|
1
|
Kluge V, Kappelmann-Fenzl M, Fischer S, Zimmermann T, Pommer M, Kuphal S, Bosserhoff AK. Alternative Wnt-signaling axis leads to a break of oncogene-induced senescence. Cell Death Dis 2024; 15:166. [PMID: 38388496 PMCID: PMC10883971 DOI: 10.1038/s41419-024-06550-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Revised: 02/06/2024] [Accepted: 02/08/2024] [Indexed: 02/24/2024]
Abstract
Oncogene-induced senescence (OIS) is an important process that suppresses tumor development, but the molecular mechanisms of OIS are still under investigation. It is known that BRAFV600E-mutated melanocytes can overcome OIS and develop melanoma, but the underlying mechanism is largely unknown. Using an established OIS model of primary melanocytes transduced with BRAFV600E, YAP activity was shown to be induced in OIS as well as in melanoma cells compared to that in normal epidermal melanocytes. This led to the assumption that YAP activation itself is not a factor involved in the disruption of OIS. However, its role and interaction partners potentially change. As Wnt molecules are known to be important in melanoma progression, these molecules were the focus of subsequent studies. Interestingly, activation of Wnt signaling using AMBMP resulted in a disruption of OIS in BRAFV600E-transduced melanocytes. Furthermore, depletion of Wnt6, Wnt10b or β-catenin expression in melanoma cells resulted in the induction of senescence. Given that melanoma cells do not exhibit canonical Wnt/β-catenin activity, alternative β-catenin signaling pathways may disrupt OIS. Here, we discovered that β-catenin is an interaction partner of YAP on DNA in melanoma cells. Furthermore, the β-catenin-YAP interaction changed the gene expression pattern from senescence-stabilizing genes to tumor-supportive genes. This switch is caused by transcriptional coactivation via the LEF1/TEAD interaction. The target genes with binding sites for LEF1 and TEAD are involved in rRNA processing and are associated with poor prognosis in melanoma patients. This study revealed that an alternative YAP-Wnt signaling axis is an essential molecular mechanism leading to OIS disruption in melanocytes.
Collapse
Affiliation(s)
- Viola Kluge
- Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Melanie Kappelmann-Fenzl
- Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
- Faculty of Computer Science, Deggendorf Institute of Technology, Dieter-Görlitz-Platz 1, 94469, Deggendorf, Germany
| | - Stefan Fischer
- Faculty of Computer Science, Deggendorf Institute of Technology, Dieter-Görlitz-Platz 1, 94469, Deggendorf, Germany
| | - Tom Zimmermann
- Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Michaela Pommer
- Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Silke Kuphal
- Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Anja-Katrin Bosserhoff
- Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
| |
Collapse
|
|
2
|
Wang J, Koch DT, Hofmann FO, Härtwig D, Beirith I, Janssen KP, Bazhin AV, Niess H, Werner J, Renz BW, Ilmer M. WNT enhancing signals in pancreatic cancer are transmitted by LGR6. Aging (Albany NY) 2023; 15:10897-10914. [PMID: 37770230 PMCID: PMC10637827 DOI: 10.18632/aging.205101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Accepted: 07/17/2023] [Indexed: 10/03/2023]
Abstract
The G-protein-coupled receptor LGR6 associates with ligands of the R-Spondin (RSPO) family to potentiate preexisting signals of the canonical WNT pathway. However, its importance in pancreatic ductal adenocarcinoma (PDAC) remains unclear. Here, we show that LGR6 is differentially expressed in various PDAC cell lines of mesenchymal and epithelial phenotype, respectively, siding with the latter subsets. LGR6 expression is altered based upon the cells' WNT activation status. Furthermore, extrinsic enhancement of WNT pathway signaling increased LGR6 expression suggestive of a reinforcing self-regulatory loop in highly WNT susceptible cells. Downregulation of LGR6 on the other hand, seemed to tamper those effects. Last, downregulation of LGR6 reduced cancer stemness as determined by functional in vitro assays. These findings shed new insights into regulatory mechanisms for the canonical WNT pathway in pancreatic cancer cells. It may also have potential value for treatment stratification of PDAC.
