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Cancers
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The Role of Hedgehog Pathway in Cancer
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The Role of Hedgehog Pathway in Cancer

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

Deadline for manuscript submissions: closed (20 July 2022) | Viewed by 20958

Special Issue Editors

Prof. Enrico De Smaele

E-Mail Website
Guest Editor
Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 29, 00161 Roma, Italy
Interests: Hedgehog Signalling; medulloblastoma; tumor; cancer stem cells; miRNA; NF-kappaB; KCTD21; KCASH2
Dr. Barbara Stecca

E-Mail Website
Guest Editor
Tumor Cell Biology Unit, Core Research Laboratory, Istituto per lo Studio la Prevenzione e la Rete Oncologica (ISPRO), 50139 Firenze, Italy
Interests: tumor growth; metastasis; stemness; melanoma; Hedgehog signaling; small molecule inhibitors

Special Issue Information

Dear Colleagues,

Aberrant activation of the Hedgehog pathway is implicated in the development of a variety of tumors, including medulloblastoma, glioblastoma, breast, colon, skin cancers, and hematological malignancies. As a result, the Hedgehog pathway represents an attractive therapeutic target for cancer treatment. Although drugs targeting this pathway have produced promising clinical results and have been approved for basal cell carcinoma (BCC), they have so far demonstrated limited clinical efficacy against most cancer types. Therefore, we need to deepen our understanding of how the Hedgehog pathway functions during tumor development and progression and how it interacts with other signaling pathways.

In this Special Issue, we will collect original articles and reviews that provide new insights into Hedgehog signaling in cancer, including, but not limited to mechanisms of canonical and non-canonical activation; regulation of GLI transcription factors; function of the Hedgehog pathway in cancer cells stemness, cancer metabolism, and metastasis; the role of Hedgehog signaling in the tumor microenvironment; miRNA and Hedgehog signaling; novel strategies to inhibit Hedgehog signaling; mechanism of resistance to Hedgehog-targeted therapy; and approaches to overcoming this resistance. With this Special Issue, we aim to provide basic and translational researchers with an overview of breakthroughs of Hedgehog signaling in cancer.

Prof. Enrico De Smaele
Dr. Barbara Stecca
Guest Editors

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 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

  • Hedgehog
  • Cancer
  • Canonical and non-canonical activation
  • GLI transcription factors and their regulation
  • Hedgehog pathway inhibitors
  • Mechanism of drug resistance
  • Cancer stem cells
  • miRNA
  • Metastasis
  • Cancer metabolism
  • Immune evasion

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Published Papers (5 papers)

