Stem cell senescence drives age-attenuated induction of pituitary tumours in mouse models of paediatric craniopharyngioma

González-Meljem, José Mario; Haston, Scott; Carreno, Gabriela; Apps, John; Pozzi, Sara; Stache, Christina; Kaushal, Grace; Virasami, Alex; Panousopoulos, Leonidas; Mousavy-Gharavy, Seyedeh N.; Guerrero, Ana Tereza Gomes; Rashid, Mamunur; Jani, Nital; Goding, Colin R.; Jacques, Thomas S.; Adams, David J.; Gil, Jesús; Andoniadou, Cynthia L.

doi:10.1038/s41467-017-01992-5

Cited by 94 publications

(107 citation statements)

References 69 publications

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“…OIS is primarily considered as a tumour suppressive mechanism (Collado et al, 2005), but senescent cells present in the tumour microenvironment can also drive tumour progression (Gonzalez‐Meljem, Apps, Fraser, & Martinez‐Barbera, 2018). We have previously demonstrated in mouse models of adamantinomatous craniopharyngioma (ACP), a pituitary paediatric tumour, that clusters of cells that accumulate nucleo‐cytoplasmic β‐catenin are senescent and drive tumour progression in a paracrine manner (Gonzalez‐Meljem et al, 2017). Indeed, β‐catenin‐positive cells are ki67 negative, express p21 Cip1 and high levels of the lysosomal β‐galactosidase GLB1 (Figure a) (Gonzalez‐Meljem et al, 2017).…”

Section: Resultsmentioning

confidence: 99%

Galactose‐modified duocarmycin prodrugs as senolytics

et al. 2020

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Senescence is a stable growth arrest that impairs the replication of damaged, old or preneoplastic cells, therefore contributing to tissue homeostasis. Senescent cells accumulate during ageing and are associated with cancer, fibrosis and many age‐related pathologies. Recent evidence suggests that the selective elimination of senescent cells can be effective on the treatment of many of these senescence‐associated diseases. A universal characteristic of senescent cells is that they display elevated activity of the lysosomal β‐galactosidase, and this has been exploited as a marker for senescence (senescence‐associated β‐galactosidase activity). Consequently, we hypothesized that galactose‐modified cytotoxic prodrugs will be preferentially processed by senescent cells, resulting in their selective killing. Here, we show that different galactose‐modified duocarmycin (GMD) derivatives preferentially kill senescent cells. GMD prodrugs induce selective apoptosis of senescent cells in a lysosomal β‐galactosidase (GLB1)‐dependent manner. GMD prodrugs can eliminate a broad range of senescent cells in culture, and treatment with a GMD prodrug enhances the elimination of bystander senescent cells that accumulate upon whole‐body irradiation treatment of mice. Moreover, taking advantage of a mouse model of adamantinomatous craniopharyngioma (ACP), we show that treatment with a GMD prodrug selectively reduced the number of β‐catenin‐positive preneoplastic senescent cells. In summary, the above results make a case for testing the potential of galactose‐modified duocarmycin prodrugs to treat senescence‐related pathologies.

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Section: Resultsmentioning

confidence: 99%

Galactose‐modified duocarmycin prodrugs as senolytics

et al. 2020

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“…OIS is primarily considered as a tumour suppressive mechanism (Collado et al 2005) but senescent cells present in the tumour microenvironment can also drive tumour progression (Gonzalez-Meljem et al 2018). We have previously demonstrated in mouse models of adamantinomatous craniopharyngioma (ACP), a pituitary paediatric tumour, that clusters of cells that accumulate nucleo-cytoplasmic b-catenin are senescent and drive tumour progression in a paracrine manner (Gonzalez-Meljem et al 2017). To understand if GMD prodrugs could eliminate these pro-tumourigenic senescent clusters, we used the Hesx1 Cre/+ ;Ctnnb1 lox(ex3)/+ ACP mouse model.…”

