cell population completely rescued all aspects of the oncogenic cooperation between EGF receptor and Pipsqueak depletion. Transformed cells promote the proliferation of the accompanying myoblast cell population not only by expressing Dpp but also by potentiating Dpp signaling in the target tissue. Perlecan, a secreted heparan sulfate proteoglycan (HSPG) that acts as a potent cofactor of several secreted growth factors [10], was shown to be highly expressed by the transformed cells and preferentially found in the myoblasts. Overexpression of Perlecan in tumor cells appears to be crucial in the oncogenic cooperation between these two cell populations, as depletion of Perlecan completely rescued tumor growth while its co-expression with EGF receptor drove neoplastic growth and induced high levels of Dpp activation in nearby proliferating myoblasts. The signaling molecule Wingless, a target of JNK in transformed epithelial cells [11], was also shown to contribute to EGF-receptor-driven tumorigenesis. However, in this case, Wingless played an autocrine role, as the inhibition of this signaling pathway in EGFreceptor-expressing cells was sufficient to rescue tumor growth. The paracrine role of Dpp in mediating tumor–stroma interactions in fly epithelial tumors resembles the
role of TGF-b in mediating interactions between colorectal cancer cells and stromal cells in distant metastatic sites [12]. In both cases, transformed cells express but do not respond to the ligand, and Dpp/TGF-b signaling in stromal cells is required to support tumor initiation and progression. While the TGF-b-regulated ligand interleukin 1 is known to signal back from the stroma to support the growth and survival of metastatic colorectal cancer cells [12], the identity of the signal in the fly tumor model remains unidentified [1]. The new study [1] provides an ideal genetic model system for the future identification of the signal. An unexpected feature of this signal is that it appears to be sufficient to drive neoplastic transformation and the invasive behavior of EGF receptor-expressing epithelial cells. The long-recognized relationship between the immune system and cancer has also been fruitfully addressed in this Drosophila epithelial tumor model. Circulating blood cells (hemocytes) are attracted by MMP-mediated disruption of the basement membrance, proliferate in response to the cytokines expressed by transformed epithelial cells, and restrict tumor growth by inducing TNF-mediated apoptosis of tumor cells [13,14]. Similarly to fibroblasts in human cancers, hemocytes also express the components of the ECM and contribute to the repair of the basement membrane during wound healing and tumorigenesis. Thus, solid epithelial tumors in Drosophila appear to be functionally and structurally
1. Herranz, H., Weng, R., and Cohen, S.M. (2014). Crosstalk between epithelial and mesenchymal tissues in tumorigenesis and imaginal disc development. Curr. Biol. 24, 1476–1484. 2. Pagliarini, R.A., and Xu, T. (2003). A genetic screen in Drosophila for metastatic behavior. Science 302, 1227–1231. 3. Brumby, A.M., and Richardson, H.E. (2003). scribble mutants cooperate with oncogenic Ras or Notch to cause neoplastic overgrowth in Drosophila. EMBO J. 22, 5769–5779. 4. Herranz, H., Hong, X., Hung, N.T., Voorhoeve, P.M., and Cohen, S.M. (2012). Oncogenic cooperation between SOCS family proteins and EGF receptor identified using a Drosophila epithelial transformation model. Genes Dev. 26, 1602–1611. 