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Research

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15 pages, 2764 KiB  
Article
MAPK15 Controls Hedgehog Signaling in Medulloblastoma Cells by Regulating Primary Ciliogenesis
by Silvia Pietrobono, Lorenzo Franci, Francesco Imperatore, Cristina Zanini, Barbara Stecca and Mario Chiariello
Cancers 2021, 13(19), 4903; https://doi.org/10.3390/cancers13194903 - 29 Sep 2021
Cited by 5 | Viewed by 3078
Abstract
In medulloblastomas, genetic alterations resulting in over-activation and/or deregulation of proteins involved in Hedgehog (HH) signaling lead to cellular transformation, which can be prevented by inhibition of primary ciliogenesis. Here, we investigated the role of MAPK15 in HH signaling and, in turn, in [...] Read more.
In medulloblastomas, genetic alterations resulting in over-activation and/or deregulation of proteins involved in Hedgehog (HH) signaling lead to cellular transformation, which can be prevented by inhibition of primary ciliogenesis. Here, we investigated the role of MAPK15 in HH signaling and, in turn, in HH-mediated cellular transformation. We first demonstrated, in NIH3T3 mouse fibroblasts, the ability of this kinase of controlling primary ciliogenesis and canonical HH signaling. Next, we took advantage of transformed human medulloblastoma cells belonging to the SHH-driven subtype, i.e., DAOY and ONS-76 cells, to ascertain the role for MAPK15 in HH-mediated cellular transformation. Specifically, medullo-spheres derived from these cells, an established in vitro model for evaluating progression and malignancy of putative tumor-initiating medulloblastoma cells, were used to demonstrate that MAPK15 regulates self-renewal of these cancer stem cell-like cells. Interestingly, by using the HH-related oncogenes SMO-M2 and GLI2-DN, we provided evidences that disruption of MAPK15 signaling inhibits oncogenic HH overactivation in a specific cilia-dependent fashion. Ultimately, we show that pharmacological inhibition of MAPK15 prevents cell proliferation of SHH-driven medulloblastoma cells, overall suggesting that oncogenic HH signaling can be counteracted by targeting the ciliary gene MAPK15, which could therefore be considered a promising target for innovative “smart” therapies in medulloblastomas. Full article
(This article belongs to the Special Issue The Role of Hedgehog Pathway in Cancer)
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23 pages, 3580 KiB  
Article
Activation of Cilia-Independent Hedgehog/GLI1 Signaling as a Novel Concept for Neuroblastoma Therapy
by Anke Koeniger, Anna Brichkina, Iris Nee, Lukas Dempwolff, Anna Hupfer, Ilya Galperin, Florian Finkernagel, Andrea Nist, Thorsten Stiewe, Till Adhikary, Wibke Diederich and Matthias Lauth
Cancers 2021, 13(8), 1908; https://doi.org/10.3390/cancers13081908 - 15 Apr 2021
Cited by 7 | Viewed by 3575
Abstract
Although being rare in absolute numbers, neuroblastoma (NB) represents the most frequent solid tumor in infants and young children. Therapy options and prognosis are comparably good for NB patients except for the high risk stage 4 class. Particularly in adolescent patients with certain [...] Read more.
Although being rare in absolute numbers, neuroblastoma (NB) represents the most frequent solid tumor in infants and young children. Therapy options and prognosis are comparably good for NB patients except for the high risk stage 4 class. Particularly in adolescent patients with certain genetic alterations, 5-year survival rates can drop below 30%, necessitating the development of novel therapy approaches. The developmentally important Hedgehog (Hh) pathway is involved in neural crest differentiation, the cell type being causal in the etiology of NB. However, and in contrast to its function in some other cancer types, Hedgehog signaling and its transcription factor GLI1 exert tumor-suppressive functions in NB, rendering GLI1 an interesting new candidate for anti-NB therapy. Unfortunately, the therapeutic concept of pharmacological Hh/GLI1 pathway activation is difficult to implement as NB cells have lost primary cilia, essential organelles for Hh perception and activation. In order to bypass this bottleneck, we have identified a GLI1-activating small molecule which stimulates endogenous GLI1 production without the need for upstream Hh pathway elements such as Smoothened or primary cilia. This isoxazole compound potently abrogates NB cell proliferation and might serve as a starting point for the development of a novel class of NB-suppressive molecules. Full article
(This article belongs to the Special Issue The Role of Hedgehog Pathway in Cancer)
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Review

