Cancer Cell
Previews Braunschweig, U., Barbosa-Morais, N.L., Pan, Q., Nachman, E.N., Alipanahi, B., GonatopoulosPournatzis, T., Frey, B., Irimia, M., and Blencowe, B.J. (2014). Genome Res. 24, 1774–1786. Fan, J., Kuai, B., Wu, G., Wu, X., Chi, B., Wang, L., Wang, K., Shi, Z., Zhang, H., Chen, S., et al. (2017). EMBO J., e201696139. Guderian, G., Peter, C., Wiesner, J., Sickmann, A., Schulze-Osthoff, K., Fischer, U., and
Grimmler, M. 1976–1986.
(2011).
J.
Biol.
Chem.
286,
Moore, M.J., Wang, Q., Kennedy, C.J., and Silver, P.A. (2010). Cell 142, 625–636.
Karni, R., de Stanchina, E., Lowe, S.W., Sinha, R., Mu, D., and Krainer, A.R. (2007). Nat. Struct. Mol. Biol. 14, 185–193.
Paronetto, M.P., Achsel, T., Massiello, A., Chalfant, C.E., and Sette, C. (2007). J. Cell Biol. 176, 929–939.
Lee, S.C., Dvinge, H., Kim, E., Cho, H., Micol, J.B., Chung, Y.R., Durham, B.H., Yoshimi, A., Kim, Y.J., Thomas, M., et al. (2016). Nat. Med. 22, 672–678.
Sinha, R., Allemand, E., Zhang, Z., Karni, R., Myers, M.P., and Krainer, A.R. (2010). Mol. Cell. Biol. 30, 2762–2774.
Neuroblastoma Metastases: Leveraging the Avian Neural Crest Tina Zheng,1,2 Marie Me´nard,1,2 and William A. Weiss1,2,* 1Departments
of Neurology, Pediatrics, and Neurosurgery, Brain Tumor Research Center Diller Family Comprehensive Cancer Center University of California, San Francisco, CA 94158, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.ccell.2017.09.012 2Helen
Neuroblastoma, an embryonal cancer of neural crest origin, shows metastases frequently at diagnosis. In this issue of Cancer Cell, Delloye-Bourgeois and colleagues demonstrate that neuroblastoma cell lines and patient-derived xenografts engraft and adopt a metastatic program in chick embryos. They identify Sema3C as a candidate switch that regulates metastatic spread. Chick embryos have been at the forefront of developmental biology research since Aristotle’s first dissection in 350 BC. While many animal embryos cannot be visualized readily during development, the chick embryo forms in a contained, self-sufficient environment, allowing easy access to perform experiments and visualize their consequences. The chick embryo can be efficiently manipulated genetically via viral infection and in ovo electroporation, enabling powerful gain-of-function or loss-of-function experiments (Stern, 2005). The application of advanced imaging, including confocal light-sheet imaging, also makes the chick embryo an attractive model in neurodevelopment. From the early 1900s, chick embryos were used to study the neural crest, a developmental structure at the origin of the peripheral nervous system, and nonneural cell types including melanocytes, smooth muscle, craniofacial bones, cartilage, and connective tissue (Bronner and Simo˜es-Costa, 2016). The neural crest
is a dynamic population of pluripotent cells that, upon undergoing epithelialto-mesenchymal transition, delaminate from the dorsal neuroepithelium of the neural tube to migrate long distances and ultimately reach widespread destinations in the embryo. Such migration requires interactions among neural crest cells as well as with their environment, directing collective migration (cells moving in concert) in response to signals delivered by guidance molecules (Bronner and Simo˜es-Costa, 2016). These characteristics of neural crest cell migration lend themselves to the biology of cancer cells (Figure 1), because metastases are similarly characterized by an epithelialto-mesenchymal transition, cell migration, invasion, and acquisition of stemcell-like properties (Shibue and Weinberg, 2017). Melanoma originates from neuralcrest-derived melanocytes. Because the natural immunodeficiency of chick embryos enables engraftment of human tumor cells in the developing embryo, Kulesa and colleagues were previously