5. Ohsawa, S., Sato, Y., Enomoto, M., Nakamura, M., Betsumiya, A., and Igaki, T. (2012). Mitochondrial defect drives non-autonomous tumour progression through Hippo signalling in Drosophila. Nature 490, 547–551. 6. Uhlirova, M., and Bohmann, D. (2006). JNK- and Fos-regulated Mmp1 expression cooperates with Ras to induce invasive tumors in Drosophila. EMBO J. 25, 5294–5304. 7. Igaki, T., Pagliarini, R.A., and Xu, T. (2006). Loss of cell polarity drives tumor growth and invasion through JNK activation in Drosophila. Curr. Biol. 16, 1139–1146. 8. Weber, U., Siegel, V., and Mlodzik, M. (1995). pipsqueak encodes a novel nuclear protein required downstream of seven-up for the development of photoreceptors R3 and R4. EMBO J. 14, 6247–6257. 9. Ferres-Marco, D., Gutierrez-Garcia, I., Vallejo, D.M., Bolivar, J., Gutierrez-Avino, F.J., and Dominguez, M. (2006). Epigenetic silencers and Notch collaborate to promote malignant tumours by Rb silencing. Nature 439, 430–436. 10. Lindner, J.R., Hillman, P.R., Barrett, A.L., Jackson, M.C., Perry, T.L., Park, Y., and Datta, S. (2007). The Drosophila Perlecan gene trol regulates multiple signaling pathways in different developmental contexts. BMC Dev. Biol. 7, 121. 11. Dekanty, A., Barrio, L., Muzzopappa, M., Auer, H., and Milan, M. (2012). Aneuploidy-induced delaminating cells drive tumorigenesis in Drosophila epithelia. Proc. Natl. Acad. Sci. USA 109, 20549–20554. 12. Calon, A., Espinet, E., Palomo-Ponce, S., Tauriello, D.V., Iglesias, M., Cespedes, M.V., Sevillano, M., Nadal, C., Jung, P., Zhang, X.H., et al. (2012). Dependency of colorectal cancer on a TGF-beta-driven program in stromal cells for metastasis initiation. Cancer Cell 22, 571–584. 13. Pastor-Pareja, J.C., Wu, M., and Xu, T. (2008). An innate immune response of blood cells to tumors and tissue damage in Drosophila. Dis. Model Mech. 1, 144–154. 14. Cordero, J.B., Macagno, J.P., Stefanatos, R.K., Strathdee, K.E., Cagan, R.L., and Vidal, M. (2010). Oncogenic Ras diverts a host TNF tumor suppressor activity into tumor promoter. Dev. Cell 18, 999–1011.
ICREA and Institute for Research in Biomedicine, Parc Cientific de Barcelona, Baldiri Reixac, 10-12, 08028 Barcelona, Spain. E-mail: [email protected] http://dx.doi.org/10.1016/j.cub.2014.05.074
assembled into a fabulous biological contraption. References 1. Smith, C.L., Varoqueaux, F., Kittelmann, M., Azzam, R.N., Cooper, B., Winters, C.A., Eitel, M., Fasshauer, D., and Reese, T.S. (2014). Novel cell types, neurosecretory cells, and body plan of the early-diverging metazoan Trichoplax adhaerens. Curr. Biol. 24, 1565–1572. 2. Srivastava, M., Simakov, O., Chapman, J., Fahey, B., Gauthier, M.E.A., Mitros, T., Richards, G.S., Conaco, C., Dacre, M., Hellsten, U., et al. (2010). The Amphimedon queenslandica genome and the evolution of animal complexity. Nature 466, 720–726. 3. Riesgo, A., Farrar, N., Windsor, P.J., Giribet, G., and Leys, S.P. (2014). The analysis of eight
