Limits...
Sonic Hedgehog promotes proliferation of Notch-dependent monociliated choroid plexus tumour cells

View Article: PubMed Central - PubMed

ABSTRACT

Aberrant Notch signaling has been linked to many cancers including choroid plexus (CP) tumours, a group of rare and predominantly pediatric brain neoplasms. We developed animal models of CP tumours by inducing sustained expression of Notch1 that recapitulate properties of human CP tumours with aberrant NOTCH signaling. Whole transcriptome and functional analyses showed that tumour cell proliferation is associated with Sonic Hedgehog (Shh) in the tumour microenvironment. Unlike CP epithelial cells, which have multiple primary cilia, tumour cells possess a solitary primary cilium as a result of Notch-mediated suppression of multiciliate diffferentiation. A Shh-driven signaling cascade in the primary cilium occurs in tumour cells but not in epithelial cells. Lineage studies show that CP tumours arise from mono-ciliated progenitors in the roof plate characterized by elevated Notch signaling. Abnormal SHH signaling and distinct ciliogenesis are detected in human CP tumours, suggesting SHH pathway and cilia differentiation as potential therapeutic avenues.

No MeSH data available.


Related in: MedlinePlus

Notch-induced CP tumour cells retain properties of roof plate progenitor. (a) Analysis of gene expression and cell proliferation in tumour cells and progenitors within hindbrain roof plate in Mcre;NICD1 and wild type (WT) animals, respectively, at day E12.5. The expression of Lmx1a (red) marks the roof plate and CP lineage. Ki-67 expression (green) labels proliferating cells, and Aqp1 expression (green) marks differentiated epithelial cells. White dotted lines demarcate domain of progenitors in hindbrain roof plate. Boxed regions of Lmx1a+/Ki-67+/Aqp1− progenitors (a, c, e, f), tumour cells (b, d) (arrows), and Lmx1a+/Ki-67−/Aqp1+ differentiated epithelial cells (b, d) (red bracket lines) are shown in higher magnification. Scale bar: 100μm. (b) Schematic diagram of interaction between Notch and Shh pathways during the roof plate/CP morphogenesis and tumour formation. Epithelial progenitors in the roof plate (RP, yellow) next to the rhombic lip (RL) exhibits active Notch signaling, possess a solitary primary cilium, and proliferate in response to Shh (green dots) secreted from multiciliated epithelial cells (grey). The self-renewal will cease as Notch pathway activity in progenitor cells is attenuated to allow for multiciliate differentiation, thereby abolishing the response of the progenitors to Shh that drives their expansion during development. (c) Epithelial progenitors with constitutive Notch pathway activity (red) remain mono-ciliated and undergo aberrant proliferation to become tumour cells that retain the ability to respond to Shh signals in the local environment and undergo Shh-driven proliferation.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4814324&req=5

Figure 8: Notch-induced CP tumour cells retain properties of roof plate progenitor. (a) Analysis of gene expression and cell proliferation in tumour cells and progenitors within hindbrain roof plate in Mcre;NICD1 and wild type (WT) animals, respectively, at day E12.5. The expression of Lmx1a (red) marks the roof plate and CP lineage. Ki-67 expression (green) labels proliferating cells, and Aqp1 expression (green) marks differentiated epithelial cells. White dotted lines demarcate domain of progenitors in hindbrain roof plate. Boxed regions of Lmx1a+/Ki-67+/Aqp1− progenitors (a, c, e, f), tumour cells (b, d) (arrows), and Lmx1a+/Ki-67−/Aqp1+ differentiated epithelial cells (b, d) (red bracket lines) are shown in higher magnification. Scale bar: 100μm. (b) Schematic diagram of interaction between Notch and Shh pathways during the roof plate/CP morphogenesis and tumour formation. Epithelial progenitors in the roof plate (RP, yellow) next to the rhombic lip (RL) exhibits active Notch signaling, possess a solitary primary cilium, and proliferate in response to Shh (green dots) secreted from multiciliated epithelial cells (grey). The self-renewal will cease as Notch pathway activity in progenitor cells is attenuated to allow for multiciliate differentiation, thereby abolishing the response of the progenitors to Shh that drives their expansion during development. (c) Epithelial progenitors with constitutive Notch pathway activity (red) remain mono-ciliated and undergo aberrant proliferation to become tumour cells that retain the ability to respond to Shh signals in the local environment and undergo Shh-driven proliferation.