able to analyze the behavior of human metastatic melanoma cells in the environment of migrating neural crest by transplanting these cells into the neural tubes of developing chick embryos. They observed migration of melanoma cells along the typical cranial neural crest migratory pathway, as well as colonization of peripheral sites. These observations suggested that melanoma cell lines retained their ability to respond to the neural crest microenvironment in the developing embryo. However, human cells formed tumors only when implanted into non-neural crest environments such as the retina (Kulesa et al., 2006). Neuroblastoma, an embryonal childhood malignancy derived from neural crest, is the most common extracranial solid malignancy of childhood. Half of patients present with metastatic disease, often to regional lymph nodes, bone marrow, bone, liver, and skin (Matthay et al., 2016). As in most cancers, metastatic spread correlates with high-risk, stage 4 disease and poor survival. In
Cancer Cell 32, October 9, 2017 ª 2017 Elsevier Inc. 395
Cancer Cell
Previews TUMOR
NEURAL CREST CELLS
NCC
Primary tumor
EMT
DRG
Blood vessel
Migration
Neural Tube
Aorta SG
Metastasis
Invasion
Figure 1. Parallels between Cancer Metastasis and Neural Crest Migration Both cell populations undergo epithelial-to-mesenchymal transition (EMT), migration, and ultimately a form of invasion, with cells settling in distant tissues. NCC, neural crest cells; DRG, dorsal root ganglia; SG, sympathetic ganglia.
this issue of Cancer Cell, Delloye-Bourgeois and colleagues present a novel model to capture the embryonic microenvironment and subsequent tumor development in chick embryos engrafted with human stage 4 neuroblastoma lines and human patient-derived tumors (PDXs). They grafted fluorescently labeled neuroblastoma cells into the dorsal neural tube of chick embryos and conducted immunofluorescent and time-lapse imaging and confocal light-sheet microscopy (Delloye-Bourgeois et al., 2017). Neuroblastoma cells followed neural crest migration to reach sympathetic ganglia, where they subsequently formed dense, proliferating masses that often spread multifocally (metastasized) to distant sites by 7 days post-engraftment. The metastatic spread proceeded through the dorsal aorta and peripheral nerves, a novel finding demonstrated in multiple human cell lines. Delloye-Bourgeois et al. then conducted RNA-seq to characterize geneexpression changes occurring between engraftment and primary (premetastatic) tumors. Forty-six neural crest genes were differentially expressed. Twentyfour were related to cell movement, and three of these were Semaphorins. The Semaphorin gene family regulates axon guidance and cardiac neural crest cell migration (Schwarz et al., 2009). They also contribute to cell migration and angiogenesis, functions that can 396 Cancer Cell 32, October 9, 2017
be used to either suppress or drive tumors, depending on cell type (Tamagnone, 2012). Levels of Semaphorin3C (Sema3C) decreased by half in neuroblastoma tumor masses compared to naive pre-engraftment cells. Sema3C small interfering RNA knockdown during neural crest migration hindered collective migration and targeting of neuroblastoma cells to sympathetic structures, and led to increased dissemination (failure to reach sympathoadrenal sites). Importantly, the authors validated that the effect of inducible Sema3C small hairpin RNA knockdown in already-established primary tumors (from human cell lines) led to increased metastatic spread in the embryos. This effect was rescued by expressing an exogenous Sema3C construct. Additionally, the authors examined potential paracrine actions of Sema3C by mixing high-Sema3C and low-Sema3C cells. Inclusion of 25% high-Sema3C cells was sufficient to block the dissemination of the neuroblastoma cells. These results clearly demonstrate the role of Sema3C in the cohesion of neuroblastoma cells and their collective migration, suggesting Sema3C as a metastasis-suppressing gene. The canonical receptors for secreted Semaphorin ligands are Neuropilins, which must complex to transmembrane Plexins to transduce downstream signals (Neufeld et al., 2012). Delloye-Bour-
