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Dally Proteoglycan Mediates the Autonomous and Nonautonomous Effects on Tissue Growth Caused by Activation of the PI3K and TOR Pathways.

Ferreira A, Milán M - PLoS Biol. (2015)

Bottom Line: Activation of these pathways leads to an autonomous induction of tissue overgrowth and to a remarkable nonautonomous reduction in growth and proliferation rates of adjacent cell populations.The observed autonomous and nonautonomous effects on tissue growth rely on the up-regulation of the proteoglycan Dally, a major element involved in modulating the spreading, stability, and activity of the growth promoting Decapentaplegic (Dpp)/transforming growth factor β(TGF-β) signaling molecule.Our findings indicate that a reduction in the amount of available growth factors contributes to the outcompetition of wild-type cells by overgrowing cell populations.

View Article: PubMed Central - PubMed

Affiliation: Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain.

ABSTRACT
How cells acquiring mutations in tumor suppressor genes outcompete neighboring wild-type cells is poorly understood. The phosphatidylinositol 3-kinase (PI3K)-phosphatase with tensin homology (PTEN) and tuberous sclerosis complex (TSC)-target of rapamycin (TOR) pathways are frequently activated in human cancer, and this activation is often causative of tumorigenesis. We utilized the Gal4-UAS system in Drosophila imaginal primordia, highly proliferative and growing tissues, to analyze the impact of restricted activation of these pathways on neighboring wild-type cell populations. Activation of these pathways leads to an autonomous induction of tissue overgrowth and to a remarkable nonautonomous reduction in growth and proliferation rates of adjacent cell populations. This nonautonomous response occurs independently of where these pathways are activated, is functional all throughout development, takes place across compartments, and is distinct from cell competition. The observed autonomous and nonautonomous effects on tissue growth rely on the up-regulation of the proteoglycan Dally, a major element involved in modulating the spreading, stability, and activity of the growth promoting Decapentaplegic (Dpp)/transforming growth factor β(TGF-β) signaling molecule. Our findings indicate that a reduction in the amount of available growth factors contributes to the outcompetition of wild-type cells by overgrowing cell populations. During normal development, the PI3K/PTEN and TSC/TOR pathways play a major role in sensing nutrient availability and modulating the final size of any developing organ. We present evidence that Dally also contributes to integrating nutrient sensing and organ scaling, the fitting of pattern to size.

No MeSH data available.


Related in: MedlinePlus

A role of Dally in tissue growth.(A) Activation of the PI3K/PTEN, TSC/TOR, or Yorkie pathways in a defined cell population (in blue) increases cell and/or tissue size in an autonomous manner and induces a nonautonomous reduction in both cell size and number in neighboring cell populations (in grey). Whereas the autonomous and nonautonomous effects on tissue size are mediated by Dally, the effects on cell size are Dally independent. The nonautonomous reduction in tissue size is a consequence of reduced Dpp signaling, most probably reflecting increased number of Dpp molecules bound to the overgrowing (Dally overexpressing) tissue and a consequent reduction in the number of available Dpp molecules to the neighboring cell population. (B) Within the feeding animal, the PI3K/PTEN and TSC/TOR pathways sense nutrient conditions and modulate both cell and tissue size. Whereas the effects on tissue size are mediated by the glypican Dally, which modulates the spreading of the Dpp morphogen throughout the tissue, the effects on cell size are Dally independent.
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pbio.1002239.g008: A role of Dally in tissue growth.(A) Activation of the PI3K/PTEN, TSC/TOR, or Yorkie pathways in a defined cell population (in blue) increases cell and/or tissue size in an autonomous manner and induces a nonautonomous reduction in both cell size and number in neighboring cell populations (in grey). Whereas the autonomous and nonautonomous effects on tissue size are mediated by Dally, the effects on cell size are Dally independent. The nonautonomous reduction in tissue size is a consequence of reduced Dpp signaling, most probably reflecting increased number of Dpp molecules bound to the overgrowing (Dally overexpressing) tissue and a consequent reduction in the number of available Dpp molecules to the neighboring cell population. (B) Within the feeding animal, the PI3K/PTEN and TSC/TOR pathways sense nutrient conditions and modulate both cell and tissue size. Whereas the effects on tissue size are mediated by the glypican Dally, which modulates the spreading of the Dpp morphogen throughout the tissue, the effects on cell size are Dally independent.