Collapse
Affiliation(s)
- Jing Wang
- Department of General, Visceral and Transplantation Surgery, Hospital of the University of Munich, Ludwig-Maximilians-University (LMU), Munich, Bavaria, Germany
- Department of General Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, P.R. China
| | - Dominik T. Koch
- Department of General, Visceral and Transplantation Surgery, Hospital of the University of Munich, Ludwig-Maximilians-University (LMU), Munich, Bavaria, Germany
| | - Felix O. Hofmann
- Department of General, Visceral and Transplantation Surgery, Hospital of the University of Munich, Ludwig-Maximilians-University (LMU), Munich, Bavaria, Germany
| | - Daniel Härtwig
- Department of General, Visceral and Transplantation Surgery, Hospital of the University of Munich, Ludwig-Maximilians-University (LMU), Munich, Bavaria, Germany
| | - Iris Beirith
- Department of General, Visceral and Transplantation Surgery, Hospital of the University of Munich, Ludwig-Maximilians-University (LMU), Munich, Bavaria, Germany
| | - Klaus Peter Janssen
- Department of Surgery, School of Medicine, Klinikum Rechts der Isar, Technical University of Munich, Munich, Bavaria, Germany
| | - Alexandr V. Bazhin
- Department of General, Visceral and Transplantation Surgery, Hospital of the University of Munich, Ludwig-Maximilians-University (LMU), Munich, Bavaria, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, Munich, Bavaria, Germany
- Bavarian Cancer Research Center (BZKF), LMU Munich, Munich, Bavaria, Germany
| | - Hanno Niess
- Department of General, Visceral and Transplantation Surgery, Hospital of the University of Munich, Ludwig-Maximilians-University (LMU), Munich, Bavaria, Germany
| | - Jens Werner
- Department of General, Visceral and Transplantation Surgery, Hospital of the University of Munich, Ludwig-Maximilians-University (LMU), Munich, Bavaria, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, Munich, Bavaria, Germany
- Bavarian Cancer Research Center (BZKF), LMU Munich, Munich, Bavaria, Germany
| | - Bernhard W. Renz
- Department of General, Visceral and Transplantation Surgery, Hospital of the University of Munich, Ludwig-Maximilians-University (LMU), Munich, Bavaria, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, Munich, Bavaria, Germany
- Bavarian Cancer Research Center (BZKF), LMU Munich, Munich, Bavaria, Germany
| | - Matthias Ilmer
- Department of General, Visceral and Transplantation Surgery, Hospital of the University of Munich, Ludwig-Maximilians-University (LMU), Munich, Bavaria, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, Munich, Bavaria, Germany
- Bavarian Cancer Research Center (BZKF), LMU Munich, Munich, Bavaria, Germany
| |
Collapse
|
|
3
|
Targeting GPCRs and Their Signaling as a Therapeutic Option in Melanoma. Cancers (Basel) 2022; 14:cancers14030706. [PMID: 35158973 PMCID: PMC8833576 DOI: 10.3390/cancers14030706] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 01/27/2022] [Accepted: 01/27/2022] [Indexed: 12/10/2022] Open
Abstract
Simple Summary Sixteen G-protein-coupled receptors (GPCRs) have been involved in melanogenesis or melanomagenesis. Here, we review these GPCRs, their associated signaling, and therapies. Abstract G-protein-coupled receptors (GPCRs) serve prominent roles in melanocyte lineage physiology, with an impact at all stages of development, as well as on mature melanocyte functions. GPCR ligands are present in the skin and regulate melanocyte homeostasis, including pigmentation. The role of GPCRs in the regulation of pigmentation and, consequently, protection against external aggression, such as ultraviolet radiation, has long been established. However, evidence of new functions of GPCRs directly in melanomagenesis has been highlighted in recent years. GPCRs are coupled, through their intracellular domains, to heterotrimeric G-proteins, which induce cellular signaling through various pathways. Such signaling modulates numerous essential cellular processes that occur during melanomagenesis, including proliferation and migration. GPCR-associated signaling in melanoma can be activated by the binding of paracrine factors to their receptors or directly by activating mutations. In this review, we present melanoma-associated alterations of GPCRs and their downstream signaling and discuss the various preclinical models used to evaluate new therapeutic approaches against GPCR activity in melanoma. Recent striking advances in our understanding of the structure, function, and regulation of GPCRs will undoubtedly broaden melanoma treatment options in the future.