geois and colleagues showed that—like Sema3C—the expression of Neuropilin 1 (NRP1) and PlexinA4 (PLXNA4) were both decreased significantly in tumor masses relative to pre-engraftment cells. Knockdown of NRP1/2 or PLXNA4 also drastically impaired cell aggregation and increased metastasis from the tumor core in vivo, mimicking the effect of Sema3C knockdown. These results correlated with retrospective data from neuroblastoma patients showing that low levels of Sema3C, NRP1, and PLXN4 were associated with poorer event-free survival. This work highlights the importance of Semaphorin/Neuropilin/Plexin signaling in neuroblastoma, with functional knockdown experiments suggesting a role in metastatic spread. Additional studies are needed to validate the functional importance of this candidate metastatic signaling pathway in neuroblastoma tumors in mammals. Finally, Delloye-Bourgeois and colleagues show that neuroblastoma patient-derived xenografts (PDXs) could be grafted into their chick embryo model and, like the cell lines, then targeted sympathoadrenal derivatives to form tumors in the embryo. Impressively, distant metastases occurred only when using cells derived from patients with metastatic neuroblastoma. Some metastatic neuroblastoma cells were also observed in the aorta, again confirming this as a preferential route for dissemination of neuroblastoma in the chick. This work by Delloye-Bourgeois and colleagues introduces a novel xenograft model in which neuroblastoma cell lines and PDXs engrafted in the neural crest environment of chick embryos and followed migration patterns of endogenous avian neural crest cells. This study opens the possibility for studying a variety of cell behaviors and testing potential therapeutics for relevance and efficacy in human disease. Additionally, although this study focused on the role of Sema3C in neuroblastoma cell cohesion, deeper analysis of the RNA-seq data generated here could identify other transcriptional changes contributing to metastatic neuroblastoma in children. Although RNA-seq analysis between pre-engraftment cells and the primary tumor was performed in this work,
Cancer Cell
Previews similar analysis between the primary tumor and metastatic cells could provide further insights on the mechanisms of metastatic spread. The mechanisms driving metastasis in neuroblastoma are challenging to investigate and are poorly recapitulated to date in existing murine models. Delloye-Bourgeois et al. highlight the considerable power of the chick embryo model for neuroblastoma. Zhu and colleagues have also shown that they can model metastasis in zebrafish, where overexpressing the transcriptional regulators LMO1 and MYCN led to metastatic spread (Zhu et al., 2017). These non-mammalian vertebrate models are already improving our understanding of metastatic neuroblastoma and have the potential to identify candidate targets for future clinical trials.
ACKNOWLEDGMENTS T.Z. is supported by UCSF’s Medical Scientist and Biomedical Sciences Training Programs. M.M. receives fellowship support from the National Cancer Children’s Cancer Project Fund. The Weiss lab is supported by NIH grants U01CA217864 and P30CA82103; NIH R01 grants CA148699, CA221969, NS091620, NS088355, and NS089868; a Bold and Basic grant from UCSF’s Quantitative Biosciences Institute and the Children’s Tumor, Pediatric Brain Tumor, Ross K. MacNeill, St. Baldrick, and Samuel G. Waxman foundations; and the Evelyn and Mattie Anderson Chair.
Kulesa, P.M., Kasemeier-Kulesa, J.C., Teddy, J.M., Margaryan, N.V., Seftor, E.A., Seftor, R.E.B., and Hendrix, M.J.C. (2006). Proc. Natl. Acad. Sci. USA 103, 3752–3757. Matthay, K.K., Maris, J.M., Schleiermacher, G., Nakagawara, A., Mackall, C.L., Diller, L., and Weiss, W.A. (2016). Nat. Rev. Dis. Primers 2, 16078. Neufeld, G., Sabag, A.D., Rabinovicz, N., and Kessler, O. (2012). Cold Spring Harb. Perspect. Med. 2, a006718. Schwarz, Q., Maden, C.H., Vieira, J.M., and Ruhrberg, C. (2009). Proc. Natl. Acad. Sci. USA 106, 6164–6169.