Mentions: Here we present evidence that targeted deregulation of the PI3K/PTEN, TSC/TOR, or hippo/Yorkie pathways, known to promote tissue overgrowth by increasing the number and/or size of cells, induces a nonautonomous reduction in tissue size of adjacent cell populations. This nonautonomous effect is a consequence of a reduction in both cell size and proliferation rates (cell number), and it is not a consequence of programmed cell death or the withdrawal of nutrients from neighboring tissues, as reducing the levels of proapoptotic genes or subjecting larvae to different amino-acid diets does not have any impact on the size reduction of neighboring cell populations. We show that the glypican Dally, which plays a major role in regulating the spread of Dpp in Drosophila tissues [49–52,59], is up-regulated upon deregulation of these tumor suppressor pathways and that the increase in Dally expression levels contributes to the autonomous effects on tissue size and to the nonautonomous reduction in cell number. Whereas the autonomous effects on tissue size caused by deregulation of these tumor suppressor pathways are most probably due, as least in part (see below), to the capacity of Dally to facilitate Dpp spreading throughout the tissue, we propose that the nonautonomous effects on cell number are a consequence of withdrawal of Dpp from neighboring tissues (Fig 8A). This proposal is based on a number of observations. First, the width of the Dpp activity gradient as well as the total amount of Dpp activity was reduced in adjacent cell populations upon targeted depletion of tumor suppressor pathways. Second, the nonautonomous effects on tissue size were fully rescued by Dally depletion, which has a rather specific role on the spread of Dpp when overexpressed. Third, the nonautonomous effects on tissue size, growth and proliferation rates, and/or Dpp availability and signaling can be phenocopied by overexpression of Dally or the Dpp receptor Tkv. We observed different strengths of the autonomous and nonautonomous effects upon deregulation of these tumor suppressor pathways or overexpression of Dally in either the A or P compartments (Fig 1 and Fig 6). Despite the mild autonomous induction of tissue growth caused by the ci-gal4 driver in A cells, it caused a relatively strong nonautonomous reduction of the neighboring compartment. On the contrary, the en-gal4 driver caused a strong autonomous induction of tissue growth in P cells but a relatively weak nonautonomous reduction of the neighboring compartment. The differential autonomous response might simply reflect different strengths of these Gal4 drivers. By contrast, the strongest nonautonomous effects caused by the ci-gal4 driver (when compared to the en-gal4 driver) might be because Dpp expression is restricted to the A compartment and increased levels of Dally in Dpp expressing cells are more efficient at titrating out the levels of this growth factor from the neighboring compartment. We noticed that the nonautonomous effects on cell size observed upon deregulation of the PI3K/PTEN, TSC/TOR, or hippo/Yorkie pathways are Dally independent, as overexpression of Dally did not cause a nonautonomous reduction in cell size. Moreover, depletion of Dally did not rescue the nonautonomous reduction in cell size caused by activation of these pathways. These results are consistent with the fact that changes in Dpp signaling do not cause any effect on cell size (S3 Fig, see also [60]) and indicate that Dally and Dpp are regulating cell number but not cell size. Somatic mutations in tumor suppressor genes such as PTEN or TSC are frequently accumulated in early events of tumor development, and these mutations are thought to contribute to the selection of tumorigenic cells. Competition for available growth factors, by modulating the levels of glypicans, such as Dally, might contribute to the outcompetition of wild-type cells and to the selection of malignant mutation-carrying cells in human cancer.


