The Cyclin-Like Protein <scp>SPY1</scp> Overrides Reprogramming Induced Senescence Through <scp>EZH2</scp> Mediated <scp>H3K27me3</scp>

Lubanska, Dorota; Qemo, Ingrid; Byrne, Megan; Matthews, Kaitlyn N.; Fifield, Bre‐Anne; Brown, Jillian R.; Silva, Elizabeth Fidalgo da; Porter, Lisa A.

doi:10.1002/stem.3453

Cited by 5 publications

(3 citation statements)

References 79 publications

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“…As a result of this mechanism Spy1 has been isolated from numerous screens and has been described for the ability to override cell cycle arrest mechanisms including DNA damage and cellular senescence 19,20 . Data from our lab show that Spy1 can enhance pluripotent reprograming by epigenetic downregulation of CDK inhibitors and is essential for overcoming reprogramming-induced senescence 21 . Work from the Nebreda lab has recently demonstrated that Spy1 is required for activation of NSCs out of quiescent state via activation of CDK2 22 .…”

Section: Introductionmentioning

confidence: 98%

Atypical Cell Cycle Regulation over Neural Stem Cell Expansion

Qemo,

Lubanska,

Stringer

et al. 2023

Preprint

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SUMMARYPopulations of quiescent adult neural stem cells (NSCs) that reside in the mammalian brain aid in neurogenesis throughout life and can be identified by molecular markers including Nestin, a type VI intermediate filament protein. Cell cycle regulation plays an important role in determining the fate of NSCs in the adult brain and maintaining a crucial balance between self-renewal and differentiation. Data from our group and others support that the atypical cyclin-like protein Spy1 (also called RingoA; geneSPDYA) plays a critical role in activating NSCs from a quiescent state. Elevated levels of Spy1 are found in aggressive human brain cancers, including glioblastoma. Using a conditional mouse model, we demonstrate that driving the expression of Spy1 in the Nestin-enriched NSC population of the brain directs the cells toward symmetric cellular division, increases stemness characteristics, decreases differentiation, and increases susceptibility to oncogenic transformation & drug resistance. This study contributes to better understanding of intricate cell cycle mechanisms which lead to deviation from the homeostatic state, promoting aberrant changes in adult NSCs.

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Section: Introductionmentioning

confidence: 98%

Atypical Cell Cycle Regulation over Neural Stem Cell Expansion

Qemo,

Lubanska,

Stringer

et al. 2023

Preprint

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“…Several publications have implicated Spy1 in expanding normal and cancer stem cell populations in the brain [28, 32, 33]. Recently, Spy1 has been shown to activate the epigenetic regulator EZH2 and support reprogramming to a pluripotent state [34]. Whether Spy1-mediated effects on stemness have any implications in the mammary gland was not previously addressed.…”

Section: Introductionmentioning

confidence: 99%

Atypical Cell Cycle Regulation Promotes Mammary Stem Cell Expansion and Therapeutic Resistance

Fifield,

Vusich,

Haberfellner

et al. 2024

Preprint

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Background: The cell cycle of mammary stem cells must be tightly regulated to ensure normal homeostasis of the mammary gland to prevent abnormal proliferation and susceptibility to tumorigenesis. The atypical cell cycle regulator, Spy1 can override cell cycle checkpoints, including those activated by the tumour suppressor p53 which mediates mammary stem cell homeostasis. Spy1 has also been shown to promote expansion of select stem cell populations in other developmental systems. Spy1 protein is elevated during proliferative stages of mammary gland development, is found at higher levels in human breast cancers, and promotes susceptibility to mammary tumourigenesis when combined with loss of p53. We hypothesized that Spy1 cooperates with loss of p53 to increase susceptibility to tumour initiation due to changes in susceptible mammary stem cell populations during development and drives the formation of more aggressive stem like tumours. Methods: Using a transgenic mouse model driving expression of Spy1 within the mammary gland, mammary development and stemness were assessed. These mice were intercrossed with p53 null mice to study the tumourigenic properties of Spy1 driven p53 null tumours, as well as global changes in signaling via RNA sequencing analysis. Results: We show that elevated levels of Spy1 leads to expansion of mammary stem cells, even in the presence of p53, and an increase in mammary tumour formation. Spy1-driven tumours have an increased cancer stem cell population, decreased checkpoint signaling, and demonstrate an increase in therapy resistance. Loss of Spy1 decreases tumor onset and reduces the cancer stem cell population. Conclusions: This data demonstrates the potential of Spy1 to expand mammary stem cell populations and contribute to the initiation and progression of aggressive, drug resistant breast cancers with increased cancer stem cell populations.

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“…Several publications have implicated Spy1 in expanding normal and cancer stem cell populations in the brain [ 28 , 32 , 33 ]. Recently, Spy1 has been shown to activate the epigenetic regulator EZH2 and support reprogramming to a pluripotent state [ 34 ]. Whether Spy1-mediated effects on stemness have any implications in the mammary gland was not previously addressed.…”

Section: Introductionmentioning

confidence: 99%

Atypical cell cycle regulation promotes mammary stem cell expansion during mammary development and tumourigenesis

Fifield,

Vusich,

Haberfellner

et al. 2024

Breast Cancer Res

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Background The cell cycle of mammary stem cells must be tightly regulated to ensure normal homeostasis of the mammary gland to prevent abnormal proliferation and susceptibility to tumorigenesis. The atypical cell cycle regulator, Spy1 can override cell cycle checkpoints, including those activated by the tumour suppressor p53 which mediates mammary stem cell homeostasis. Spy1 has also been shown to promote expansion of select stem cell populations in other developmental systems. Spy1 protein is elevated during proliferative stages of mammary gland development, is found at higher levels in human breast cancers, and promotes susceptibility to mammary tumourigenesis when combined with loss of p53. We hypothesized that Spy1 cooperates with loss of p53 to increase susceptibility to tumour initiation due to changes in susceptible mammary stem cell populations during development and drives the formation of more aggressive stem like tumours. Methods Using a transgenic mouse model driving expression of Spy1 within the mammary gland, mammary development and stemness were assessed. These mice were intercrossed with p53 null mice to study the tumourigenic properties of Spy1 driven p53 null tumours, as well as global changes in signaling via RNA sequencing analysis. Results We show that elevated levels of Spy1 leads to expansion of mammary stem cells, even in the presence of p53, and an increase in mammary tumour formation. Spy1-driven tumours have an increased cancer stem cell population, decreased checkpoint signaling, and demonstrate an increase in therapy resistance. Loss of Spy1 decreases tumor onset and reduces the cancer stem cell population. Conclusions This data demonstrates the potential of Spy1 to expand mammary stem cell populations and contribute to the initiation and progression of aggressive, breast cancers with increased cancer stem cell populations.

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The Cyclin-Like Protein SPY1 Overrides Reprogramming Induced Senescence Through EZH2 Mediated H3K27me3

Cited by 5 publications

References 79 publications

Atypical Cell Cycle Regulation over Neural Stem Cell Expansion

Atypical Cell Cycle Regulation over Neural Stem Cell Expansion

Atypical Cell Cycle Regulation Promotes Mammary Stem Cell Expansion and Therapeutic Resistance

Atypical cell cycle regulation promotes mammary stem cell expansion during mammary development and tumourigenesis

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