REFERENCES
Shibue, T., and Weinberg, R.A. (2017). Nat. Rev. Clin. Oncol. 14, 611–629.
Bronner, M.E., and Simo˜es-Costa, M. (2016). Curr. Top. Dev. Biol. 116, 115–134.
Stern, C.D. (2005). Dev. Cell 8, 9–17.
Delloye-Bourgeois, C., Bertin, L., Thoinet, K., Jarrosson, L., Kindbeiter, K., Buffet, T., Tauszig-Delamasure, S., Bozon, M., Marabelle, A., Combaret, V., et al. (2017). Cancer Cell 32, this issue, 427–443.
Tamagnone, L. (2012). Cancer Cell 22, 145–152. Zhu, S., Zhang, X., Weichert-Leahey, N., Dong, Z., Zhang, C., Lopez, G., Tao, T., He, S., Wood, A.C., Oldridge, D., et al. (2017). Cancer Cell 32, 310–323.e5.
Tumor Suppression by p53: Bring in the Hippo! Yael Aylon1,* and Moshe Oren1,* 1Department of Molecular Cell Biology, The Weizmann Institute, Rehovot 76100, Israel *Correspondence: [email protected] (Y.A.), [email protected] (M.O.) http://dx.doi.org/10.1016/j.ccell.2017.09.010
In this issue of Cancer Cell, Mello et al. investigated how p53 suppresses pancreatic cancer and discovered a key role for the tyrosine phosphatase PTPN14, a p53 transcriptional target. PTPN14 restrains YAP, curbing its potential oncogenic effects. The p53-PTPN14-YAP axis highlights the importance of signaling pathway coordination in cancer prevention. Proper regulation of cell fate requires integration between numerous signaling pathways, operating contemporaneously within the same cell. Tumor suppressor pathways play important roles in regulation of cell fate and tissue homeostasis, calling for close coordination of their activities. Not surprisingly, loss of such coordination opens the door wide for cancer progression. p53 is a major player in the cancer arena: about half of all human tumors harbor mutations in the TP53 gene, encoding p53, making it the most frequent genetic alteration in human cancer. The primary consequence of those mutations is abrogation of the tumor suppressive capacity of the wild-type (WT) p53 protein; in addi-
tion, at least some cancer-associated mutant p53 variants may also acquire oncogenic gain of function, rendering them active contributors to cancer progression. The remainder of the tumors retain WT p53 but often manifest alterations in other components of the extended p53 pathway, which either downregulate p53 or compromise its tumor-suppressor potency. p53 is primarily a transcription factor, capable of transactivating hundreds of genes and repressing many others. It is activated in response to a plethora of genotoxic and oncogenic stresses and perturbations to metabolic homeostasis and acts to curb the undesirable consequences of such stresses. When acti-
vated, p53 orchestrates a multitude of biochemical and biological outcomes, ranging from fine-tuning of cellular metabolism and enhancement of DNA repair, to transient antiproliferative effects, to replicative senescence and apoptosis. The amply documented ability of p53 to enforce senescence and apoptosis in response to persistent oncogenic stress provides a highly intuitive mechanistic explanation for its tumor-suppressor capacity. Surprisingly, mouse model studies demonstrated unequivocally that both senescence and apoptosis are dispensable for p53-mediated tumor suppression (Li et al., 2012), suggesting that a lessintuitive activity of p53 might actually hold the clues to cancer prevention. Mello
Cancer Cell 32, October 9, 2017 ª 2017 Elsevier Inc. 397
Previews Braunschweig, U., Barbosa-Morais, N.L., Pan, Q., Nachman, E.N., Alipanahi, B., GonatopoulosPournatzis, T., Frey, B., Irimia, M., and Blencowe, B.J. (2014). Genome Res. 24, 1774–1786. Fan, J., Kuai, B., Wu, G., Wu, X., Chi, B., Wang, L., Wang, K., Shi, Z., Zhang, H., Chen, S., et al. (2017). EMBO J., e201696139. Guderian, G., Peter, C., Wiesner, J., Sickmann, A., Schulze-Osthoff, K., Fischer, U., and
Grimmler, M. 1976–1986.