Dally Proteoglycan Mediates the Autonomous and Nonautonomous Effects on Tissue Growth Caused by Activation of the PI3K and TOR Pathways.

Ferreira A, Milán M - PLoS Biol. (2015)

A role of Dally in tissue growth.(A) Activation of the PI3K/PTEN, TSC/TOR, or Yorkie pathways in a defined cell population (in blue) increases cell and/or tissue size in an autonomous manner and induces a nonautonomous reduction in both cell size and number in neighboring cell populations (in grey). Whereas the autonomous and nonautonomous effects on tissue size are mediated by Dally, the effects on cell size are Dally independent. The nonautonomous reduction in tissue size is a consequence of reduced Dpp signaling, most probably reflecting increased number of Dpp molecules bound to the overgrowing (Dally overexpressing) tissue and a consequent reduction in the number of available Dpp molecules to the neighboring cell population. (B) Within the feeding animal, the PI3K/PTEN and TSC/TOR pathways sense nutrient conditions and modulate both cell and tissue size. Whereas the effects on tissue size are mediated by the glypican Dally, which modulates the spreading of the Dpp morphogen throughout the tissue, the effects on cell size are Dally independent.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4551486&req=5

pbio.1002239.g008: A role of Dally in tissue growth.(A) Activation of the PI3K/PTEN, TSC/TOR, or Yorkie pathways in a defined cell population (in blue) increases cell and/or tissue size in an autonomous manner and induces a nonautonomous reduction in both cell size and number in neighboring cell populations (in grey). Whereas the autonomous and nonautonomous effects on tissue size are mediated by Dally, the effects on cell size are Dally independent. The nonautonomous reduction in tissue size is a consequence of reduced Dpp signaling, most probably reflecting increased number of Dpp molecules bound to the overgrowing (Dally overexpressing) tissue and a consequent reduction in the number of available Dpp molecules to the neighboring cell population. (B) Within the feeding animal, the PI3K/PTEN and TSC/TOR pathways sense nutrient conditions and modulate both cell and tissue size. Whereas the effects on tissue size are mediated by the glypican Dally, which modulates the spreading of the Dpp morphogen throughout the tissue, the effects on cell size are Dally independent.
Mentions: Here we present evidence that targeted deregulation of the PI3K/PTEN, TSC/TOR, or hippo/Yorkie pathways, known to promote tissue overgrowth by increasing the number and/or size of cells, induces a nonautonomous reduction in tissue size of adjacent cell populations. This nonautonomous effect is a consequence of a reduction in both cell size and proliferation rates (cell number), and it is not a consequence of programmed cell death or the withdrawal of nutrients from neighboring tissues, as reducing the levels of proapoptotic genes or subjecting larvae to different amino-acid diets does not have any impact on the size reduction of neighboring cell populations. We show that the glypican Dally, which plays a major role in regulating the spread of Dpp in Drosophila tissues [49–52,59], is up-regulated upon deregulation of these tumor suppressor pathways and that the increase in Dally expression levels contributes to the autonomous effects on tissue size and to the nonautonomous reduction in cell number. Whereas the autonomous effects on tissue size caused by deregulation of these tumor suppressor pathways are most probably due, as least in part (see below), to the capacity of Dally to facilitate Dpp spreading throughout the tissue, we propose that the nonautonomous effects on cell number are a consequence of withdrawal of Dpp from neighboring tissues (Fig 8A). This proposal is based on a number of observations. First, the width of the Dpp activity gradient as well as the total amount of Dpp activity was reduced in adjacent cell populations upon targeted depletion of tumor suppressor pathways. Second, the nonautonomous effects on tissue size were fully rescued by Dally depletion, which has a rather specific role on the spread of Dpp when overexpressed. Third, the nonautonomous effects on tissue size, growth and proliferation rates, and/or Dpp availability and signaling can be phenocopied by overexpression of Dally or the Dpp receptor Tkv. We observed different strengths of the autonomous and nonautonomous effects upon deregulation of these tumor suppressor pathways or overexpression of Dally in either the A or P compartments (Fig 1 and Fig 6). Despite the mild autonomous induction of tissue growth caused by the ci-gal4 driver in A cells, it caused a relatively strong nonautonomous reduction of the neighboring compartment. On the contrary, the en-gal4 driver caused a strong autonomous induction of tissue growth in P cells but a relatively weak nonautonomous reduction of the neighboring compartment. The differential autonomous response might simply reflect different strengths of these Gal4 drivers. By contrast, the strongest nonautonomous effects caused by the ci-gal4 driver (when compared to the en-gal4 driver) might be because Dpp expression is restricted to the A compartment and increased levels of Dally in Dpp expressing cells are more efficient at titrating out the levels of this growth factor from the neighboring compartment. We noticed that the nonautonomous effects on cell size observed upon deregulation of the PI3K/PTEN, TSC/TOR, or hippo/Yorkie pathways are Dally independent, as overexpression of Dally did not cause a nonautonomous reduction in cell size. Moreover, depletion of Dally did not rescue the nonautonomous reduction in cell size caused by activation of these pathways. These results are consistent with the fact that changes in Dpp signaling do not cause any effect on cell size (S3 Fig, see also [60]) and indicate that Dally and Dpp are regulating cell number but not cell size. Somatic mutations in tumor suppressor genes such as PTEN or TSC are frequently accumulated in early events of tumor development, and these mutations are thought to contribute to the selection of tumorigenic cells. Competition for available growth factors, by modulating the levels of glypicans, such as Dally, might contribute to the outcompetition of wild-type cells and to the selection of malignant mutation-carrying cells in human cancer.

