Topic Editors

Hematology Unit, Ospedale dell’Angelo, Mestre-Venezia, Italy
Clinical Hematology Department, ICO-Hospital Germans Trias i Pujol, Josep Carreras Research Institute, Badalona, Spain
Department of Obstetrics and Gynaecology, The Ohio State University Wexner Medical Center, Columbus, OH, USA

Targeting Signaling Networks for Cancer Therapy

Abstract submission deadline
4 July 2023
Manuscript submission deadline
5 September 2023
Viewed by
8369

Topic Information

Dear Colleagues,

We know that cancer-associated signaling networks, HER signaling, EGF signaling, Wnt signaling, Notch signaling, TGF-β pathway, mTOR pathway, PD-1/PD-L1 axis, etc., are all involved in normal cell survival regulation. However, any abnormal modulation might result in uncontrollable cell growth, or a tumor. To survive, tumor cells must try to avoid attacks from the native immune system. Cancer cells interact with nearby healthy host cells through the same signaling networks to prevent them from being removed. The dysregulated signaling factors of cancer cells provide possible targets, which could allow for us to control them. Cancer vaccines, chemical drugs, small molecules, monoclonal antibodies, etc., could modify the interactions between cancer and host cells, as well as adjusting the tumor microenvironment and active immune response against cancer cells. However, current cancer treatments, either traditional chemotherapy or the latest checkpoint inhibition and cell immunotherapy, have limitations and some serious side effects, such as damaging conditions in the body, drug resistance, partial response, tumor metastasis, etc. This Special Issue will focus on the current state of cancer signaling network research, from bench work to bedside clinical daily practice, to better understand carcinogenesis, lower toxicity and develop more effective treatment strategies against cancer.

Prof. Dr. Renato Bassan

Prof. Dr. Jose-Maria Ribera

Dr. Linlin Guo
Topic Editors

Keywords

  • cancer research
  • cancer therapy
  • signaling pathway
  • HER
  • EGF
  • Wnt
  • Notch
  • TGF-β
  • mTOR
  • PD-1/PD-L1

Participating Journals

Journal Name Impact Factor CiteScore Launched Year First Decision (median) APC
Biology
biology
5.168 2.8 2012 16.1 Days 2200 CHF Submit
Biomedicines
biomedicines
4.757 3.0 2013 17.4 Days 2200 CHF Submit
Cancers
cancers
6.575 5.8 2009 17.4 Days 2600 CHF Submit
Current Oncology
curroncol
3.109 3.5 1994 19.6 Days 1800 CHF Submit
Onco
onco
- - 2021 15.0 days * 1000 CHF Submit

* Median value for all MDPI journals in the second half of 2022.


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Published Papers (6 papers)

