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Drosophila still flying high in cancer research
FEATURE
Drosophila still flying high in cancer research
952
its previously established role in regulating cell proliferation”, Montell reports. The group is also doing genetic screens to identify new loci involved in border cell migration. “As we identify new genes, we plan to test whether they are likely to play roles in
Rights were not granted to include this image in electronic media. Please refer to the printed journal. As popular as ever
human cancer, with a particular focus on ovarian cancer”, she says. Drosophila featured in cancer research again in late January this year, when researchers at the Howard Hughes Medical Institute (Baylor College of Medicine, Houston, TX, USA) used mutant fruit fly larvae to demonstrate that the Hrs protein may be a valid new target for anticancer drugs. Tom Lloyd, Hugo Bellen, and colleagues showed that receptors such as the epidermal growth factor receptor (EGFR) are removed from the cell cytoplasm by Hrs, which guides them to lysosomes for degradation. Bellen and colleagues looked at mutant fly larvae that lacked functional Hrs. Using electron microscopy they were able to show that stomach cells in the larvae had enlarged endosomes within their cytoplasm. “These abnormalities seem to be due to defects in the endosome’s capacity to form multivesicular bodies that carry vesicles containing active receptors to lysosomes for disposal”, says Bellen. EGFR and Torso tyrosine kinase receptor remained switched on in the mutant fruit flies, as they could not be shunted to lysosomes by Hrs (Cell 2002; 108: 261–69). “Without Hrs, the receptors stay active in the cytoplasm and the resulting overactivity of the signals they produce might underly many cancers”, says Bellen. Most recently, at the end of last month, Wufan Tao (University of Minnesota, Minneapolis, MN, USA) and colleagues showed that the LATS1 gene can be used to transduce human breast cancer cells to inhibit in-vitro cell proliferation. LATS1 is a mammalian homologue of the Drosophila large tumour suppressor (lats) gene that has been previously
Science Photo Library
rosophila melanogaster, the stalwart experimental animal that has been bred and used relentlessly for at least 100 years, shows no signs of losing popularity with researchers—but can it still have things to tell us and is fruit fly research still sexy enough to get funding? Denise Montell (Johns Hopkins School of Medicine, Baltimore, MD, USA) thinks the answer to both questions is “Yes”. In December last year, Montell and Debra Silver used the fruit fly to study the JAK/STAT signalling pathway, which is constitutively active in various human cancers. “JAK and STAT are both required to convert the border cells in the Drosophila ovary from stationary epithelial cells to migratory, invasive cells”, reports Montell (Cell 2001; 107: 831–41). This step in cancer progression is poorly understood compared with the mechanisms regulating proliferation and survival of tumour cells but Montell’s fruit fly studies have identified several signalling pathways that regulate the ability of epithelial cells to become migratory. “I think our work demonstrates the value of funding basic research into developmental biology in model organisms, before there is a clear and simple link to a particular type of human cancer”, she stresses. Montell’s studies during the past 2 years have shown that a steroid hormone signal controls when the border cells in the Drosophila ovary become migratory and invade the neighbouring germ cell cluster and coordinates this event with other developmental events that occur at the same stage (Cell 2000; 103: 1047–58). A growth factor related to platelet-derived growth factor and vascular endothelial growth factor, discovered by the laboratory of Pernille Rørth (EMBL Heidelberg, Germany), probably contributes to guiding the cells to their destination (Cell 2001; 107: 17–26) and a highly localised cytokine signal that activates the JAK/STAT pathway defines which epithelial cells become migratory (Cell 2001; 107: 831–41). Montell now suspects that substantial changes in gene expression are required to convert epithelial cells to migratory cells. “We are currently using genomics to identify the downstream targets of the transcription factors required for this process. Work with human ovarian cancer cells has now started in order to determine if the JAK/STAT pathway regulates the motility of these cells, in addition to
D
shown to cause spontaneous tumours in lats mosaic flies. “Our biochemical and genetic data have shown that the LATS protein is a negative cell cycle regulator that modulates CDC2/cyclin A activity. We are currently studying the mechanism(s) by which the LATS1 gene controls tumorigenesis”, reports Tao. The latest study shows that ectopic expression of LATS1 in human breast cancer cells and lung cancer cells upregulates the amount of BAX proteins and induces apoptosis. Tao’s group and Tian Xu’s laboratory at Yale University (Connecticut, CT, USA) are also studying LATS2. Tian Xu and colleagues have shown that expression of the mammalian LATS2 in the fruit fly rescues the lethality phenotypes of Drosophila that are LATS deficient. “This suggests that LATS2 is also a potential tumour suppressor in mammals”, adds Tao. Rosemary Akhurst (UCSF, Mount Zion, Cancer Research Institute, San Francisco), whose main research interest is the involvement of the TGFb1 signalling pathway in embryonic and neoplastic development points out that this and many other developmental signalling pathways currently being studied for their role in cancer were originally identified by developmental screens of Drosophila. “Despite the pressure to undertake research relevant to human disease, I believe that it is very important to support research into basic developmental mechanisms for themselves.” Joan Massagué (Memorial SloanKettering Cancer Center, New York, USA), whose research also centres on the TGFb family of growth regulatory factors agrees that “in principle, developmental biology research should be driven by developmental biology problems”. But he points out that in some settings, such as in the cancer research institute, “developmental biologists find extra opportunities and incentives to explore important developmental mechanisms and processes that are also relevant to tumour growth”. Nevertheless, Akhurst argues that the most important breakthroughs that have given rise to today’s applied genetic-based biomedical sciences were made by scientists working on what, at the time, might have seemed quite obscure research. With the help of the fruit fly, we may be saying the same thing in another 100 years. Kathryn Senior