Collapse
|
|
4
|
Naїja A, Merhi M, Inchakalody V, Fernandes Q, Mestiri S, Prabhu KS, Uddin S, Dermime S. The role of PAK4 in the immune system and its potential implication in cancer immunotherapy. Cell Immunol 2021; 367:104408. [PMID: 34246086 DOI: 10.1016/j.cellimm.2021.104408] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2021] [Revised: 06/27/2021] [Accepted: 06/28/2021] [Indexed: 01/06/2023]
Abstract
The p21 activated kinases (PAKs) are known to play a role in the regulation of cell morphology and functions. Among the various members of PAKs family, only the PAK4 protein has been shown to be overexpressed in cancer cells and its upregulation was associated with tumor development. Indeed, several studies have shown that PAK4 overexpression is implicated in carcinogenesis by different mechanisms including promotion of cell proliferation, invasion and migration, protection of cells from apoptosis, stimulation of the tumor-specific anchorage-independent cell growth and regulation of the cytoskeletal organisation and adhesion. Moreover, high PAK4 protein levels have been observed in several solid tumors and have been shown able to enhance cancer cell resistance to many treatments especially chemotherapy. Interestingly, it has been recently demonstrated that PAK4 downregulation can inhibit the PD-1/PD-L1 immune regulatory pathway. Taken together, these findings not only implicate PAK4 in oncogenic transformation and in prediction of tumor response to treatment but also suggest its role as an attractive target for immunotherapy. In the current review we will summarize the different mechanisms of PAK4 implication in tumor development, describe its role as a regulator of the immune response and as a potential novel target for cancer immunotherapy.
Collapse
Affiliation(s)
- Azza Naїja
- Translational Cancer Research Facility, Translational Research Institute, Hamad Medical Corporation, Doha, Qatar
| | - Maysaloun Merhi
- National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar; Translational Cancer Research Facility, Translational Research Institute, Hamad Medical Corporation, Doha, Qatar
| | - Varghese Inchakalody
- National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar; Translational Cancer Research Facility, Translational Research Institute, Hamad Medical Corporation, Doha, Qatar
| | - Queenie Fernandes
- National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar; Translational Cancer Research Facility, Translational Research Institute, Hamad Medical Corporation, Doha, Qatar; College of Medicine, Qatar University, Doha, Qatar
| | - Sarra Mestiri
- National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar; Translational Cancer Research Facility, Translational Research Institute, Hamad Medical Corporation, Doha, Qatar
| | - Kirti S Prabhu
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Shahab Uddin
- Translational Research Institute and Dermatology Institute, Academic health system, Hamad medical Corporation, Doha, Qatar
| | - Said Dermime
- National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar; Translational Cancer Research Facility, Translational Research Institute, Hamad Medical Corporation, Doha, Qatar; College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar.