transcriptomes from all poriferan classes reveals surprising genetic complexity in sponges. Mol. Biol. Evol. 31, 1102–1120. 4. Ryan, J.F., Pang, K., Schnitzler, C.E., Nguyen, A.-D., Moreland, R.T., Simmons, D.K., Koch, B.J., Francis, W.R., Havlak, P., et al.; NISC Comparative Sequencing Program (2013). The genome of the ctenophore Mnemiopsis leidyi and its implications for cell type evolution. Science 342, 1242592. 5. Moroz, L.L., Kocot, K.M., Citarella, M.R., Dosung, S., Norekian, T.P., Povolotskaya, I.S., Grigorenko, A.P., Dailey, C., Berezikov, E., Buckley, K.M., et al. (2014). The ctenophore genome and the evolutionary origins of neural systems. Nature 510, 109–114. 6. Srivastava, M., Begovic, E., Chapman, J., Putnam, N.H., Hellsten, U., Kawashima, T., Kuo, A., Mitros, T., Salamov, A., Carpenter, M.L., et al. (2008). The Trichoplax genome and
Tumor Models: Tumor–Stroma Interactions Drive Neoplastic Transformation in Drosophila Stromal cells play a supportive role in the initiation and progression of carcinomas. A new study in Drosophila implicates mesenchymal cells in supporting EGF receptor-driven tumor growth and cellular transformation of epithelial tissues. Marco Mila´n Carcinomas, malignant neoplasms of epithelial origin, are the most common form of human cancer. Mesenchymal cells in the stroma regulate the expression and remodeling of the extracellular matrix (ECM) and produce growth factors that support the survival and proliferation of epithelial transformed cells. As they reported recently in Current Biology, Herranz et al. [1] have used the genetic model species Drosophila to dissect the underlying molecular and cellular mechanisms driving tumor–stroma interactions. This work underscores the contribution of resident mesenchymal cells in promoting the neoplastic transformation of EGF-receptor-expressing epithelial cells and identifies Dpp and Wingless as the signaling molecules driving growth of these two cell populations. EGF-receptor gene amplification has been reported in a wide range of carcinomas, and mutations that activate the small G protein Ras are found in 20–25% of all human tumors. However, neither EGF-receptor overexpression nor the presence of activated Ras is sufficient to drive malignant transformation, and
additional oncogenic mutations are required for disease progression. In this regard, the imaginal primordia of Drosophila — monolayered epithelia within the feeding larvae that grow one-thousand fold in cell number and tissue size — have been used to identify new molecular elements that cooperate with these two oncogenes in driving tumor growth, epithelial transformation, basement membrane degradation, and invasive behavior [2–5]. Mutations that affect the Scribbled–Disc Large–Lgl cell polarity complex or those causing mitochondrial dysfunction, or overexpression of certain miRNAs, cooperate with EGF receptor/Ras dysregulation in promoting tumorigenesis. In all these cases, tumorigenesis relies on a JNK-dependent transcriptional program that regulates the invasion of transformed cells, drives the expression of the mitogenic molecules responsible for tumor growth, and induces the expression of matrix metalloproteins (MMPs) involved in basement membrane degradation, a prerequisite for tissue invasiveness [6,7]. The work of Herranz et al. [1] stems from the observation that depletion of the Polycomb group epigenetic silencer Pipsqueak, a BTB-containing
the nature of placozoans. Nature 454, 955–960. 7. Hobson, R.J., Liu, Q., Watanabe, S., and Jorgensen, E.M. (2011). Complexin maintains vesicles in the primed state in C. elegans. Curr. Biol. 21, 106–113. 8. Feuda, R., Hamilton, S.C., McInerney, J.O., and Pisani, D. (2012). Metazoan opsin evolution reveals a simple route to animal vision. Proc. Natl. Acad. Sci. USA 109, 18868–18872.