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Review
Tumor-Suppressive Functions of the Aryl Hydrocarbon Receptor (AhR) and AhR as a Therapeutic Target in Cancer
Biology 2023, 12(4), 526; https://doi.org/10.3390/biology12040526 - 30 Mar 2023
Viewed by 789
Abstract
The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor involved in regulating a wide range of biological responses. A diverse array of xenobiotics and endogenous small molecules bind to the receptor and drive unique phenotypic responses. Due in part to its role [...] Read more.
The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor involved in regulating a wide range of biological responses. A diverse array of xenobiotics and endogenous small molecules bind to the receptor and drive unique phenotypic responses. Due in part to its role in mediating toxic responses to environmental pollutants, AhR activation has not been traditionally viewed as a viable therapeutic approach. Nonetheless, the expression and activation of AhR can inhibit the proliferation, migration, and survival of cancer cells, and many clinically approved drugs transcriptionally activate AhR. Identification of novel select modulators of AhR-regulated transcription that promote tumor suppression is an active area of investigation. The development of AhR-targeted anticancer agents requires a thorough understanding of the molecular mechanisms driving tumor suppression. Here, we summarized the tumor-suppressive mechanisms regulated by AhR with an emphasis on the endogenous functions of the receptor in opposing carcinogenesis. In multiple different cancer models, the deletion of AhR promotes increased tumorigenesis, but a precise understanding of the molecular cues and the genetic targets of AhR involved in this process is lacking. The intent of this review was to synthesize the evidence supporting AhR-dependent tumor suppression and distill insights for development of AhR-targeted cancer therapeutics. Full article
(This article belongs to the Topic Targeting Signaling Networks for Cancer Therapy)
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Article
Inhibitors of the Oncogenic PA2G4-MYCN Protein-Protein Interface
Cancers 2023, 15(6), 1822; https://doi.org/10.3390/cancers15061822 - 17 Mar 2023
Viewed by 599
Abstract
MYCN is a major oncogenic driver for neuroblastoma tumorigenesis, yet there are no direct MYCN inhibitors. We have previously identified PA2G4 as a direct protein-binding partner of MYCN and drive neuroblastoma tumorigenesis. A small molecule known to bind PA2G4, WS6, significantly decreased tumorigenicity [...] Read more.
MYCN is a major oncogenic driver for neuroblastoma tumorigenesis, yet there are no direct MYCN inhibitors. We have previously identified PA2G4 as a direct protein-binding partner of MYCN and drive neuroblastoma tumorigenesis. A small molecule known to bind PA2G4, WS6, significantly decreased tumorigenicity in TH-MYCN neuroblastoma mice, along with the inhibition of PA2G4 and MYCN interactions. Here, we identified a number of novel WS6 analogues, with 80% structural similarity, and used surface plasmon resonance assays to determine their binding affinity. Analogues #5333 and #5338 showed direct binding towards human recombinant PA2G4. Importantly, #5333 and #5338 demonstrated a 70-fold lower toxicity for normal human myofibroblasts compared to WS6. Structure-activity relationship analysis showed that a 2,3 dimethylphenol was the most suitable substituent at the R1 position. Replacing the trifluoromethyl group on the phenyl ring at the R2 position, with a bromine or hydrogen atom, increased the difference between efficacy against neuroblastoma cells and normal myofibroblast toxicity. The WS6 analogues inhibited neuroblastoma cell phenotype in vitro, in part through effects on apoptosis, while their anti-cancer effects required both PA2G4 and MYCN expression. Collectively, chemical inhibition of PA2G4-MYCN binding by WS6 analogues represents a first-in-class drug discovery which may have implications for other MYCN-driven cancers. Full article
(This article belongs to the Topic Targeting Signaling Networks for Cancer Therapy)
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Article
High Tumor Mutation Burden Is Associated with Poor Clinical Outcome in EGFR-Mutated Lung Adenocarcinomas Treated with Targeted Therapy
Biomedicines 2022, 10(9), 2109; https://doi.org/10.3390/biomedicines10092109 - 29 Aug 2022
Viewed by 1086
Abstract
This study aimed to determine the association between TMB and treatment outcomes in patients with epidermal growth factor receptor (EGFR)-mutated lung cancer that were treated with tyrosine kinase inhibitors (TKIs). The TMB was assessed using a 409-gene targeted next-generation sequencing panel. We compared [...] Read more.
This study aimed to determine the association between TMB and treatment outcomes in patients with epidermal growth factor receptor (EGFR)-mutated lung cancer that were treated with tyrosine kinase inhibitors (TKIs). The TMB was assessed using a 409-gene targeted next-generation sequencing panel. We compared the response rate (RR), progression-free survival (PFS), overall survival (OS), and frequency of secondary T790M mutations among the different TMB groups. The median TMB of the study population (n = 88) was 3.36/megabases. We divided 52 (59%) and 36 (41%) patients into the low and high TMB groups, respectively. A high TMB level was significantly associated with liver metastasis and more advanced stage (all p < 0.05). RR was significantly lower in the high TMB group than that of the low TMB group (50.0% vs. 80.7%, all p = 0.0384). In multivariate analysis, high TMB was independently associated with a shorter PFS (hazard ratio [HR] = 1.80, p = 0.0427) and shorter OS (HR = 2.05, p = 0.0397) than that of the low TMB group. Further, high TMB was independently associated with decreased T790M mutation development. These results suggest that high TMB may be a predictive biomarker for adverse treatment outcomes and represent a patients’ subgroup warranting tailored therapeutic approaches. Full article
(This article belongs to the Topic Targeting Signaling Networks for Cancer Therapy)
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Article
CD44 Depletion in Glioblastoma Cells Suppresses Growth and Stemness and Induces Senescence
Cancers 2022, 14(15), 3747; https://doi.org/10.3390/cancers14153747 - 31 Jul 2022
Cited by 2 | Viewed by 1835
Abstract