| |
Collapse
|
|
5
|
Pinczewski J, Obeng RC, Slingluff CL, Engelhard VH. Phospho-β-catenin expression in primary and metastatic melanomas and in tumor-free visceral tissues, and associations with expression of PD-L1 and PD-L2. Pathol Res Pract 2021; 224:153527. [PMID: 34167064 PMCID: PMC8645338 DOI: 10.1016/j.prp.2021.153527] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 06/10/2021] [Accepted: 06/14/2021] [Indexed: 12/18/2022]
Abstract
β-catenin (βcat) is an important downstream effector in the Wnt signaling pathway and plays important roles in the development and progression of many cancers including melanoma. βcat expression is regulated by GSK-3β-mediated phosphorylation at positions 33, 37 and 41. In normal cells, phosphorylation at these sites triggers proteasomal degradation, which prevents accumulation of free cytoplasmic βcat. In cancer cells, stabilized β-catenin translocates into the nucleus, where it associates with TCF/Lef proteins to activate transcription of genes that promote tumorigenesis and metastasis, including PD-L1. It has been suggested that nuclear phospho-βcat (pβcat) staining may be diagnostically useful in differentiating primary from metastatic melanoma. Also, a pβcat peptide (residues 30-39, with only S33 phosphorylated) is naturally presented by melanoma cells as a T-cell target. We evaluated expression of pS33-βcat in primary and metastatic melanomas by immunohistochemistry and found its expression varied widely but was most commonly cytoplasmic. Nuclear staining was identified in only 18% of metastatic melanomas. Staining with antibodies to pS33-βcat and pS33/37/T41-βcat was most intense in mitotic melanoma cells; however, pS33-βcat intensity was not significantly associated with AJCC stage, tumor location, BRAF mutation status, or immune infiltrates. Yet, PD-L1 and PD-L2 expression by tumor cells were significantly higher in tumors with high pS33-βcat expression. The low rate of nuclear pS33-βcat expression suggests that pS33-βcat may have limited utility for identifying metastatic melanomas. However, high expression in dividing cells and strong associations with PD-L1 and PD-L2 expression may inform future personalized therapies for tumors with high pS33-βcat expression.
Collapse
Affiliation(s)
- Joel Pinczewski
- Department of Pathology, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Rebecca C Obeng
- Department of Microbiology, Immunology and Cancer Biology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA; Beirne Carter Center for Immunology Research, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
| | - Craig L Slingluff
- Beirne Carter Center for Immunology Research, University of Virginia School of Medicine, Charlottesville, VA 22908, USA; Department of Surgery, University of Virginia School of Medicine, Charlottesville, VA 22908, USA; UVA Cancer Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
| | - Victor H Engelhard
- Department of Microbiology, Immunology and Cancer Biology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA; Beirne Carter Center for Immunology Research, University of Virginia School of Medicine, Charlottesville, VA 22908, USA; UVA Cancer Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
| |
Collapse
|
|
6
|
Chao JT, Roskelley CD, Loewen CJR. MAPS: machine-assisted phenotype scoring enables rapid functional assessment of genetic variants by high-content microscopy. BMC Bioinformatics 2021; 22:202. [PMID: 33879063 PMCID: PMC8056608 DOI: 10.1186/s12859-021-04117-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Accepted: 04/02/2021] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Genetic testing is widely used in evaluating a patient's predisposition to hereditary diseases. In the case of cancer, when a functionally impactful mutation (i.e. genetic variant) is identified in a disease-relevant gene, the patient is at elevated risk of developing a lesion in their lifetime. Unfortunately, as the rate and coverage of genetic testing has accelerated, our ability to assess the functional status of new variants has fallen behind. Therefore, there is an urgent need for more practical, streamlined and cost-effective methods for classifying variants. RESULTS To directly address this issue, we designed a new approach that uses alterations in protein subcellular localization as a key indicator of loss of function. Thus, new variants can be rapidly functionalized using high-content microscopy (HCM). To facilitate the analysis of the large amounts of imaging data, we developed a new software toolkit, named MAPS for machine-assisted phenotype scoring, that utilizes deep learning to extract and classify cell-level features. MAPS helps users leverage cloud-based deep learning services that are easy to train and deploy to fit their specific experimental conditions. Model training is code-free and can be done with limited training images. Thus, MAPS allows cell biologists to easily incorporate deep learning into their image analysis pipeline. We demonstrated an effective variant functionalization workflow that integrates HCM and MAPS to assess missense variants of PTEN, a tumor suppressor that is frequently mutated in hereditary and somatic cancers. CONCLUSIONS This paper presents a new way to rapidly assess variant function using cloud deep learning. Since most tumor suppressors have well-defined subcellular localizations, our approach could be widely applied to functionalize variants of uncertain significance and help improve the utility of genetic testing.