Dept. of Biology, University of Utah, Howard Hughes Medical Institute, Salt Lake City, UT, USA. E-mail: [email protected]
http://dx.doi.org/10.1016/j.cub.2014.06.036
nuclear protein [8], cooperates with EGF receptor to elicit malignant neoplastic growth of imaginal primordia. The multilayered tumor induces the expression of MMP1 and the consequent degradation of the basement membrane and becomes highly metastatic, as transformed cells are found in distant internal organs such as the gut and malphigian tubules. Remarkably, Pipsqueak behaves as a tumor-promoting gene in a Drosophila Notch-driven epithelial tumor model [9]. This observation thus reinforces the context-dependent tumor suppressor or tumor-promoting roles of many cancer genes. As is often the case, the initial observation made by Herranz et al. [1] that allowed the identification of a mesenchymal cell population supporting EGF-receptor-driven tumor growth was unexpected, but a key finding. During the characterization of the oncogenic cooperation between EGF receptor and Pipsqueak, GFP-positive EGF-receptor-expressing cells were found to intermingle with ‘‘groups of cells not expressing GFP’’ (Figure 1). Further functional characterization of this population indicated that the GFP-negative cells are resident myoblasts that proliferate in response to Dpp — a member of the TGF-b superfamily — produced by the tumor. Thus, those myoblasts abutting the transformed cell population showed strong activation of the Dpp pathway and elevated mitotic activity. Genetically elegant experiments performed by Herranz et al. [1] demonstrated that the proliferative myoblast population plays a major role in driving neoplastic tumor growth. Thus, selective ablation of the myoblasts
Dispatch R659
organized as organs, as they consist of transformed and stromal cells that interact to promote growth and to shape the tumor. These results highlight that the differences between invertebrate and mammalian tumors are, in fact, fewer than what was originally believed. References
Figure 1. Tumor–stroma interactions in Drosophila epithelial tumors. A sketch depicting the spatial organization of epithelial (green) and mesenchymal (red) cells during normal development and in a neoplastic tumor. EGF receptor-expressing (green nuclei) transformed epithelial cells induce the expression of the mitogenic molecules Wingless and Dpp, which drive proliferation of epithelial and mesenchymal cells, respectively. The expression of Perlecan by the transformed cells is thought to potentiate Dpp signaling in mesenchymal cells. These cells support tumor growth and are required for epithelial transformation.
by the expression of the pro-apoptotic gene reaper, depletion of the Dpp signaling molecule in the transformed cell population, or blockade of the Dpp signaling transduction pathway in the myoblast cell population completely rescued all aspects of the oncogenic cooperation between EGF receptor and Pipsqueak depletion. Transformed cells promote the proliferation of the accompanying myoblast cell population not only by expressing Dpp but also by potentiating Dpp signaling in the target tissue. Perlecan, a secreted heparan sulfate proteoglycan (HSPG) that acts as a potent cofactor of several secreted growth factors [10], was shown to be highly expressed by the transformed cells and preferentially found in the myoblasts. Overexpression of Perlecan in tumor cells appears to be crucial in the oncogenic cooperation between these two cell populations, as depletion of Perlecan completely rescued tumor growth while its co-expression with EGF receptor drove neoplastic growth and induced high levels of Dpp activation in nearby proliferating myoblasts. The signaling molecule Wingless, a target of JNK in transformed epithelial cells [11], was also shown to contribute to EGF-receptor-driven tumorigenesis. However, in this case, Wingless played an autocrine role, as the inhibition of this signaling pathway in EGFreceptor-expressing cells was sufficient to rescue tumor growth. The paracrine role of Dpp in mediating tumor–stroma interactions in fly epithelial tumors resembles the