(2011).
J.
Biol.
Chem.
286,
Moore, M.J., Wang, Q., Kennedy, C.J., and Silver, P.A. (2010). Cell 142, 625–636.
Karni, R., de Stanchina, E., Lowe, S.W., Sinha, R., Mu, D., and Krainer, A.R. (2007). Nat. Struct. Mol. Biol. 14, 185–193.
Paronetto, M.P., Achsel, T., Massiello, A., Chalfant, C.E., and Sette, C. (2007). J. Cell Biol. 176, 929–939.
Lee, S.C., Dvinge, H., Kim, E., Cho, H., Micol, J.B., Chung, Y.R., Durham, B.H., Yoshimi, A., Kim, Y.J., Thomas, M., et al. (2016). Nat. Med. 22, 672–678.
Sinha, R., Allemand, E., Zhang, Z., Karni, R., Myers, M.P., and Krainer, A.R. (2010). Mol. Cell. Biol. 30, 2762–2774.
Neuroblastoma Metastases: Leveraging the Avian Neural Crest Tina Zheng,1,2 Marie Me´nard,1,2 and William A. Weiss1,2,* 1Departments
of Neurology, Pediatrics, and Neurosurgery, Brain Tumor Research Center Diller Family Comprehensive Cancer Center University of California, San Francisco, CA 94158, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.ccell.2017.09.012 2Helen
Neuroblastoma, an embryonal cancer of neural crest origin, shows metastases frequently at diagnosis. In this issue of Cancer Cell, Delloye-Bourgeois and colleagues demonstrate that neuroblastoma cell lines and patient-derived xenografts engraft and adopt a metastatic program in chick embryos. They identify Sema3C as a candidate switch that regulates metastatic spread. Chick embryos have been at the forefront of developmental biology research since Aristotle’s first dissection in 350 BC. While many animal embryos cannot be visualized readily during development, the chick embryo forms in a contained, self-sufficient environment, allowing easy access to perform experiments and visualize their consequences. The chick embryo can be efficiently manipulated genetically via viral infection and in ovo electroporation, enabling powerful gain-of-function or loss-of-function experiments (Stern, 2005). The application of advanced imaging, including confocal light-sheet imaging, also makes the chick embryo an attractive model in neurodevelopment. From the early 1900s, chick embryos were used to study the neural crest, a developmental structure at the origin of the peripheral nervous system, and nonneural cell types including melanocytes, smooth muscle, craniofacial bones, cartilage, and connective tissue (Bronner and Simo˜es-Costa, 2016). The neural crest
is a dynamic population of pluripotent cells that, upon undergoing epithelialto-mesenchymal transition, delaminate from the dorsal neuroepithelium of the neural tube to migrate long distances and ultimately reach widespread destinations in the embryo. Such migration requires interactions among neural crest cells as well as with their environment, directing collective migration (cells moving in concert) in response to signals delivered by guidance molecules (Bronner and Simo˜es-Costa, 2016). These characteristics of neural crest cell migration lend themselves to the biology of cancer cells (Figure 1), because metastases are similarly characterized by an epithelialto-mesenchymal transition, cell migration, invasion, and acquisition of stemcell-like properties (Shibue and Weinberg, 2017). Melanoma originates from neuralcrest-derived melanocytes. Because the natural immunodeficiency of chick embryos enables engraftment of human tumor cells in the developing embryo, Kulesa and colleagues were previously