Collapse
Affiliation(s)
- Jesse T Chao
- Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, V6T1Z3, Canada.
| | - Calvin D Roskelley
- Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, V6T1Z3, Canada
| | - Christopher J R Loewen
- Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, V6T1Z3, Canada
| |
Collapse
|
|
7
|
Cruz RGB, Madden SF, Richards CE, Vellanki SH, Jahns H, Hudson L, Fay J, O’Farrell N, Sheehan K, Jirström K, Brennan K, Hopkins AM. Human Epidermal Growth Factor Receptor-3 Expression Is Regulated at Transcriptional Level in Breast Cancer Settings by Junctional Adhesion Molecule-A via a Pathway Involving Beta-Catenin and FOXA1. Cancers (Basel) 2021; 13:cancers13040871. [PMID: 33669586 PMCID: PMC7922773 DOI: 10.3390/cancers13040871] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 02/08/2021] [Accepted: 02/15/2021] [Indexed: 01/29/2023] Open
Abstract
Simple Summary Signaling from the human epidermal growth factor receptor (HER) family of proteins increases in many cancers, including breast. HER2-high breast cancers are successfully treated with anti-HER2 therapies, but these drugs are limited by the fact that patients frequently develop resistance to them. One common mechanism by which resistance develops is when tumors acquire high levels of a family member called HER3. We had previously shown that a protein called JAM-A regulates the level of HER2 in breast cancer cells, and is associated with the development of resistance to HER2-targeted therapies. In this study we show for the first time that JAM-A levels also regulate those of HER3. Using breast cancer cell and tissue models and culminating in patient tissue material, we provide evidence that JAM-A regulates HER3 expression via a pathway involving the transcription factors β-catenin and FOXA1. We suggest that JAM-A merits future investigation as a novel drug target for its potential to reduce HER3 tumorigenic signaling and to offset the development of resistance to HER2-targeted therapies. Abstract The success of breast cancer therapies targeting the human epidermal growth factor receptor-2 (HER2) is limited by the development of drug resistance by mechanisms including upregulation of HER3. Having reported that HER2 expression and resistance to HER2-targeted therapies can be regulated by Junctional Adhesion Molecule-A (JAM-A), this study investigated if JAM-A regulates HER3 expression. Expressional alteration of JAM-A in breast cancer cells was used to test expressional effects on HER3 and its effectors, alongside associated functional behaviors, in vitro and semi-in vivo. HER3 transcription factors were identified and tested for regulation by JAM-A. Finally a patient tissue microarray was used to interrogate connections between putative pathway components connecting JAM-A and HER3. This study reveals for the first time that HER3 and its effectors are regulated at gene/protein expression level by JAM-A in breast cancer cell lines; with functional consequences in in vitro and semi-in vivo models. In bioinformatic, cellular and patient tissue models, this was associated with regulation of the HER3 transcription factor FOXA1 by JAM-A via a pathway involving β-catenin. Our data suggest a novel model whereby JAM-A expression regulates β-catenin localization, in turn regulating FOXA1 expression, which could drive HER3 gene transcription. JAM-A merits investigation as a novel target to prevent upregulation of HER3 during the development of resistance to HER2-targeted therapies, or to reduce HER3-dependent tumorigenic signaling.