Section: Prodrug a Eliminates Bystander Senescent Cells In Vivomentioning

confidence: 99%

“…For in vivo treatment, ABT-263 was prepared in ethanol:polyethylene glycol 400:Phosal 50 PG at 10:30:60 as previously described . Mice were gavaged with vehicle Immunofluorescence staining was performed as previously described (Gonzalez-Meljem et al 2017). The proportion of β-catenin-accumulating and p21-positive cells was calculated as an index out of the total DAPI-stained nuclei.…”

Section: Determining Senolytic Activity For Oncogene-induced Senescementioning

confidence: 99%

Galactose-modified duocarmycin prodrugs as senolytics

Guerrero

Guiho

Herranz

et al. 2019

Preprint

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Senescence is a stable growth arrest that impairs the replication of damaged, old or preneoplastic cells, therefore contributing to tissue homeostasis. Senescent cells accumulate during ageing and are associated with diseases, such as cancer, fibrosis and many age-related pathologies. Recent evidence suggests that the selective elimination of senescent cells can be effective on the treatment of many of these senescence-associated diseases. A universal characteristic of senescent cells is that they display elevated activity of the lysosomal b-galactosidase this has been exploited as a marker for senescence (senescence-associated b-galactosidase activity). Consequently, we hypothesised that galactose-modified cytotoxic prodrugs will be preferentially processed by senescent cells, resulting in their selective killing. Here, we show that different galactose-modified duocarmycin (GMD) derivatives preferentially kill senescent cells. GMD prodrugs induce selective apoptosis of senescent cells in a lysosomal b-galactosidase (GLB1)-dependent manner. GMD prodrugs can eliminate a broad range of senescent cells in culture, and treatment with a GMD prodrug enhances the elimination of bystander senescent cells that accumulate upon whole body irradiation or doxorubicin treatment of mice. Moreover, taking advantage of a mouse model of human adamantinomatous craniopharyngioma (ACP), we show that treatment with a GMD pro-drug result selectively reduced the number of b-cateninpositive preneoplastic senescent cells, what could have therapeutic implications. In summary, the above results show that galactose-modified duocarmycin prodrugs behave as senolytics, suggesting that they could be used to treat a wide range of senescence-related pathologies. Guerrero et al. 4

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“…Recent work reveals that the tumours form when mutant cells enter senescence and robustly activate the senescence- associated secretory pathway (SASP) [45]. The SASP response leads to secretion of a range of mitogens, chemokines, and cytokines from the mutated stem cells.…”

Section: Signalling Pathways In the Control Of Proliferative Functionmentioning

confidence: 99%

Basic Research Advances on Pituitary Stem Cell Function and Regulation

Russell¹,

Lodge²,

Andoniadou³

2018

Neuroendocrinology

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As a central regulator of major physiological processes, the pituitary gland is a highly dynamic organ, capable of responding to hormonal demand and hypothalamic influence, through adapting secretion as well as remodelling cell numbers among its seven populations of differentiated cells. Stem cells of the pituitary have been shown to actively generate new cells during postnatal development but remain mostly quiescent during adulthood, where they persist as a long-lived population. Despite a significant body of research characterising attributes of anterior pituitary stem cells, the regulation of this population is poorly understood. A better grasp on the signalling mechanisms influencing stem proliferation and cell fate decisions can impact on our future treatments of pituitary gland disorders such as organ failure and pituitary tumours, which can disrupt endocrine homeostasis with life-long consequences. This minireview addresses the current methodologies aiming to understand better the attributes of pituitary stem cells and the normal regulation of this population in the organ, and discusses putative future avenues to manipulate pituitary stem cells during disease states or regenerative medicine approaches.

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Stem cell senescence drives age-attenuated induction of pituitary tumours in mouse models of paediatric craniopharyngioma

Cited by 94 publications

References 69 publications

Galactose‐modified duocarmycin prodrugs as senolytics

Galactose‐modified duocarmycin prodrugs as senolytics

Galactose-modified duocarmycin prodrugs as senolytics

Basic Research Advances on Pituitary Stem Cell Function and Regulation

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