Glioblastoma multiforme (GBM) is a lethal brain tumor, characterized by enhanced proliferation and invasion, as well as increased vascularization and chemoresistance. The expression of the hyaluronan receptor CD44 has been shown to correlate with GBM progression and poor prognosis. Here, we sought to [...] Read more.
Glioblastoma multiforme (GBM) is a lethal brain tumor, characterized by enhanced proliferation and invasion, as well as increased vascularization and chemoresistance. The expression of the hyaluronan receptor CD44 has been shown to correlate with GBM progression and poor prognosis. Here, we sought to elucidate the molecular mechanisms by which CD44 promotes GBM progression by knocking out (KO) CD44, employing CRISPR/Cas9 gene editing in U251MG cells. CD44-depleted cells exhibited an impaired proliferation rate, as shown by the decreased cell numbers, decreased Ki67-positive cell nuclei, diminished phosphorylation of CREB, and increased levels of the cell cycle inhibitor p16 compared to control cells. Furthermore, the CD44 KO cells showed decreased stemness and increased senescence, which was manifested upon serum deprivation. In stem cell-like enriched spheres, RNA-sequencing analysis of U251MG cells revealed a CD44 dependence for gene signatures related to hypoxia, the glycolytic pathway, and G2 to M phase transition. Partially similar results were obtained when cells were treated with the γ-secretase inhibitor DAPT, which inhibits CD44 cleavage and therefore inhibits the release of the intracellular domain (ICD) of CD44, suggesting that certain transcriptional responses are dependent on CD44-ICD. Interestingly, the expression of molecules involved in hyaluronan synthesis, degradation, and interacting matrix proteins, as well as of platelet-derived growth factor (PDGF) isoforms and PDGF receptors, were also deregulated in CD44 KO cells. These results were confirmed by the knockdown of CD44 in another GBM cell line, U2990. Notably, downregulation of hyaluronan synthase 2 (HAS2) impaired the hypoxia-related genes and decreased the CD44 protein levels, suggesting a CD44/hyaluronan feedback circuit contributing to GBM progression. Full article
(This article belongs to the Topic Targeting Signaling Networks for Cancer Therapy)
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Article
Regulation of Interleukin-36γ/IL-36R Signaling Axis by PIN1 in Epithelial Cell Transformation and Breast Tumorigenesis
Cancers 2022, 14(15), 3654; https://doi.org/10.3390/cancers14153654 - 27 Jul 2022
Cited by 1 | Viewed by 1110
Abstract
Given the increasing recognition of the relationship between IL-1 cytokines, inflammation, and cancer, the significance of distinct members of the IL-1 cytokine family in the etiology of cancer has been widely researched. In the present study, we investigated the underlying mechanism of the [...] Read more.
Given the increasing recognition of the relationship between IL-1 cytokines, inflammation, and cancer, the significance of distinct members of the IL-1 cytokine family in the etiology of cancer has been widely researched. In the present study, we investigated the underlying mechanism of the IL-36γ/IL-36R axis during breast cancer progression, which has not yet been elucidated. Initially, we determined the effects of IL-36γ on the proliferation and epithelial cell transformation of JB6 Cl41 mouse epidermal and MCF7 human breast cancer cells using BrdU incorporation and anchorage-independent growth assays. We found that treatment with IL-36γ increased the proliferation and colony formation of JB6 Cl41 and MCF7 cells. Analysis of the mechanism underlying the neoplastic cell transformation revealed that IL-36γ induced IL-36R-mediated phosphorylation of MEK1/2, ERK1/2, JNK1/2, and c-Jun, resulting in increased c-Fos, c-Jun, and AP-1 activities in JB6 Cl41 and MCF7 cells. Furthermore, the IL-36γ-induced tumorigenic capacity of MCF7 cells was considerably enhanced by PIN1, following MEK/ERK and JNK/c-Jun signaling. Interestingly, blocking PIN1 activity using juglone suppressed the IL-36γ-induced increase in the anchorage-independent growth of 4T1 metastatic mouse breast cancer cells. Finally, in a syngeneic mouse model, IL-36γ-induced tumor growth in the breast mammary gland was significantly inhibited following PIN1 knockout. Full article
(This article belongs to the Topic Targeting Signaling Networks for Cancer Therapy)
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Review
N6-Methyladenosine RNA-Binding Protein YTHDF1 in Gastrointestinal Cancers: Function, Molecular Mechanism and Clinical Implication
Cancers 2022, 14(14), 3489; https://doi.org/10.3390/cancers14143489 - 18 Jul 2022
Cited by 6 | Viewed by 2217
Abstract
N6-methyladenosine (m6A) is the most abundant internal modification in eukaryotic cell mRNA, and this modification plays a key role in regulating mRNA translation, splicing, and stability. Emerging evidence implicates aberrant m6A as a crucial player in the [...] Read more.
N6-methyladenosine (m6A) is the most abundant internal modification in eukaryotic cell mRNA, and this modification plays a key role in regulating mRNA translation, splicing, and stability. Emerging evidence implicates aberrant m6A as a crucial player in the occurrence and development of diseases, especially GI cancers. Among m6A regulators, YTHDF1 is the most abundant m6A reader that functionally connects m6A-modified mRNA to its eventual fate, mostly notably protein translation. Here, we summarized the function, molecular mechanisms, and clinical implications of YTHDF1 in GI cancers. YTHDF1 is largely upregulated in multiple GI cancer and its high expression predicts poor patient survival. In vitro and in vivo experimental evidence largely supports the role of YTDHF1 in promoting cancer initiation, progression, and metastasis, which suggests the oncogenic function of YTHDF1 in GI cancers. Besides, YTHDF1 overexpression is associated with changes in the tumor microenvironment that are favorable to tumorigenesis. Mechanistically, YTHDF1 regulates the expression of target genes by promoting translation, thereby participating in cancer-related signaling pathways. Targeting YTHDF1 holds therapeutic potential, as the overexpression of YTHDF1 is associated with tumor resistance to chemotherapy and immunotherapy. In summary, YTHDF1-mediated regulation of m6A modified mRNA is an actionable target and a prognostic factor for GI cancers. Full article
(This article belongs to the Topic Targeting Signaling Networks for Cancer Therapy)
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