Bottom Line: Activation of these pathways leads to an autonomous induction of tissue overgrowth and to a remarkable nonautonomous reduction in growth and proliferation rates of adjacent cell populations.The observed autonomous and nonautonomous effects on tissue growth rely on the up-regulation of the proteoglycan Dally, a major element involved in modulating the spreading, stability, and activity of the growth promoting Decapentaplegic (Dpp)/transforming growth factor β(TGF-β) signaling molecule.Our findings indicate that a reduction in the amount of available growth factors contributes to the outcompetition of wild-type cells by overgrowing cell populations.

View Article: PubMed Central - PubMed

Affiliation: Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain.

ABSTRACT
How cells acquiring mutations in tumor suppressor genes outcompete neighboring wild-type cells is poorly understood. The phosphatidylinositol 3-kinase (PI3K)-phosphatase with tensin homology (PTEN) and tuberous sclerosis complex (TSC)-target of rapamycin (TOR) pathways are frequently activated in human cancer, and this activation is often causative of tumorigenesis. We utilized the Gal4-UAS system in Drosophila imaginal primordia, highly proliferative and growing tissues, to analyze the impact of restricted activation of these pathways on neighboring wild-type cell populations. Activation of these pathways leads to an autonomous induction of tissue overgrowth and to a remarkable nonautonomous reduction in growth and proliferation rates of adjacent cell populations. This nonautonomous response occurs independently of where these pathways are activated, is functional all throughout development, takes place across compartments, and is distinct from cell competition. The observed autonomous and nonautonomous effects on tissue growth rely on the up-regulation of the proteoglycan Dally, a major element involved in modulating the spreading, stability, and activity of the growth promoting Decapentaplegic (Dpp)/transforming growth factor β(TGF-β) signaling molecule. Our findings indicate that a reduction in the amount of available growth factors contributes to the outcompetition of wild-type cells by overgrowing cell populations. During normal development, the PI3K/PTEN and TSC/TOR pathways play a major role in sensing nutrient availability and modulating the final size of any developing organ. We present evidence that Dally also contributes to integrating nutrient sensing and organ scaling, the fitting of pattern to size.

No MeSH data available.


Related in: MedlinePlus