Notch Inhibition: a Promising Strategy to Improve Radiosensitivity and Curability of Radiotherapy

Jayaprakash, K. Thippu; Michael, A.

doi:10.1016/j.clon.2020.06.015

Cited by 6 publications

(6 citation statements)

References 47 publications

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“…SLUG is involved in a wide variety of biological processes, such as tumor metastasis, epithelial-mesenchymal transition (EMT), stem cell biology, cellular differentiation, vascular remodeling, and DNA damage repair [ 61 ]. In addition, in the glioma context, both the Notch1 pathway [ 62 , 63 ] and SLUG gene expression have been found to be implicated in radio-resistance [ 64 , 65 ]. The link that we have established here between Notch1 activation and SLUG expression in GSC will serve as a basis to further understand how GBM cells resist radiotherapy and if SLUG is instrumental in this process.…”

Section: Discussionmentioning

confidence: 99%

SLUG and Truncated TAL1 Reduce Glioblastoma Stem Cell Growth Downstream of Notch1 and Define Distinct Vascular Subpopulations in Glioblastoma Multiforme

Guelfi

Orsetti

Deleuze

et al. 2021

Cancers

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Glioblastomas (GBM) are high-grade brain tumors, containing cells with distinct phenotypes and tumorigenic potentials, notably aggressive and treatment-resistant multipotent glioblastoma stem cells (GSC). The molecular mechanisms controlling GSC plasticity and growth have only partly been elucidated. Contact with endothelial cells and the Notch1 pathway control GSC proliferation and fate. We used three GSC cultures and glioma resections to examine the expression, regulation, and role of two transcription factors, SLUG (SNAI2) and TAL1 (SCL), involved in epithelial to mesenchymal transition (EMT), hematopoiesis, vascular identity, and treatment resistance in various cancers. In vitro, SLUG and a truncated isoform of TAL1 (TAL1-PP22) were strongly upregulated upon Notch1 activation in GSC, together with LMO2, a known cofactor of TAL1, which formed a complex with truncated TAL1. SLUG was also upregulated by TGF-β1 treatment and by co-culture with endothelial cells. In patient samples, the full-length isoform TAL1-PP42 was expressed in all glioma grades. In contrast, SLUG and truncated TAL1 were preferentially overexpressed in GBMs. SLUG and TAL1 are expressed in the tumor microenvironment by perivascular and endothelial cells, respectively, and to a minor extent, by a fraction of epidermal growth factor receptor (EGFR) -amplified GBM cells. Mechanistically, both SLUG and truncated TAL1 reduced GSC growth after their respective overexpression. Collectively, this study provides new evidence for the role of SLUG and TAL1 in regulating GSC plasticity and growth.

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Section: Discussionmentioning

confidence: 99%

SLUG and Truncated TAL1 Reduce Glioblastoma Stem Cell Growth Downstream of Notch1 and Define Distinct Vascular Subpopulations in Glioblastoma Multiforme

Guelfi

Orsetti

Deleuze

et al. 2021

Cancers

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“…Targeting the P53 signaling pathway could enhance radiosensitivity, which has been demonstrated in a variety of cancers [34][35][36]. Notch signaling mainly regulates the cell cycle, inhibits apoptosis by suppressing PTEN expression, and triggers tumor progression together with PI3K-AKT signaling [37]. Activation of the Notch pathway in NSCLC patients is closely bound up with a worse prognosis, and cancer cells with high Notch expression are more resistant to irradiation [38].…”

Section: Discussionmentioning

confidence: 99%

A Radioresponse-Related lncRNA Biomarker Signature for Risk Classification and Prognosis Prediction in Non-Small-Cell Lung Cancer

Song

Zhang

Sun

et al. 2021

Journal of Oncology

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Purpose. Radiotherapy resistance is now recognized as the major obstacle to the effective therapeutic management of non-small-cell lung cancer (NSCLC). As a single biomarker has limited effect in stratifying NSCLC patients, this research aimed to identify long non-coding RNAs (lncRNAs) correlated with radiotherapy response to ameliorate forecast of NSCLC prognosis. Methods. In a cohort of NSCLC patients with radiotherapy history (n = 96) from TCGA, genetic data of lncRNA expression profiling were performed. To identify radioresponse-related lncRNA sets which dysregulated significantly between radiosensitive (RS) and radioresistant (RR) groups, differential expression analysis was carried out. Cox relative regression was implemented to set up a radioresponse-related risk model. Moreover, we adopted survival analysis to measure the predictive potentiality of the prognosis model. Results. Four radioresponse-related lncRNAs (CASC19, LINC01977, LINC02471, and MAGI2-AS3) were screened to create a prognostic signature. Then, we described a lncRNA signature-based regulatory network and explored the correlation of the immune microenvironment and the signature. Additionally, in vitro assays uncovered inhibition of LINC01977 weakened radioresistance of NSCLC cells. Conclusion. We provided a novel radioresponse-related lncRNAs signature with excellent clinical potency for an effective prognostic forecast of patients.

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“…Thus, inhibiting NOTCH could be the efficient strategy to radiosensitize CSCs, bypassing their ability to detoxify from ROS. To date, clinical trials testing NOTCH inhibitors have not included RMS tumors as well as the combination with RT, but their use as radiosensitizers has been recently encouraged ( 239 ). More recently, boron neutron capture therapy and carbon-ion particle therapy have been proposed in combination with PARPi as effective strategies for the treatment of radioresistant clear cell sarcoma and osteosarcoma, opening up the possibility of successfully treating patients with RMS by combined treatment with RT and PARPi.…”

Section: Mechanisms Of Radioresistance In Rmsmentioning

confidence: 99%

Radioresistance in rhabdomyosarcomas: Much more than a question of dose

Camero

Cassandri²,

Pomella³

et al. 2022

Front. Oncol.

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Management of rhabdomyosarcoma (RMS), the most common soft tissue sarcoma in children, frequently accounting the genitourinary tract is complex and requires a multimodal therapy. In particular, as a consequence of the advancement in dose conformity technology, radiation therapy (RT) has now become the standard therapeutic option for patients with RMS. In the clinical practice, dose and timing of RT are adjusted on the basis of patients’ risk stratification to reduce late toxicity and side effects on normal tissues. However, despite the substantial improvement in cure rates, local failure and recurrence frequently occur. In this review, we summarize the general principles of the treatment of RMS, focusing on RT, and the main molecular pathways and specific proteins involved into radioresistance in RMS tumors. Specifically, we focused on DNA damage/repair, reactive oxygen species, cancer stem cells, and epigenetic modifications that have been reported in the context of RMS neoplasia in both in vitro and in vivo studies. The precise elucidation of the radioresistance-related molecular mechanisms is of pivotal importance to set up new more effective and tolerable combined therapeutic approaches that can radiosensitize cancer cells to finally ameliorate the overall survival of patients with RMS, especially for the most aggressive subtypes.

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Notch Inhibition: a Promising Strategy to Improve Radiosensitivity and Curability of Radiotherapy

Cited by 6 publications

References 47 publications

SLUG and Truncated TAL1 Reduce Glioblastoma Stem Cell Growth Downstream of Notch1 and Define Distinct Vascular Subpopulations in Glioblastoma Multiforme

SLUG and Truncated TAL1 Reduce Glioblastoma Stem Cell Growth Downstream of Notch1 and Define Distinct Vascular Subpopulations in Glioblastoma Multiforme

A Radioresponse-Related lncRNA Biomarker Signature for Risk Classification and Prognosis Prediction in Non-Small-Cell Lung Cancer

Radioresistance in rhabdomyosarcomas: Much more than a question of dose

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