role of TGF-b in mediating interactions between colorectal cancer cells and stromal cells in distant metastatic sites [12]. In both cases, transformed cells express but do not respond to the ligand, and Dpp/TGF-b signaling in stromal cells is required to support tumor initiation and progression. While the TGF-b-regulated ligand interleukin 1 is known to signal back from the stroma to support the growth and survival of metastatic colorectal cancer cells [12], the identity of the signal in the fly tumor model remains unidentified [1]. The new study [1] provides an ideal genetic model system for the future identification of the signal. An unexpected feature of this signal is that it appears to be sufficient to drive neoplastic transformation and the invasive behavior of EGF receptor-expressing epithelial cells. The long-recognized relationship between the immune system and cancer has also been fruitfully addressed in this Drosophila epithelial tumor model. Circulating blood cells (hemocytes) are attracted by MMP-mediated disruption of the basement membrance, proliferate in response to the cytokines expressed by transformed epithelial cells, and restrict tumor growth by inducing TNF-mediated apoptosis of tumor cells [13,14]. Similarly to fibroblasts in human cancers, hemocytes also express the components of the ECM and contribute to the repair of the basement membrane during wound healing and tumorigenesis. Thus, solid epithelial tumors in Drosophila appear to be functionally and structurally
1. Herranz, H., Weng, R., and Cohen, S.M. (2014). Crosstalk between epithelial and mesenchymal tissues in tumorigenesis and imaginal disc development. Curr. Biol. 24, 1476–1484. 2. Pagliarini, R.A., and Xu, T. (2003). A genetic screen in Drosophila for metastatic behavior. Science 302, 1227–1231. 3. Brumby, A.M., and Richardson, H.E. (2003). scribble mutants cooperate with oncogenic Ras or Notch to cause neoplastic overgrowth in Drosophila. EMBO J. 22, 5769–5779. 4. Herranz, H., Hong, X., Hung, N.T., Voorhoeve, P.M., and Cohen, S.M. (2012). Oncogenic cooperation between SOCS family proteins and EGF receptor identified using a Drosophila epithelial transformation model. Genes Dev. 26, 1602–1611. 5. Ohsawa, S., Sato, Y., Enomoto, M., Nakamura, M., Betsumiya, A., and Igaki, T. (2012). Mitochondrial defect drives non-autonomous tumour progression through Hippo signalling in Drosophila. Nature 490, 547–551. 6. Uhlirova, M., and Bohmann, D. (2006). JNK- and Fos-regulated Mmp1 expression cooperates with Ras to induce invasive tumors in Drosophila. EMBO J. 25, 5294–5304. 7. Igaki, T., Pagliarini, R.A., and Xu, T. (2006). Loss of cell polarity drives tumor growth and invasion through JNK activation in Drosophila. Curr. Biol. 16, 1139–1146. 8. Weber, U., Siegel, V., and Mlodzik, M. (1995). pipsqueak encodes a novel nuclear protein required downstream of seven-up for the development of photoreceptors R3 and R4. EMBO J. 14, 6247–6257. 9. Ferres-Marco, D., Gutierrez-Garcia, I., Vallejo, D.M., Bolivar, J., Gutierrez-Avino, F.J., and Dominguez, M. (2006). Epigenetic silencers and Notch collaborate to promote malignant tumours by Rb silencing. Nature 439, 430–436. 10. Lindner, J.R., Hillman, P.R., Barrett, A.L., Jackson, M.C., Perry, T.L., Park, Y., and Datta, S. (2007). The Drosophila Perlecan gene trol regulates multiple signaling pathways in different developmental contexts. BMC Dev. Biol. 7, 121. 11. Dekanty, A., Barrio, L., Muzzopappa, M., Auer, H., and Milan, M. (2012). Aneuploidy-induced delaminating cells drive tumorigenesis in Drosophila epithelia. Proc. Natl. Acad. Sci. USA 109, 20549–20554. 12. Calon, A., Espinet, E., Palomo-Ponce, S., Tauriello, D.V., Iglesias, M., Cespedes, M.V., Sevillano, M., Nadal, C., Jung, P., Zhang, X.H., et al. (2012). Dependency of colorectal cancer on a TGF-beta-driven program in stromal cells for metastasis initiation. Cancer Cell 22, 571–584. 13. Pastor-Pareja, J.C., Wu, M., and Xu, T. (2008). An innate immune response of blood cells to tumors and tissue damage in Drosophila. Dis. Model Mech. 1, 144–154. 14. Cordero, J.B., Macagno, J.P., Stefanatos, R.K., Strathdee, K.E., Cagan, R.L., and Vidal, M. (2010). Oncogenic Ras diverts a host TNF tumor suppressor activity into tumor promoter. Dev. Cell 18, 999–1011.
ICREA and Institute for Research in Biomedicine, Parc Cientific de Barcelona, Baldiri Reixac, 10-12, 08028 Barcelona, Spain. E-mail: [email protected] http://dx.doi.org/10.1016/j.cub.2014.05.074