able to analyze the behavior of human metastatic melanoma cells in the environment of migrating neural crest by transplanting these cells into the neural tubes of developing chick embryos. They observed migration of melanoma cells along the typical cranial neural crest migratory pathway, as well as colonization of peripheral sites. These observations suggested that melanoma cell lines retained their ability to respond to the neural crest microenvironment in the developing embryo. However, human cells formed tumors only when implanted into non-neural crest environments such as the retina (Kulesa et al., 2006). Neuroblastoma, an embryonal childhood malignancy derived from neural crest, is the most common extracranial solid malignancy of childhood. Half of patients present with metastatic disease, often to regional lymph nodes, bone marrow, bone, liver, and skin (Matthay et al., 2016). As in most cancers, metastatic spread correlates with high-risk, stage 4 disease and poor survival. In
Cancer Cell 32, October 9, 2017 ª 2017 Elsevier Inc. 395
Cancer Cell
Previews TUMOR
NEURAL CREST CELLS
NCC
Primary tumor
EMT
DRG
Blood vessel
Migration
Neural Tube
Aorta SG
Metastasis
Invasion
Figure 1. Parallels between Cancer Metastasis and Neural Crest Migration Both cell populations undergo epithelial-to-mesenchymal transition (EMT), migration, and ultimately a form of invasion, with cells settling in distant tissues. NCC, neural crest cells; DRG, dorsal root ganglia; SG, sympathetic ganglia.
this issue of Cancer Cell, Delloye-Bourgeois and colleagues present a novel model to capture the embryonic microenvironment and subsequent tumor development in chick embryos engrafted with human stage 4 neuroblastoma lines and human patient-derived tumors (PDXs). They grafted fluorescently labeled neuroblastoma cells into the dorsal neural tube of chick embryos and conducted immunofluorescent and time-lapse imaging and confocal light-sheet microscopy (Delloye-Bourgeois et al., 2017). Neuroblastoma cells followed neural crest migration to reach sympathetic ganglia, where they subsequently formed dense, proliferating masses that often spread multifocally (metastasized) to distant sites by 7 days post-engraftment. The metastatic spread proceeded through the dorsal aorta and peripheral nerves, a novel finding demonstrated in multiple human cell lines. Delloye-Bourgeois et al. then conducted RNA-seq to characterize geneexpression changes occurring between engraftment and primary (premetastatic) tumors. Forty-six neural crest genes were differentially expressed. Twentyfour were related to cell movement, and three of these were Semaphorins. The Semaphorin gene family regulates axon guidance and cardiac neural crest cell migration (Schwarz et al., 2009). They also contribute to cell migration and angiogenesis, functions that can 396 Cancer Cell 32, October 9, 2017
be used to either suppress or drive tumors, depending on cell type (Tamagnone, 2012). Levels of Semaphorin3C (Sema3C) decreased by half in neuroblastoma tumor masses compared to naive pre-engraftment cells. Sema3C small interfering RNA knockdown during neural crest migration hindered collective migration and targeting of neuroblastoma cells to sympathetic structures, and led to increased dissemination (failure to reach sympathoadrenal sites). Importantly, the authors validated that the effect of inducible Sema3C small hairpin RNA knockdown in already-established primary tumors (from human cell lines) led to increased metastatic spread in the embryos. This effect was rescued by expressing an exogenous Sema3C construct. Additionally, the authors examined potential paracrine actions of Sema3C by mixing high-Sema3C and low-Sema3C cells. Inclusion of 25% high-Sema3C cells was sufficient to block the dissemination of the neuroblastoma cells. These results clearly demonstrate the role of Sema3C in the cohesion of neuroblastoma cells and their collective migration, suggesting Sema3C as a metastasis-suppressing gene. The canonical receptors for secreted Semaphorin ligands are Neuropilins, which must complex to transmembrane Plexins to transduce downstream signals (Neufeld et al., 2012). Delloye-Bour-