Collapse
Affiliation(s)
- Rodrigo G. B. Cruz
- Department of Surgery, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland; (R.G.B.C.); (C.E.R.); (S.H.V.); (L.H.); (K.B.)
| | - Stephen F. Madden
- Data Science Centre, Royal College of Surgeons in Ireland, Dublin 2, Ireland;
| | - Cathy E. Richards
- Department of Surgery, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland; (R.G.B.C.); (C.E.R.); (S.H.V.); (L.H.); (K.B.)
| | - Sri HariKrishna Vellanki
- Department of Surgery, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland; (R.G.B.C.); (C.E.R.); (S.H.V.); (L.H.); (K.B.)
| | - Hanne Jahns
- Pathobiology Section, UCD School of Veterinary Medicine, University College Dublin, Dublin 4, Ireland;
| | - Lance Hudson
- Department of Surgery, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland; (R.G.B.C.); (C.E.R.); (S.H.V.); (L.H.); (K.B.)
| | - Joanna Fay
- Department of Pathology, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland; (J.F.); (N.O.); (K.S.)
| | - Naoimh O’Farrell
- Department of Pathology, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland; (J.F.); (N.O.); (K.S.)
| | - Katherine Sheehan
- Department of Pathology, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland; (J.F.); (N.O.); (K.S.)
| | - Karin Jirström
- Department of Clinical Sciences Lund, Division of Oncology and Therapeutic Pathology, Lund University, SE 221 85 Lund, Sweden;
| | - Kieran Brennan
- Department of Surgery, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland; (R.G.B.C.); (C.E.R.); (S.H.V.); (L.H.); (K.B.)
| | - Ann M. Hopkins
- Department of Surgery, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland; (R.G.B.C.); (C.E.R.); (S.H.V.); (L.H.); (K.B.)
- Correspondence: ; Tel.: +353-1-809-3858
| |
Collapse
|
|
8
|
Bellei B, Migliano E, Picardo M. A Framework of Major Tumor-Promoting Signal Transduction Pathways Implicated in Melanoma-Fibroblast Dialogue. Cancers (Basel) 2020; 12:cancers12113400. [PMID: 33212834 PMCID: PMC7697272 DOI: 10.3390/cancers12113400] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 11/11/2020] [Accepted: 11/13/2020] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Melanoma cells reside in a complex stromal microenvironment, which is a critical component of disease onset and progression. Mesenchymal or fibroblastic cell type are the most abundant cellular element of tumor stroma. Factors secreted by melanoma cells can activate non-malignant associated fibroblasts to become melanoma associate fibroblasts (MAFs). MAFs promote tumorigenic features by remodeling the extracellular matrix, supporting tumor cells proliferation, neo-angiogenesis and drug resistance. Additionally, environmental factors may contribute to the acquisition of pro-tumorigenic phenotype of fibroblasts. Overall, in melanoma, perturbed tissue homeostasis contributes to modulation of major oncogenic intracellular signaling pathways not only in tumor cells but also in neighboring cells. Thus, targeted molecular therapies need to be considered from the reciprocal point of view of melanoma and stromal cells. Abstract The development of a modified stromal microenvironment in response to neoplastic onset is a common feature of many tumors including cutaneous melanoma. At all stages, melanoma cells are embedded in a complex tissue composed by extracellular matrix components and several different cell populations. Thus, melanomagenesis is not only driven by malignant melanocytes, but also by the altered communication between melanocytes and non-malignant cell populations, including fibroblasts, endothelial and immune cells. In particular, cancer-associated fibroblasts (CAFs), also referred as melanoma-associated fibroblasts (MAFs) in the case of melanoma, are the most abundant stromal cells and play a significant contextual role in melanoma initiation, progression and metastasis. As a result of dynamic intercellular molecular dialogue between tumor and the stroma, non-neoplastic cells gain specific phenotypes and functions that are pro-tumorigenic. Targeting MAFs is thus considered a promising avenue to improve melanoma therapy. Growing evidence demonstrates that aberrant regulation of oncogenic signaling is not restricted to transformed cells but also occurs in MAFs. However, in some cases, signaling pathways present opposite regulation in melanoma and surrounding area, suggesting that therapeutic strategies need to carefully consider the tumor–stroma equilibrium. In this novel review, we analyze four major signaling pathways implicated in melanomagenesis, TGF-β, MAPK, Wnt/β-catenin and Hyppo signaling, from the complementary point of view of tumor cells and the microenvironment.
