Targeting Notch in oncology: the path forward

Majumder, Samarpan; Crabtree, Judy S.; Golde, Todd E.; Minter, Lisa M.; Osborne, Barbara A.; Miele, Lucio

doi:10.1038/s41573-020-00091-3

Cited by 190 publications

(202 citation statements)

References 251 publications

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“…Notch signaling plays complex roles in regulating cellular behaviors during cancer progression, and each Notch receptor has its specific pattern ( Majumder et al, 2021 ). A major role of Notch3 is maintaining the stemness of cancer stem cells (CSCs).…”

Section: Introductionmentioning

confidence: 99%

The Role of Notch3 Signaling in Cancer Stemness and Chemoresistance: Molecular Mechanisms and Targeting Strategies

Xiu

Wang

et al. 2021

Front. Mol. Biosci.

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Aberrant Notch signaling profoundly affects cancer progression. Especially the Notch3 receptor was found to be dysregulated in cancer, where its expression is correlated with worse clinicopathological features and poor prognosis. The activation of Notch3 signaling is closely related to the activation of cancer stem cells (CSCs), a small subpopulation in cancer that is responsible for cancer progression. In addition, Notch3 signaling also contributes to tumor chemoresistance against several drugs, including doxorubicin, platinum, taxane, epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitors (TKIs) and gemcitabine, through complex mechanisms. In this review, we mainly focus on discussing the molecular mechanisms by which Notch3 modulates cancer stemness and chemoresistance, as well as other cancer behaviors including metastasis and angiogenesis. What’s more, we propose potential treatment strategies to block Notch3 signaling, such as non-coding RNAs, antibodies and antibody-drug conjugates, providing a comprehensive reference for research on precise targeted cancer therapy.

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Section: Introductionmentioning

confidence: 99%

The Role of Notch3 Signaling in Cancer Stemness and Chemoresistance: Molecular Mechanisms and Targeting Strategies

Xiu

Wang

et al. 2021

Front. Mol. Biosci.

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“… 33 Although the direct role of KDELC1 in cancer has not been extensively studied, it has been shown to play an important role in the glycosylation of the heterodimeric Notch receptor, and the letter is significantly decisive in the initiation of Notch signaling that has great relevance to multiple aspects of cancer biology, including angiogenesis, tumor immunity and the maintenance of cancer stem-like cells. 34 Additionally, as a novel glycosyltransferase, its abnormal dysregulation may be associated with the development of cancer. 35 We thus speculate that it can potentially serve as a novel biomarker for ccRCC progression.…”

Section: Discussionmentioning

confidence: 99%

“…relevance to multiple aspects of cancer biology, including angiogenesis, tumor immunity and the maintenance of cancer stem-like cells. 34 Additionally, as a novel glycosyltransferase, its abnormal dysregulation may be associated with the development of cancer. 35 We thus speculate that it can potentially serve as a novel biomarker A-D) Results from GSE15641, GSE36895, GSE53757 and GSE66272 indicated that KDELC1 was significantly higher in ccRCC tissues than in normal renal tissues; (E-H) results from GSE15641, GSE36895, GSE53757 and GSE66272 indicated that TRMT1 was significantly higher in ccRCC tissues than in normal renal tissues; (I and J) KDELC1 and TRMT1 protein were highly expressed in ccRCC samples (UALCAN database); (K) representative immunohistochemical staining showed that tumor tissue had much higher expression of KDELC1 than normal renal tissue (The Human Protein Atlas database); (L) no immunohistochemical staining difference was found between tumor and normal tissues for TRMT1 (The Human Protein Atlas database).…”

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confidence: 99%

KDELC1 and TRMT1 Serve as Prognosis-Related SARS-CoV-2 Proteins Binding Human mRNAs and Promising Biomarkers in Clear Cell Renal Cell Carcinoma

