PTBP1-Mediated Alternative Splicing Regulates the Inflammatory Secretome and the Pro-tumorigenic Effects of Senescent Cells

Georgilis, Athena; Klotz, Sabrina; Hanley, Christopher J.; Herranz, Nicolás; Weirich, Benedikt; Morancho, Beatriz; Leote, Ana Carolina; D’Artista, Luana; Gallage, Suchira; Seehawer, Marco; Carroll, Thomas; Dharmalingam, Gopuraja; Wee, Keng Boon; Mellone, Massimiliano; Pombo, Joaquim; Heide, Danijela; Guccione, Ernesto; Arribas, Joaquı́n; Barbosa‐Morais, Nuno L.; Heikenwälder, Mathias; Thomas, Gareth J.; Zender, Lars; Gil, Jesús

doi:10.1016/j.ccell.2018.06.007

Cited by 189 publications

(178 citation statements)

References 54 publications

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“…Alternative approaches to target senescent cells have been explored. Georgilis and colleagues have split the unwanted protumorigenic effects from the beneficial proliferation arrest of senescent cells by specifically targeting the secretory pathway of SASP . Notably, the suppression of SASP is associated with poor immune cell infiltration, apparently with no augmented risk of tumorigenesis, but further investigations are needed.…”

Section: Discussionmentioning

confidence: 99%

“…Georgilis and colleagues have split the unwanted protumorigenic effects from the beneficial proliferation arrest of senescent cells by specifically targeting the secretory pathway of SASP. 53 Notably, the suppression of SASP is associated with poor immune cell infiltration, apparently with no augmented risk of tumorigenesis, but further investigations are needed. Kim and colleagues, instead, identified dipeptidyl peptidase 4 (DPP4) or CD26 by MS analysis as a surface protein specifically expressed by senescent fibroblasts.…”

Section: Discussionmentioning

confidence: 99%

“…An interesting strategy to erase the side effects of SASP has been exploited by Georgilis and colleagues. Through a large‐scale RNA interference library screen in RAS‐driven senescent human diploid fibroblasts, the authors have identified and targeted transcripts associated to the SASP pathway without interfering with the senescent cell growth arrest . All together, these studies focus on the importance of SASP‐associated cytokines and chemokines to drive the immune surveillance of senescent cancer cells, but recent evidence has shown that also SASP‐derived extracellular vesicles (EVs) can significantly contribute to this effect.…”

Section: Nk Cell‐mediated Clearance Of Senescent Tumor Cellsmentioning

confidence: 99%

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Senescent cells: Living or dying is a matter of NK cells

Antonangeli

Zingoni

Soriani

et al. 2019

Journal of Leukocyte Biology

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NK cells are lymphocytes of the innate immune system, which are able to deal promptly with stressed cells. Cellular senescence is a cell stress response leading to cell cycle arrest that plays a key role during tissue homeostasis and carcinogenesis. In this review, how senescent cells trigger an immune response and, in particular, the ability of NK cells to recognize and clear senescent cells are discussed. Special attention is given to the NK cell‐mediated clearance of senescent tumor cells. NK cells kill senescent cells through a mechanism involving perforin‐ and granzyme‐containing granule exocytosis, and produce IFN‐γ following senescent cell interaction, leading to hypothesize that NK cell‐mediated immune clearance of senescent cells not only relies on direct killing but also on cytokine production, that in turn can promote macrophage activation. These aspects, as well as the ability of the senescence‐associated secretory phenotype and senescent cell‐produced extracellular vesicles to modulate NK cell effector functions, are described.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Nk Cell‐mediated Clearance Of Senescent Tumor Cellsmentioning

confidence: 99%

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Senescent cells: Living or dying is a matter of NK cells

Antonangeli

Zingoni

Soriani

et al. 2019

Journal of Leukocyte Biology

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“…Other potential SASP‐associated targets have been reported, including the alternative splicing modulator polypyrimidine tract binding protein 1 (PTBP1), which regulates a pro‐inflammatory secretome. Inhibition of PTBP1 attenuated SASP‐induced tumour promotion in a mouse model of hepatocellular carcinoma (Georgilis et al , ). PTBP1 may therefore be a potential therapeutic target.…”

Section: Introductionmentioning

confidence: 99%

Targeting senescent cells in translational medicine

et al. 2019

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Organismal ageing is a complex process driving progressive impairment of functionality and regenerative potential of tissues. Cellular senescence is a state of stable cell cycle arrest occurring in response to damage and stress and is considered a hallmark of ageing. Senescent cells accumulate in multiple organs during ageing, contribute to tissue dysfunction and give rise to pathological manifestations. Senescence is therefore a defining feature of a variety of human age‐related disorders, including cancer, and targeted elimination of these cells has recently emerged as a promising therapeutic approach to ameliorate tissue damage and promote repair and regeneration. In addition, in vivo identification of senescent cells has significant potential for early diagnosis of multiple pathologies. Here, we review existing senolytics, small molecules and drug delivery tools used in preclinical therapeutic strategies involving cellular senescence, as well as probes to trace senescent cells. We also review the clinical research landscape in senescence and discuss how identifying and targeting cellular senescence might positively affect pathological and ageing processes.

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“…This oncogenic activity of the SASP is normally restrained by Rb‐Suv39 signaling or p53 . The detrimental effects of senescent cells are mainly related to the inflammatory secretome they produced since targeting the SASP prevents these deleterious effects …”

Section: The Senescence‐associated Secretory Phenotypementioning

confidence: 99%

Proteomics Approaches to Define Senescence Heterogeneity and Chemotherapy Response

et al. 2019

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In primary cells, senescence induces a permanent proliferative arrest to prevent the propagation of malignant cells. However, the outcome of senescence is more complex in advanced cancer cells where senescent states are heterogeneous. Here, this heterogeneity is discussed and it is proposed that proteomic analysis should be used to identify specific signatures of cancer cells that use this pathway as an adaptive mechanism. Since senescent cells produce an inflammatory secretome, MRM approaches and quantification with internal standards might be particularly suited to follow the expression of the corresponding markers in body fluids. Used in combination with imaging medical technics, a better characterization of senescence heterogeneity should help to monitor the response to chemotherapy treatment.

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PTBP1-Mediated Alternative Splicing Regulates the Inflammatory Secretome and the Pro-tumorigenic Effects of Senescent Cells

Cited by 189 publications

References 54 publications

Senescent cells: Living or dying is a matter of NK cells

Senescent cells: Living or dying is a matter of NK cells

Targeting senescent cells in translational medicine

Proteomics Approaches to Define Senescence Heterogeneity and Chemotherapy Response

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