THE LANCET • Vol 359 • March 16, 2002 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Drosophila still flying high in cancer research
952
its previously established role in regulating cell proliferation”, Montell reports. The group is also doing genetic screens to identify new loci involved in border cell migration. “As we identify new genes, we plan to test whether they are likely to play roles in
Rights were not granted to include this image in electronic media. Please refer to the printed journal. As popular as ever
human cancer, with a particular focus on ovarian cancer”, she says. Drosophila featured in cancer research again in late January this year, when researchers at the Howard Hughes Medical Institute (Baylor College of Medicine, Houston, TX, USA) used mutant fruit fly larvae to demonstrate that the Hrs protein may be a valid new target for anticancer drugs. Tom Lloyd, Hugo Bellen, and colleagues showed that receptors such as the epidermal growth factor receptor (EGFR) are removed from the cell cytoplasm by Hrs, which guides them to lysosomes for degradation. Bellen and colleagues looked at mutant fly larvae that lacked functional Hrs. Using electron microscopy they were able to show that stomach cells in the larvae had enlarged endosomes within their cytoplasm. “These abnormalities seem to be due to defects in the endosome’s capacity to form multivesicular bodies that carry vesicles containing active receptors to lysosomes for disposal”, says Bellen. EGFR and Torso tyrosine kinase receptor remained switched on in the mutant fruit flies, as they could not be shunted to lysosomes by Hrs (Cell 2002; 108: 261–69). “Without Hrs, the receptors stay active in the cytoplasm and the resulting overactivity of the signals they produce might underly many cancers”, says Bellen. Most recently, at the end of last month, Wufan Tao (University of Minnesota, Minneapolis, MN, USA) and colleagues showed that the LATS1 gene can be used to transduce human breast cancer cells to inhibit in-vitro cell proliferation. LATS1 is a mammalian homologue of the Drosophila large tumour suppressor (lats) gene that has been previously
Science Photo Library
rosophila melanogaster, the stalwart experimental animal that has been bred and used relentlessly for at least 100 years, shows no signs of losing popularity with researchers—but can it still have things to tell us and is fruit fly research still sexy enough to get funding? Denise Montell (Johns Hopkins School of Medicine, Baltimore, MD, USA) thinks the answer to both questions is “Yes”. In December last year, Montell and Debra Silver used the fruit fly to study the JAK/STAT signalling pathway, which is constitutively active in various human cancers. “JAK and STAT are both required to convert the border cells in the Drosophila ovary from stationary epithelial cells to migratory, invasive cells”, reports Montell (Cell 2001; 107: 831–41). This step in cancer progression is poorly understood compared with the mechanisms regulating proliferation and survival of tumour cells but Montell’s fruit fly studies have identified several signalling pathways that regulate the ability of epithelial cells to become migratory. “I think our work demonstrates the value of funding basic research into developmental biology in model organisms, before there is a clear and simple link to a particular type of human cancer”, she stresses. Montell’s studies during the past 2 years have shown that a steroid hormone signal controls when the border cells in the Drosophila ovary become migratory and invade the neighbouring germ cell cluster and coordinates this event with other developmental events that occur at the same stage (Cell 2000; 103: 1047–58). A growth factor related to platelet-derived growth factor and vascular endothelial growth factor, discovered by the laboratory of Pernille Rørth (EMBL Heidelberg, Germany), probably contributes to guiding the cells to their destination (Cell 2001; 107: 17–26) and a highly localised cytokine signal that activates the JAK/STAT pathway defines which epithelial cells become migratory (Cell 2001; 107: 831–41). Montell now suspects that substantial changes in gene expression are required to convert epithelial cells to migratory cells. “We are currently using genomics to identify the downstream targets of the transcription factors required for this process. Work with human ovarian cancer cells has now started in order to determine if the JAK/STAT pathway regulates the motility of these cells, in addition to
D
shown to cause spontaneous tumours in lats mosaic flies. “Our biochemical and genetic data have shown that the LATS protein is a negative cell cycle regulator that modulates CDC2/cyclin A activity. We are currently studying the mechanism(s) by which the LATS1 gene controls tumorigenesis”, reports Tao. The latest study shows that ectopic expression of LATS1 in human breast cancer cells and lung cancer cells upregulates the amount of BAX proteins and induces apoptosis. Tao’s group and Tian Xu’s laboratory at Yale University (Connecticut, CT, USA) are also studying LATS2. Tian Xu and colleagues have shown that expression of the mammalian LATS2 in the fruit fly rescues the lethality phenotypes of Drosophila that are LATS deficient. “This suggests that LATS2 is also a potential tumour suppressor in mammals”, adds Tao. Rosemary Akhurst (UCSF, Mount Zion, Cancer Research Institute, San Francisco), whose main research interest is the involvement of the TGFb1 signalling pathway in embryonic and neoplastic development points out that this and many other developmental signalling pathways currently being studied for their role in cancer were originally identified by developmental screens of Drosophila. “Despite the pressure to undertake research relevant to human disease, I believe that it is very important to support research into basic developmental mechanisms for themselves.” Joan Massagué (Memorial SloanKettering Cancer Center, New York, USA), whose research also centres on the TGFb family of growth regulatory factors agrees that “in principle, developmental biology research should be driven by developmental biology problems”. But he points out that in some settings, such as in the cancer research institute, “developmental biologists find extra opportunities and incentives to explore important developmental mechanisms and processes that are also relevant to tumour growth”. Nevertheless, Akhurst argues that the most important breakthroughs that have given rise to today’s applied genetic-based biomedical sciences were made by scientists working on what, at the time, might have seemed quite obscure research. With the help of the fruit fly, we may be saying the same thing in another 100 years. Kathryn Senior
THE LANCET • Vol 359 • March 16, 2002 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.