Mentions: The similarity in gene expression between tumour and roof plate cells, together with elevated Notch signaling and solitary primary cilium in the latter, suggests that Notch-induced CP tumour is related to the roof plate. To delineate the developmental origin of CP tumour, we first analyzed the distribution of Atoh1+ progenitors in hindbrain roof plate using Math1M1GFP mice with enhanced green fluorescent protein (EGFP) fused to the C-terminal of Atoh143. In addition to rhombic lip, Atoh1:EGFP+ cells are present in the Lmx1+/Otx2+ upper roof plate but largely absent from lower roof plate (Fig. 7a, Supplementary Fig. 8a). Second, we analyzed tumour formation in Mcre;NICD1 animals during development. At day E12.5, though many NICD1+/GFP+ cells are located in rhombic lip bordering Lmx1a+ roof plate, some NICD1+/GFP+ cells are present within CP forming into papillary structures (Fig. 7b). These prospective Lmx1a+ tumour cells undergo proliferation (Ki-67+), and remain undifferentiated (Aqp1−) (Fig. 7b, Supplementary Fig. 8b). At day E14.5, most NICD1+/GFP+ tumour cells are found in Lmx1a+ upper roof plate and rostral half of the CP (Fig. 7c). Third, proliferative progenitors (Lmx1a+/Ki-67+/Aqp1−) in hindbrain roof plate differentiate into post-mitotic epithelial cells that form the CP epithelium (Lmx1a+/Ki-67−/Aqp1+) during embryogenesis44, 45. The shape and size roof plate are similar between wild type and Mcre;NICD1 mice; however, tumour cells remain proliferative and undifferentiated (Ki-67+/Aqp1−) even after their incorporation into CP epithelium (Fig. 8a, Supplementary Fig. 8c). Together, these results indicate that CP tumours in these animals arise from roof plate progenitors and migrate into the CP where they continue to undergo Shh-driven proliferation throughout development (Fig. 8b, 8c).


Sonic Hedgehog promotes proliferation of Notch-dependent monociliated choroid plexus tumour cells
Notch-induced CP tumour cells retain properties of roof plate progenitor. (a) Analysis of gene expression and cell proliferation in tumour cells and progenitors within hindbrain roof plate in Mcre;NICD1 and wild type (WT) animals, respectively, at day E12.5. The expression of Lmx1a (red) marks the roof plate and CP lineage. Ki-67 expression (green) labels proliferating cells, and Aqp1 expression (green) marks differentiated epithelial cells. White dotted lines demarcate domain of progenitors in hindbrain roof plate. Boxed regions of Lmx1a+/Ki-67+/Aqp1− progenitors (a, c, e, f), tumour cells (b, d) (arrows), and Lmx1a+/Ki-67−/Aqp1+ differentiated epithelial cells (b, d) (red bracket lines) are shown in higher magnification. Scale bar: 100μm. (b) Schematic diagram of interaction between Notch and Shh pathways during the roof plate/CP morphogenesis and tumour formation. Epithelial progenitors in the roof plate (RP, yellow) next to the rhombic lip (RL) exhibits active Notch signaling, possess a solitary primary cilium, and proliferate in response to Shh (green dots) secreted from multiciliated epithelial cells (grey). The self-renewal will cease as Notch pathway activity in progenitor cells is attenuated to allow for multiciliate differentiation, thereby abolishing the response of the progenitors to Shh that drives their expansion during development. (c) Epithelial progenitors with constitutive Notch pathway activity (red) remain mono-ciliated and undergo aberrant proliferation to become tumour cells that retain the ability to respond to Shh signals in the local environment and undergo Shh-driven proliferation.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4814324&req=5