geois and colleagues showed that—like Sema3C—the expression of Neuropilin 1 (NRP1) and PlexinA4 (PLXNA4) were both decreased significantly in tumor masses relative to pre-engraftment cells. Knockdown of NRP1/2 or PLXNA4 also drastically impaired cell aggregation and increased metastasis from the tumor core in vivo, mimicking the effect of Sema3C knockdown. These results correlated with retrospective data from neuroblastoma patients showing that low levels of Sema3C, NRP1, and PLXN4 were associated with poorer event-free survival. This work highlights the importance of Semaphorin/Neuropilin/Plexin signaling in neuroblastoma, with functional knockdown experiments suggesting a role in metastatic spread. Additional studies are needed to validate the functional importance of this candidate metastatic signaling pathway in neuroblastoma tumors in mammals. Finally, Delloye-Bourgeois and colleagues show that neuroblastoma patient-derived xenografts (PDXs) could be grafted into their chick embryo model and, like the cell lines, then targeted sympathoadrenal derivatives to form tumors in the embryo. Impressively, distant metastases occurred only when using cells derived from patients with metastatic neuroblastoma. Some metastatic neuroblastoma cells were also observed in the aorta, again confirming this as a preferential route for dissemination of neuroblastoma in the chick. This work by Delloye-Bourgeois and colleagues introduces a novel xenograft model in which neuroblastoma cell lines and PDXs engrafted in the neural crest environment of chick embryos and followed migration patterns of endogenous avian neural crest cells. This study opens the possibility for studying a variety of cell behaviors and testing potential therapeutics for relevance and efficacy in human disease. Additionally, although this study focused on the role of Sema3C in neuroblastoma cell cohesion, deeper analysis of the RNA-seq data generated here could identify other transcriptional changes contributing to metastatic neuroblastoma in children. Although RNA-seq analysis between pre-engraftment cells and the primary tumor was performed in this work,
Cancer Cell
Previews similar analysis between the primary tumor and metastatic cells could provide further insights on the mechanisms of metastatic spread. The mechanisms driving metastasis in neuroblastoma are challenging to investigate and are poorly recapitulated to date in existing murine models. Delloye-Bourgeois et al. highlight the considerable power of the chick embryo model for neuroblastoma. Zhu and colleagues have also shown that they can model metastasis in zebrafish, where overexpressing the transcriptional regulators LMO1 and MYCN led to metastatic spread (Zhu et al., 2017). These non-mammalian vertebrate models are already improving our understanding of metastatic neuroblastoma and have the potential to identify candidate targets for future clinical trials.
ACKNOWLEDGMENTS T.Z. is supported by UCSF’s Medical Scientist and Biomedical Sciences Training Programs. M.M. receives fellowship support from the National Cancer Children’s Cancer Project Fund. The Weiss lab is supported by NIH grants U01CA217864 and P30CA82103; NIH R01 grants CA148699, CA221969, NS091620, NS088355, and NS089868; a Bold and Basic grant from UCSF’s Quantitative Biosciences Institute and the Children’s Tumor, Pediatric Brain Tumor, Ross K. MacNeill, St. Baldrick, and Samuel G. Waxman foundations; and the Evelyn and Mattie Anderson Chair.
Kulesa, P.M., Kasemeier-Kulesa, J.C., Teddy, J.M., Margaryan, N.V., Seftor, E.A., Seftor, R.E.B., and Hendrix, M.J.C. (2006). Proc. Natl. Acad. Sci. USA 103, 3752–3757. Matthay, K.K., Maris, J.M., Schleiermacher, G., Nakagawara, A., Mackall, C.L., Diller, L., and Weiss, W.A. (2016). Nat. Rev. Dis. Primers 2, 16078. Neufeld, G., Sabag, A.D., Rabinovicz, N., and Kessler, O. (2012). Cold Spring Harb. Perspect. Med. 2, a006718. Schwarz, Q., Maden, C.H., Vieira, J.M., and Ruhrberg, C. (2009). Proc. Natl. Acad. Sci. USA 106, 6164–6169.