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13 pages, 969 KiB  
Review
Hedgehog Signaling in Myeloid Malignancies
by Ajay Abraham and William Matsui
Cancers 2021, 13(19), 4888; https://doi.org/10.3390/cancers13194888 - 29 Sep 2021
Cited by 11 | Viewed by 2754
Abstract
Myeloid malignancies arise from normal hematopoiesis and include several individual disorders with a wide range of clinical manifestations, treatment options, and clinical outcomes. The Hedgehog (HH) signaling pathway is aberrantly activated in many of these diseases, and glasdegib, a Smoothened (SMO) antagonist and [...] Read more.
Myeloid malignancies arise from normal hematopoiesis and include several individual disorders with a wide range of clinical manifestations, treatment options, and clinical outcomes. The Hedgehog (HH) signaling pathway is aberrantly activated in many of these diseases, and glasdegib, a Smoothened (SMO) antagonist and HH pathway inhibitor, has recently been approved for the treatment of acute myeloid leukemia (AML). The efficacy of SMO inhibitors in AML suggests that they may be broadly active, but clinical studies in other myeloid malignancies have been largely inconclusive. We will discuss the biological role of the HH pathway in normal hematopoiesis and myeloid malignancies and review clinical studies targeting HH signaling in these diseases. In addition, we will examine SMO-independent pathway activation and highlight potential strategies that may expand the clinical utility of HH pathway antagonists. Full article
(This article belongs to the Special Issue The Role of Hedgehog Pathway in Cancer)
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20 pages, 865 KiB  
Review
The Role of the Hedgehog Pathway in Cholangiocarcinoma
by Giulia Anichini, Laura Carrassa, Barbara Stecca, Fabio Marra and Chiara Raggi
Cancers 2021, 13(19), 4774; https://doi.org/10.3390/cancers13194774 - 24 Sep 2021
Cited by 11 | Viewed by 2870
Abstract
Cholangiocarcinoma (CCA) is a poorly treatable type of cancer and, along with hepatocellular carcinoma (HCC), is the predominant type of primitive liver cancer in adults. The lack of understanding of CCA biology has slowed down the identification of novel targets and the development [...] Read more.
Cholangiocarcinoma (CCA) is a poorly treatable type of cancer and, along with hepatocellular carcinoma (HCC), is the predominant type of primitive liver cancer in adults. The lack of understanding of CCA biology has slowed down the identification of novel targets and the development of effective treatments. While tumors share some general characteristics, detailed knowledge of specific features is essential for the development of effectively tailored therapeutic approaches. The Hedgehog (HH) signaling cascade regulates stemness biology, embryonal development, tissue homeostasis, and cell proliferation and differentiation. Its aberrant activation has been associated with a variety of solid and hematological human malignancies. Several HH-inhibiting compounds have been indeed developed as potential anticancer agents in different types of tumors, with Smoothened and GLI inhibitors showing the most promising results. Beside its well-established function in other tumors, findings regarding the HH signaling in CCA are still controversial. Here we will give an overview of the most important clinical and molecular features of cholangiocarcinoma, and we will discuss the available evidence of the crosstalk between the HH signaling pathway and the cholangiocarcinoma cell biology. Full article
(This article belongs to the Special Issue The Role of Hedgehog Pathway in Cancer)
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26 pages, 2936 KiB  
Review
Hedgehog/GLI Signaling Pathway: Transduction, Regulation, and Implications for Disease
by Ashley N. Sigafoos, Brooke D. Paradise and Martin E. Fernandez-Zapico
Cancers 2021, 13(14), 3410; https://doi.org/10.3390/cancers13143410 - 7 Jul 2021
Cited by 102 | Viewed by 7333
Abstract
The Hh/GLI signaling pathway was originally discovered in Drosophila as a major regulator of segment patterning in development. This pathway consists of a series of ligands (Shh, Ihh, and Dhh), transmembrane receptors (Ptch1 and Ptch2), transcription factors (GLI1–3), and signaling regulators (SMO, HHIP, [...] Read more.
The Hh/GLI signaling pathway was originally discovered in Drosophila as a major regulator of segment patterning in development. This pathway consists of a series of ligands (Shh, Ihh, and Dhh), transmembrane receptors (Ptch1 and Ptch2), transcription factors (GLI1–3), and signaling regulators (SMO, HHIP, SUFU, PKA, CK1, GSK3β, etc.) that work in concert to repress (Ptch1, Ptch2, SUFU, PKA, CK1, GSK3β) or activate (Shh, Ihh, Dhh, SMO, GLI1–3) the signaling cascade. Not long after the initial discovery, dysregulation of the Hh/GLI signaling pathway was implicated in human disease. Activation of this signaling pathway is observed in many types of cancer, including basal cell carcinoma, medulloblastoma, colorectal, prostate, pancreatic, and many more. Most often, the activation of the Hh/GLI pathway in cancer occurs through a ligand-independent mechanism. However, in benign disease, this activation is mostly ligand-dependent. The upstream signaling component of the receptor complex, SMO, is bypassed, and the GLI family of transcription factors can be activated regardless of ligand binding. Additional mechanisms of pathway activation exist whereby the entirety of the downstream signaling pathway is bypassed, and PTCH1 promotes cell cycle progression and prevents caspase-mediated apoptosis. Throughout this review, we summarize each component of the signaling cascade, non-canonical modes of pathway activation, and the implications in human disease, including cancer. Full article
(This article belongs to the Special Issue The Role of Hedgehog Pathway in Cancer)
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