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Cancers
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Notch Signaling Pathway in Cancers
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Notch Signaling Pathway in Cancers

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (31 March 2023) | Viewed by 9850

Special Issue Editor

Dr. Stephanie Roessler

E-Mail Website
Guest Editor
Institute of Pathology, Heidelberg University Hospital, 69120 Heidelberg, Germany
Interests: Notch; STAT3; liver cancer; genomics; epigenetics; tumor suppression; tumor microenvironment

Special Issue Information

Dear Colleagues,

Notch signaling is a highly conserved pathway and a key player of cell fate determination, embryonic development and adult tissue homeostasis. In carcinogenesis, Notch signaling has been found to be frequently altered and to either act as an oncogene or tumor suppressor depending on the tissue and cellular context. Oncogenic activation of Notch signaling has been linked to increased cellular proliferation, reduced apoptosis, suppression of cellular differentiation and induction of cancer stem cell features. Over the last several years, it has become clear that the bidirectional interaction between cancer cells and non-neoplastic cells of the tumor microenvironment is required for cancer progression and metastasis. As Notch is activated through the binding of transmembrane ligands on neighboring cells, altered expression of Notch receptor ligands on cells of the tumor microenvironment may induce aberrant Notch signaling in tumor cells. Along this line, the critical role of Notch signaling has been highlighted in the overall regulation of tumor angiogenesis, whereby the induction of Notch signaling in endothelial cells may either promote or inhibit tumor progression. In addition, non-canonical Notch signaling may antagonize Wnt/β-catenin signaling independent of Notch ligand-dependent cleavage or nuclear localization. Thus, inhibition of Notch signaling is considered a promising therapeutic option in certain cancers, but the molecular mechanisms of Notch signal transduction have not yet been fully uncovered.

This Special Issue will highlight basic and preclinical aspects of the role of Notch signaling in cancers that will advance our understanding of the underlying molecular mechanisms.

I am looking forward to your contributions and exciting findings.

Dr. Stephanie Roessler
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • notch
  • cancer
  • tumorigenesis
  • metastasis
  • invasion
  • cancer progression
  • signaling
  • therapy
  • tumor microenvironment

Published Papers (4 papers)