Collapse
Affiliation(s)
- Barbara Bellei
- Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, 00144 Rome, Italy;
- Correspondence: ; Tel.: +39-0652666246
| | - Emilia Migliano
- Department of Plastic and Regenerative Surgery, San Gallicano Dermatological Institute, IRCCS, 00144 Rome, Italy;
| | - Mauro Picardo
- Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, 00144 Rome, Italy;
| |
Collapse
|
|
9
|
Cinobufagin Suppresses Melanoma Cell Growth by Inhibiting LEF1. Int J Mol Sci 2020; 21:ijms21186706. [PMID: 32933177 PMCID: PMC7554883 DOI: 10.3390/ijms21186706] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 09/09/2020] [Accepted: 09/11/2020] [Indexed: 02/07/2023] Open
Abstract
Constitutive activation of the β-catenin dependent canonical Wnt signaling pathway, which enhances tumor growth and progression in multiple types of cancer, is commonly observed in melanoma. LEF1 activates β-catenin/TCF4 transcriptional activity, promoting tumor growth and progression. Although several reports have shown that LEF1 is highly expressed in melanoma, the functional role of LEF1 in melanoma growth is not fully understood. While A375, A2058, and G361 melanoma cells exhibit abnormally high LEF1 expression, lung cancer cells express lower LEF1 levels. A luciferase assay-based high throughput screening (HTS) with a natural compound library showed that cinobufagin suppressed β-catenin/TCF4 transcriptional activity by inhibiting LEF1 expression. Cinobufagin decreases LEF1 expression in a dose-dependent manner and Wnt/β-catenin target genes such as Axin-2, cyclin D1, and c-Myc in melanoma cell lines. Cinobufagin sensitively attenuates cell viability and induces apoptosis in LEF1 expressing melanoma cells compared to LEF1-low expressing lung cancer cells. In addition, ectopic LEF1 expression is sufficient to attenuate cinobufagin-induced apoptosis and cell growth retardation in melanoma cells. Thus, we suggest that cinobufagin is a potential anti-melanoma drug that suppresses tumor-promoting Wnt/β-catenin signaling via LEF1 inhibition.
Collapse
|
|
10
|
Gajos-Michniewicz A, Czyz M. WNT Signaling in Melanoma. Int J Mol Sci 2020; 21:E4852. [PMID: 32659938 PMCID: PMC7402324 DOI: 10.3390/ijms21144852] [Citation(s) in RCA: 146] [Impact Index Per Article: 29.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 07/06/2020] [Accepted: 07/07/2020] [Indexed: 12/12/2022] Open
Abstract
WNT-signaling controls important cellular processes throughout embryonic development and adult life, so any deregulation of this signaling can result in a wide range of pathologies, including cancer. WNT-signaling is classified into two categories: β-catenin-dependent signaling (canonical pathway) and β-catenin-independent signaling (non-canonical pathway), the latter can be further divided into WNT/planar cell polarity (PCP) and calcium pathways. WNT ligands are considered as unique directional growth factors that contribute to both cell proliferation and polarity. Origin of cancer can be diverse and therefore tissue-specific differences can be found in WNT-signaling between cancers, including specific mutations contributing to cancer development. This review focuses on the role of the WNT-signaling pathway in melanoma. The current view on the role of WNT-signaling in cancer immunity as well as a short summary of WNT pathway-related drugs under investigation are also provided.