Figure 8: Notch-induced CP tumour cells retain properties of roof plate progenitor. (a) Analysis of gene expression and cell proliferation in tumour cells and progenitors within hindbrain roof plate in Mcre;NICD1 and wild type (WT) animals, respectively, at day E12.5. The expression of Lmx1a (red) marks the roof plate and CP lineage. Ki-67 expression (green) labels proliferating cells, and Aqp1 expression (green) marks differentiated epithelial cells. White dotted lines demarcate domain of progenitors in hindbrain roof plate. Boxed regions of Lmx1a+/Ki-67+/Aqp1− progenitors (a, c, e, f), tumour cells (b, d) (arrows), and Lmx1a+/Ki-67−/Aqp1+ differentiated epithelial cells (b, d) (red bracket lines) are shown in higher magnification. Scale bar: 100μm. (b) Schematic diagram of interaction between Notch and Shh pathways during the roof plate/CP morphogenesis and tumour formation. Epithelial progenitors in the roof plate (RP, yellow) next to the rhombic lip (RL) exhibits active Notch signaling, possess a solitary primary cilium, and proliferate in response to Shh (green dots) secreted from multiciliated epithelial cells (grey). The self-renewal will cease as Notch pathway activity in progenitor cells is attenuated to allow for multiciliate differentiation, thereby abolishing the response of the progenitors to Shh that drives their expansion during development. (c) Epithelial progenitors with constitutive Notch pathway activity (red) remain mono-ciliated and undergo aberrant proliferation to become tumour cells that retain the ability to respond to Shh signals in the local environment and undergo Shh-driven proliferation.
Mentions: The similarity in gene expression between tumour and roof plate cells, together with elevated Notch signaling and solitary primary cilium in the latter, suggests that Notch-induced CP tumour is related to the roof plate. To delineate the developmental origin of CP tumour, we first analyzed the distribution of Atoh1+ progenitors in hindbrain roof plate using Math1M1GFP mice with enhanced green fluorescent protein (EGFP) fused to the C-terminal of Atoh143. In addition to rhombic lip, Atoh1:EGFP+ cells are present in the Lmx1+/Otx2+ upper roof plate but largely absent from lower roof plate (Fig. 7a, Supplementary Fig. 8a). Second, we analyzed tumour formation in Mcre;NICD1 animals during development. At day E12.5, though many NICD1+/GFP+ cells are located in rhombic lip bordering Lmx1a+ roof plate, some NICD1+/GFP+ cells are present within CP forming into papillary structures (Fig. 7b). These prospective Lmx1a+ tumour cells undergo proliferation (Ki-67+), and remain undifferentiated (Aqp1−) (Fig. 7b, Supplementary Fig. 8b). At day E14.5, most NICD1+/GFP+ tumour cells are found in Lmx1a+ upper roof plate and rostral half of the CP (Fig. 7c). Third, proliferative progenitors (Lmx1a+/Ki-67+/Aqp1−) in hindbrain roof plate differentiate into post-mitotic epithelial cells that form the CP epithelium (Lmx1a+/Ki-67−/Aqp1+) during embryogenesis44, 45. The shape and size roof plate are similar between wild type and Mcre;NICD1 mice; however, tumour cells remain proliferative and undifferentiated (Ki-67+/Aqp1−) even after their incorporation into CP epithelium (Fig. 8a, Supplementary Fig. 8c). Together, these results indicate that CP tumours in these animals arise from roof plate progenitors and migrate into the CP where they continue to undergo Shh-driven proliferation throughout development (Fig. 8b, 8c).

View Article: PubMed Central - PubMed

ABSTRACT

Aberrant Notch signaling has been linked to many cancers including choroid plexus (CP) tumours, a group of rare and predominantly pediatric brain neoplasms. We developed animal models of CP tumours by inducing sustained expression of Notch1 that recapitulate properties of human CP tumours with aberrant NOTCH signaling. Whole transcriptome and functional analyses showed that tumour cell proliferation is associated with Sonic Hedgehog (Shh) in the tumour microenvironment. Unlike CP epithelial cells, which have multiple primary cilia, tumour cells possess a solitary primary cilium as a result of Notch-mediated suppression of multiciliate diffferentiation. A Shh-driven signaling cascade in the primary cilium occurs in tumour cells but not in epithelial cells. Lineage studies show that CP tumours arise from mono-ciliated progenitors in the roof plate characterized by elevated Notch signaling. Abnormal SHH signaling and distinct ciliogenesis are detected in human CP tumours, suggesting SHH pathway and cilia differentiation as potential therapeutic avenues.

No MeSH data available.


Related in: MedlinePlus