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Research

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16 pages, 2569 KiB  
Article
The NOTCH-RIPK4-IRF6-ELOVL4 Axis Suppresses Squamous Cell Carcinoma
by Yue Yan, Marc-Andre Gauthier, Ahmad Malik, Iosifina Fotiadou, Michael Ostrovski, Dzana Dervovic, Logine Ghadban, Ricky Tsai, Gerald Gish, Sampath Kumar Loganathan and Daniel Schramek
Cancers 2023, 15(3), 737; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15030737 - 25 Jan 2023
Cited by 4 | Viewed by 2240
Abstract
Receptor-interacting serine/threonine protein kinase 4 (RIPK4) and its kinase substrate the transcription factor interferon regulatory factor 6 (IRF6) play critical roles in the development and maintenance of the epidermis. In addition, ourselves and others have previously shown that RIPK4 is a NOTCH target [...] Read more.
Receptor-interacting serine/threonine protein kinase 4 (RIPK4) and its kinase substrate the transcription factor interferon regulatory factor 6 (IRF6) play critical roles in the development and maintenance of the epidermis. In addition, ourselves and others have previously shown that RIPK4 is a NOTCH target gene that suppresses the development of cutaneous and head and neck squamous cell carcinomas (HNSCCs). In this study, we used autochthonous mouse models, where the expression of Pik3caH1047R oncogene predisposes the skin and oral cavity to tumor development, and show that not only loss of Ripk4, but also loss of its kinase substrate Irf6, triggers rapid SCC development. In vivo rescue experiments using Ripk4 or a kinase-dead Ripk4 mutant showed that the tumor suppressive function of Ripk4 is dependent on its kinase activity. To elucidate critical mediators of this tumor suppressive pathway, we performed transcriptional profiling of Ripk4-deficient epidermal cells followed by multiplexed in vivo CRISPR screening to identify genes with tumor suppressive capabilities. We show that Elovl4 is a critical Notch-Ripk4-Irf6 downstream target gene, and that Elovl4 loss itself triggers SCC development. Importantly, overexpression of Elovl4 suppressed tumor growth of Ripk4-deficient keratinocytes. Altogether, our work identifies a potent Notch1-Ripk4-Irf6-Elovl4 tumor suppressor axis. Full article
(This article belongs to the Special Issue Notch Signaling Pathway in Cancers)
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21 pages, 5313 KiB  
Article
IL-15 Prevents the Development of T-ALL from Aberrant Thymocytes with Impaired DNA Repair Functions and Increased NOTCH1 Activation
by Madhuparna Nandi, Amit Ghosh, Sara Ali Akbari, Diwakar Bobbala, Marie-Josée Boucher, Alfredo Menendez, Trang Hoang, Subburaj Ilangumaran and Sheela Ramanathan
Cancers 2023, 15(3), 671; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15030671 - 21 Jan 2023
Cited by 2 | Viewed by 1641
Abstract
We previously reported that NOD.Scid mice lacking interleukin-15 (IL-15), or IL-15 receptor alpha-chain, develop T-acute lymphoblastic leukemia (T-ALL). To understand the mechanisms by which IL-15 signaling controls T-ALL development, we studied the thymocyte developmental events in IL-15-deficient Scid mice from NOD and [...] Read more.
We previously reported that NOD.Scid mice lacking interleukin-15 (IL-15), or IL-15 receptor alpha-chain, develop T-acute lymphoblastic leukemia (T-ALL). To understand the mechanisms by which IL-15 signaling controls T-ALL development, we studied the thymocyte developmental events in IL-15-deficient Scid mice from NOD and C57BL/6 genetic backgrounds. Both kinds of mice develop T-ALL characterized by circulating TCR-negative cells expressing CD4, CD8 or both. Analyses of thymocytes in NOD.Scid.Il15−/− mice prior to T-ALL development revealed discernible changes within the CD4−CD8− double-negative (DN) thymocyte developmental stages and increased frequencies of CD4+CD8+ double-positive cells with a high proportion of TCR-negative CD4+ and CD8+ cells. The DN cells also showed elevated expressions of CXCR4 and CD117, molecules implicated in the expansion of DN thymocytes. T-ALL cell lines and primary leukemic cells from IL-15-deficient NOD.Scid and C57BL/6.Scid mice displayed increased NOTCH1 activation that was inhibited by NOTCH1 inhibitors and blockers of the PI3K/AKT pathway. Primary leukemic cells from NOD.Scid.Il15−/− mice survived and expanded when cultured with MS5 thymic stromal cells expressing Delta-like ligand 4 and supplemented with IL-7 and FLT3 ligand. These findings suggest that IL-15 signaling in the thymus controls T-ALL development from aberrant thymocytes with an impaired DNA repair capacity and increased NOTCH1 activation. Full article
(This article belongs to the Special Issue Notch Signaling Pathway in Cancers)
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12 pages, 2657 KiB  
Article
Notch Signaling Suppresses Melanoma Tumor Development in BRAF/Pten Mice
by Dareen Mikheil, Kirthana Prabhakar, Tun Lee Ng, Sireesh Teertam, B. Jack Longley, Michael A. Newton and Vijayasaradhi Setaluri
Cancers 2023, 15(2), 519; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15020519 - 14 Jan 2023
Cited by 2 | Viewed by 1570
Abstract
Both oncogenic and tumor suppressor roles have been assigned to Notch signaling in melanoma. In clinical trials, Notch inhibitors proved to be ineffective for melanoma treatment. Notch signaling has also been implicated in melanoma transdifferentiation, a prognostic feature in primary melanoma. In this [...] Read more.
Both oncogenic and tumor suppressor roles have been assigned to Notch signaling in melanoma. In clinical trials, Notch inhibitors proved to be ineffective for melanoma treatment. Notch signaling has also been implicated in melanoma transdifferentiation, a prognostic feature in primary melanoma. In this study, we investigated the role of Notch signaling in melanoma tumor development and growth using the genetic model of mouse melanoma by crossing BRAFCA/+/Pten+/+/Tyr-CreER+ (B) and BRAFCA/+/Pten-/-/Tyr-CreER + (BP) mice with Notch1 or Notch2 floxed allele mice. The topical application of tamoxifen induced tumors in BP mice but not in B mice with or without the deletion of either Notch1 or Notch2. These data show that the loss of either Notch1 nor Notch2 can substitute the tumor suppressor function of Pten in BRAFV600E-induced melanomagenesis. However, in Pten-null background, the loss of either Notch1 or Notch2 appeared to accelerate BRAFV600E-induced tumor development, suggesting a tumor suppressor role for Notch1 and Notch2 in BRAFV600E/Pten-null driven melanomagenesis. Quantitative immunochemical analysis of a human cutaneous melanoma tissue microarray that consists of >100 primary tumors with complete clinical history showed a weak to moderate correlation between NOTCH protein levels and clinical and pathological parameters. Our data show that Notch signaling is involved during melanomagenesis and suggest that the identification of genes and signaling pathways downstream of Notch could help devise strategies for melanoma prevention. Full article
(This article belongs to the Special Issue Notch Signaling Pathway in Cancers)
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Review

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10 pages, 563 KiB  
Review
Understanding the Notch Signaling Pathway in Acute Myeloid Leukemia Stem Cells: From Hematopoiesis to Neoplasia
by Daniel Láinez-González, Juana Serrano-López and Juan Manuel Alonso-Dominguez
Cancers 2022, 14(6), 1459; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14061459 - 12 Mar 2022
Cited by 7 | Viewed by 3664
Abstract
The Notch signaling pathway is fundamental to early fetal development, but its role in acute myeloid leukemia is still unclear. It is important to elucidate the function that contains Notch, not only in acute myeloid leukemia, but in leukemic stem cells (LSCs). LSCs [...] Read more.
The Notch signaling pathway is fundamental to early fetal development, but its role in acute myeloid leukemia is still unclear. It is important to elucidate the function that contains Notch, not only in acute myeloid leukemia, but in leukemic stem cells (LSCs). LSCs seem to be the principal cause of patient relapse. This population is in a quiescent state. Signaling pathways that govern this process must be understood to increase the chemosensitivity of this compartment. In this review, we focus on the conserved Notch signaling pathway, and its repercussions in hematopoiesis and hematological neoplasia. We found in the literature both visions regarding Notch activity in acute myeloid leukemia. On one hand, the activation of Notch leads to cell proliferation, on the other hand, the activation of Notch leads to cell cycle arrest. This dilemma requires further experiments to be answered, in order to understand the role of Notch not only in acute myeloid leukemia, but especially in LSCs. Full article
(This article belongs to the Special Issue Notch Signaling Pathway in Cancers)
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