IER2-induced senescence drives melanoma invasion through osteopontin

Kyjacová, Lenka; Saup, Rafael; Rönsch, Kerstin; Wallbaum, Sabine; Dukowic-Schulze, Stefanie; Foss, Amelia; Scherer, Sandra D.; Rothley, Melanie; Neeb, Antje; Grau, Nicole; Thiele, Wilko; Thaler, Sonja; Cremers, Natascha; Sticht, Carsten; Gretz, Norbert; Garvalov, Boyan K.; Utikal, Jochen; Sleeman, Jonathan P.

doi:10.1038/s41388-021-02027-6

Cited by 22 publications

(18 citation statements)

References 101 publications

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“…Senescent tumor cells can contribute to metastatic dissemination in a number of ways, including the fostering of tumor cell invasion [ 29 ] and metastatic progression [ 30 ] and protecting against anti-tumor immune responses [ 6 ]. Mechanistically, the SASP produced by senescent cells in cancer tissue plays a major role in increasing the malignant potency of cancer cells [ 31 ].…”

Section: Discussionmentioning

confidence: 99%

“…Paradoxically, senescent cells within tumors can promote the growth and progression of non-senescent cancer cells. Many SASP components are pro-tumorigenic growth factors, matrix metalloproteinases (MMPs), and cytokines that are known to stimulate the aggressive behavior of cancer cells in vitro [ 26 , 27 , 28 , 29 , 30 ]. Through their SASP, senescent cells can promote the progression of both precancerous cells and established cancer cells in mouse xenograft models [ 26 , 31 ].…”

Section: Introductionmentioning

confidence: 99%

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Detection of Cellular Senescence Reveals the Existence of Senescent Tumor Cells within Invasive Breast Carcinomas and Related Metastases

Cotarelo

Schad

Schmidt

et al. 2023

Cancers

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Oncogene-induced senescence is thought to constitute a barrier to carcinogenesis by arresting cells at risk of malignant transformation. However, numerous findings suggest that senescent cells may conversely promote tumor growth and metastatic progression, for example, through the senescence-associated secretory phenotype (SASP) they produce. Here, we investigated the degree to which senescent tumor cells exist within untreated human primary breast carcinomas and whether the presence of senescent cancer cells in primary tumors is recapitulated in their matched lymph node metastases. For the detection of senescence, we used SA-β-galactosidase (SA-β-gal) staining and other senescence markers such as Ki67, p21, p53, and p16. In patients with invasive luminal A and B breast carcinomas, we found broad similarities in the appearance of cancer cells between primary tumors and their corresponding metastases. Analysis of lymph nodes from patients with other breast cancer subtypes also revealed senescent tumor cells within metastatic lesions. Collectively, our findings show that senescent tumor cells exist within primary breast carcinomas and metastatic lesions. These results suggest a potential role for senescent breast tumor cells during metastatic progression and raise the question as to whether the targeting of senescent tumor cells with anti-senescent drugs might represent a novel avenue for improved treatment of breast and other cancers.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Detection of Cellular Senescence Reveals the Existence of Senescent Tumor Cells within Invasive Breast Carcinomas and Related Metastases

Cotarelo

Schad

Schmidt

et al. 2023

Cancers

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“…The induction of G 0 ‐positive cells in SK‐MEL‐2 cells was associated with dysregulation of the ‘Cell cycle’, ‘VEGFA‐VEGFR2’ and ‘p53 transcriptional gene network’ signaling pathways, where the number of genes upregulated was increased following dacarbazine treatment. However, ‘VEGFA‐VEGFR2’ signaling could be referred to as senescence and SASP, 50 even though the SASP expression pattern genes Interleukin 6 ( IL‐ 6), C‐X‐C Motif Chemokine Ligand 8 ( CXCL8 ), Interleukin 1 Alpha ( IL‐1 α), Interleukin 1 Beta ( IL‐1β ), Secreted Phosphoprotein 1 ( SPP1 ), Matrix Metallopeptidase 3 ( MMP3 ), Matrix Metallopeptidase 2 ( MMP2 ), C‐C Motif Chemokine Ligand 2 ( CCL2 ), C‐X‐C Motif Chemokine Ligand 1 ( CXCL1 ), C‐X‐C Motif Chemokine Ligand 2 ( CXCL2 ) and C‐X‐C Motif Chemokine Ligand 5 ( CXCL5 ) 51 , 52 were not altered in SK‐MEL‐2 or BRO cells upon dacarbazine treatment. However, VEGF produced by tumor cells was shown to stimulate focal adhesion kinase‐mediated vascular permeability in lungs, thus favoring tumor cells homing in lungs, 53 which is in the line with the present observation of increased G 0 ‐positive cells percentage; however, further studies are necessary to demonstrate a potential association between these two events.…”