REFERENCES
Shibue, T., and Weinberg, R.A. (2017). Nat. Rev. Clin. Oncol. 14, 611–629.
Bronner, M.E., and Simo˜es-Costa, M. (2016). Curr. Top. Dev. Biol. 116, 115–134.
Stern, C.D. (2005). Dev. Cell 8, 9–17.
Delloye-Bourgeois, C., Bertin, L., Thoinet, K., Jarrosson, L., Kindbeiter, K., Buffet, T., Tauszig-Delamasure, S., Bozon, M., Marabelle, A., Combaret, V., et al. (2017). Cancer Cell 32, this issue, 427–443.
Tamagnone, L. (2012). Cancer Cell 22, 145–152. Zhu, S., Zhang, X., Weichert-Leahey, N., Dong, Z., Zhang, C., Lopez, G., Tao, T., He, S., Wood, A.C., Oldridge, D., et al. (2017). Cancer Cell 32, 310–323.e5.
Tumor Suppression by p53: Bring in the Hippo! Yael Aylon1,* and Moshe Oren1,* 1Department of Molecular Cell Biology, The Weizmann Institute, Rehovot 76100, Israel *Correspondence: [email protected] (Y.A.), [email protected] (M.O.) http://dx.doi.org/10.1016/j.ccell.2017.09.010
In this issue of Cancer Cell, Mello et al. investigated how p53 suppresses pancreatic cancer and discovered a key role for the tyrosine phosphatase PTPN14, a p53 transcriptional target. PTPN14 restrains YAP, curbing its potential oncogenic effects. The p53-PTPN14-YAP axis highlights the importance of signaling pathway coordination in cancer prevention. Proper regulation of cell fate requires integration between numerous signaling pathways, operating contemporaneously within the same cell. Tumor suppressor pathways play important roles in regulation of cell fate and tissue homeostasis, calling for close coordination of their activities. Not surprisingly, loss of such coordination opens the door wide for cancer progression. p53 is a major player in the cancer arena: about half of all human tumors harbor mutations in the TP53 gene, encoding p53, making it the most frequent genetic alteration in human cancer. The primary consequence of those mutations is abrogation of the tumor suppressive capacity of the wild-type (WT) p53 protein; in addi-
tion, at least some cancer-associated mutant p53 variants may also acquire oncogenic gain of function, rendering them active contributors to cancer progression. The remainder of the tumors retain WT p53 but often manifest alterations in other components of the extended p53 pathway, which either downregulate p53 or compromise its tumor-suppressor potency. p53 is primarily a transcription factor, capable of transactivating hundreds of genes and repressing many others. It is activated in response to a plethora of genotoxic and oncogenic stresses and perturbations to metabolic homeostasis and acts to curb the undesirable consequences of such stresses. When acti-
vated, p53 orchestrates a multitude of biochemical and biological outcomes, ranging from fine-tuning of cellular metabolism and enhancement of DNA repair, to transient antiproliferative effects, to replicative senescence and apoptosis. The amply documented ability of p53 to enforce senescence and apoptosis in response to persistent oncogenic stress provides a highly intuitive mechanistic explanation for its tumor-suppressor capacity. Surprisingly, mouse model studies demonstrated unequivocally that both senescence and apoptosis are dispensable for p53-mediated tumor suppression (Li et al., 2012), suggesting that a lessintuitive activity of p53 might actually hold the clues to cancer prevention. Mello
Cancer Cell 32, October 9, 2017 ª 2017 Elsevier Inc. 397