Li¹,

Yao²,

Long³

et al. 2021

IJGM

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Background SARS-CoV-2 proteins binding human mRNAs (SPBRs) have been proven to regulate a variety of tumor-related functions in different types of cancer. However, their biological roles and potential mechanisms in clear cell renal cell carcinoma (ccRCC) are still elusive. Herein, we investigate the expression and prognostic value of SPBRs in ccRCC through bioinformatics methods. Methods Data downloaded from the Cancer Genome Atlas (TCGA) database was used to screen differentially expressed SPBRs (DE-SPBRs) between ccRCC samples and noncancerous samples. Metascape was utilized to perform function and pathway enrichment analyses of these DE-SPBRs. Kaplan–Meier method of overall survival (OS) was used to assess the prognostic value of DE-SPBRs in ccRCC patients. Univariate and multivariate Cox regression analyses were applied to identify candidate SPBRs, which were independently associated with overall survival of ccRCC patients. Subsequently, several internationally renowned databases were employed to conduct a comprehensive analysis of candidate SPBRs to further investigate their roles and mechanisms in ccRCC. Results A total of 33 DE-SPBRs, including 18 upregulated SPBRs and 17 downregulated SPBRs, were screened between ccRCC samples and noncancerous samples. Among them, two candidate SPBRs, KDELC1 and TRMT1, were identified. Additionally, we observed that upregulated KDELC1/TRMT1 expression in ccRCC at both gene and protein levels was significantly associated with clinicopathological features. Furthermore, we found that KDELC1/TRMT1 genetic mutation has an unfavorable influence on prognosis of patients with ccRCC. Functional enrichment analysis revealed that KDELC1/TRMT1 was closely enriched in several vital biological processes and pathways. Finally, we noticed that KDELC1/TRMT1 was remarkably associated with immune infiltrates. Conclusion In summary, we screened DE-SPBRs of ccRCC, which were enriched mainly in various biological and signaling pathways with tumor progression. Furthermore, we identified two candidate DE-SPBRs (KDELC1 and TRMT1), which could serve as promising biomarkers and therapeutic targets of patients with ccRCC.

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“…Further, Notch signaling supports survival of cancer cells through altered Notch expression. Understanding the role of Notch ligands in disease where Notch ligand-receptor interaction drives aberrant Notch activation may lead to important therapeutic targets [128].…”

Section: Lateral Induction Of Notch Signaling and Interaction With The Micro-environmentmentioning

confidence: 99%

To Be, or Notch to Be: Mediating Cell Fate from Embryogenesis to Lymphopoiesis

Quail

Cruickshank

et al. 2021

Biomolecules

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Notch signaling forms an evolutionarily conserved juxtacrine pathway crucial for cellular development. Initially identified in Drosophila wing morphogenesis, Notch signaling has since been demonstrated to play pivotal roles in governing mammalian cellular development in a large variety of cell types. Indeed, abolishing Notch constituents in mouse models result in embryonic lethality, demonstrating that Notch signaling is critical for development and differentiation. In this review, we focus on the crucial role of Notch signaling in governing embryogenesis and differentiation of multiple progenitor cell types. Using hematopoiesis as a diverse cellular model, we highlight the role of Notch in regulating the cell fate of common lymphoid progenitors. Additionally, the influence of Notch through microenvironment interplay with lymphoid cells and how dysregulation influences disease processes is explored. Furthermore, bi-directional and lateral Notch signaling between ligand expressing source cells and target cells are investigated, indicating potentially novel therapeutic options for treatment of Notch-mediated diseases. Finally, we discuss the role of cis‑inhibition in regulating Notch signaling in mammalian development.

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Targeting Notch in oncology: the path forward

Cited by 190 publications

References 251 publications

The Role of Notch3 Signaling in Cancer Stemness and Chemoresistance: Molecular Mechanisms and Targeting Strategies

The Role of Notch3 Signaling in Cancer Stemness and Chemoresistance: Molecular Mechanisms and Targeting Strategies

KDELC1 and TRMT1 Serve as Prognosis-Related SARS-CoV-2 Proteins Binding Human mRNAs and Promising Biomarkers in Clear Cell Renal Cell Carcinoma

To Be, or Notch to Be: Mediating Cell Fate from Embryogenesis to Lymphopoiesis

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