Section: Discussionmentioning

confidence: 99%

Focal adhesion alterations in G0‐positive melanoma cells

et al. 2022

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Background Melanoma is a highly heterogeneous malignant tumor that exhibits various forms of drug resistance. Recently, reversal transition of cancer cells to the G 0 phase of the cell cycle under the influence of therapeutic drugs has been identified as an event associated with tumor dissemination. In the present study, we investigated the ability of chemotherapeutic agent dacarbazine to induce a transition of melanoma cells to the G 0 phase as a mechanism of chemoresistance. Methods We used the flow cytometry to analyze cell distribution within cell cycle phases after dacarbazine treatment as well as to identifyG 0 ‐positive cells population. Transcriptome profiling was provided to determine genes associated with dacarbazine resistance . We evaluated the activity of β‐galactosidase in cells treated with dacarbazine by substrate hydrolysis. Cell adhesion strength was measured by centrifugal assay application with subsequent staining of adhesive cells with Ki‐67 monoclonal antibodies. Ability of melanoma cells to metabolize dacarbazine was determined by expressional analysis of CYP1A1, CYP1A2, CYP2E1 followed by CYP1A1 protein level evaluation by the ELISA method. Results The present study determined that dacarbazine treatment of melanoma cells could induce an increase in the percentage of cells in G 0 phase without alterations of β‐galactosidase positive cells which corresponded to the fraction of the senescent cells. Transcriptomic profiling of cells under dacarbazine induction of G 0 ‐positive cells percentage revealed that ‘VEGFA‐VEGFR2 signaling pathway’ and ‘Cell cycle’ signaling were mostly enriched by dysregulated genes. ‘Focal adhesion’ signaling was also found to be triggered by dacarbazine. In melanoma cells treated with dacarbazine, an increase in G 0 ‐positive cells among adherent cells was found. Conclusions Dacarbazine induces the alteration in a percentage of melanoma cells residing in G 0 phase of a cell cycle. The altered adhesive phenotype of cancer cells under transition in the G 0 phase may refer to a specific intercellular communication pattern of quiescent/senescent cancer cells.

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“…The immediate early response gene 2 (IER2) has been associated with the progression of several types of cancer. The sustained expression of IER2 induced senescence in a subset of melanoma cells in a p53/mitogen-activated protein kinase (MAPK)/AKT-dependent manner [ 57 ]. The senescent cells produced extracellular factors, such as osteopontin (OPN).…”

Section: Oncogene-induced Senescencementioning

confidence: 99%

“…The senescent cells produced extracellular factors, such as osteopontin (OPN). OPN secreted by IER2-expressing senescent cells stimulated the migration and invasion of non-senescent melanoma cells [ 57 ]. The downregulation of OPN enhanced sensitivity to 5-fluorouracil (5-FU) in HepG2 cells [ 58 ].…”

Section: Oncogene-induced Senescencementioning

confidence: 99%

The Potential of Senescence as a Target for Developing Anticancer Therapy

Shim

Jeoung

2023

IJMS

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Senescence occurs in response to various stimuli. Senescence has attracted attention because of its potential use in anticancer therapy as it plays a tumor-suppressive role. It also promotes tumorigeneses and therapeutic resistance. Since senescence can induce therapeutic resistance, targeting senescence may help to overcome therapeutic resistance. This review provides the mechanisms of senescence induction and the roles of the senescence-associated secretory phenotype (SASP) in various life processes, including therapeutic resistance and tumorigenesis. The SASP exerts pro-tumorigenic or antitumorigenic effects in a context-dependent manner. This review also discusses the roles of autophagy, histone deacetylases (HDACs), and microRNAs in senescence. Many reports have suggested that targeting HDACs or miRNAs could induce senescence, which, in turn, could enhance the effects of current anticancer drugs. This review presents the view that senescence induction is a powerful method of inhibiting cancer cell proliferation.

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IER2-induced senescence drives melanoma invasion through osteopontin

Cited by 22 publications

References 101 publications

Detection of Cellular Senescence Reveals the Existence of Senescent Tumor Cells within Invasive Breast Carcinomas and Related Metastases

Detection of Cellular Senescence Reveals the Existence of Senescent Tumor Cells within Invasive Breast Carcinomas and Related Metastases

Focal adhesion alterations in G0‐positive melanoma cells

The Potential of Senescence as a Target for Developing Anticancer Therapy

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