Collapse
Affiliation(s)
| | - Malgorzata Czyz
- Department of Molecular Biology of Cancer, Medical University of Lodz, 6/8 Mazowiecka Street, 92–215 Lodz, Poland;
| |
Collapse
|
|
11
|
Kato S, Weng QY, Insco ML, Chen KY, Muralidhar S, Pozniak J, Diaz JMS, Drier Y, Nguyen N, Lo JA, van Rooijen E, Kemeny LV, Zhan Y, Feng Y, Silkworth W, Powell CT, Liau BB, Xiong Y, Jin J, Newton-Bishop J, Zon LI, Bernstein BE, Fisher DE. Gain-of-Function Genetic Alterations of G9a Drive Oncogenesis. Cancer Discov 2020; 10:980-997. [PMID: 32269030 PMCID: PMC7334057 DOI: 10.1158/2159-8290.cd-19-0532] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Revised: 02/05/2020] [Accepted: 04/03/2020] [Indexed: 11/16/2022]
Abstract
Epigenetic regulators, when genomically altered, may become driver oncogenes that mediate otherwise unexplained pro-oncogenic changes lacking a clear genetic stimulus, such as activation of the WNT/β-catenin pathway in melanoma. This study identifies previously unrecognized recurrent activating mutations in the G9a histone methyltransferase gene, as well as G9a genomic copy gains in approximately 26% of human melanomas, which collectively drive tumor growth and an immunologically sterile microenvironment beyond melanoma. Furthermore, the WNT pathway is identified as a key tumorigenic target of G9a gain-of-function, via suppression of the WNT antagonist DKK1. Importantly, genetic or pharmacologic suppression of mutated or amplified G9a using multiple in vitro and in vivo models demonstrates that G9a is a druggable target for therapeutic intervention in melanoma and other cancers harboring G9a genomic aberrations. SIGNIFICANCE: Oncogenic G9a abnormalities drive tumorigenesis and the "cold" immune microenvironment by activating WNT signaling through DKK1 repression. These results reveal a key druggable mechanism for tumor development and identify strategies to restore "hot" tumor immune microenvironments.This article is highlighted in the In This Issue feature, p. 890.
Collapse
Affiliation(s)
- Shinichiro Kato
- Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts
| | - Qing Yu Weng
- Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts
| | - Megan L Insco
- Howard Hughes Medical Institute, Chevy Chase, Maryland
- Stem Cell Program and Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
- Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Cambridge, Massachusetts
| | - Kevin Y Chen
- Howard Hughes Medical Institute, Chevy Chase, Maryland
- Stem Cell Program and Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
- Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Cambridge, Massachusetts
| | - Sathya Muralidhar
- Institute of Medical Research at St James's, University of Leeds, Leeds, United Kingdom
| | - Joanna Pozniak
- Institute of Medical Research at St James's, University of Leeds, Leeds, United Kingdom
| | - Joey Mark S Diaz
- Institute of Medical Research at St James's, University of Leeds, Leeds, United Kingdom
| | - Yotam Drier
- Center for Cancer Research, Massachusetts General Hospital, Boston, Massachusetts
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | - Nhu Nguyen
- Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts
| | - Jennifer A Lo
- Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts
| | - Ellen van Rooijen
- Howard Hughes Medical Institute, Chevy Chase, Maryland
- Stem Cell Program and Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
| | - Lajos V Kemeny
- Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts
| | - Yao Zhan
- Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts
| | - Yang Feng
- Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts
| | - Whitney Silkworth
- Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts
| | - C Thomas Powell
- Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts
| | - Brian B Liau
- Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts
| | - Yan Xiong
- Mount Sinai Center for Therapeutics Discovery, Department of Pharmaceutical Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Jian Jin
- Mount Sinai Center for Therapeutics Discovery, Department of Pharmaceutical Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Julia Newton-Bishop
- Institute of Medical Research at St James's, University of Leeds, Leeds, United Kingdom
| | - Leonard I Zon
- Howard Hughes Medical Institute, Chevy Chase, Maryland
- Stem Cell Program and Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
| | - Bradley E Bernstein
- Center for Cancer Research, Massachusetts General Hospital, Boston, Massachusetts
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | - David E Fisher
- Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts.
| |
Collapse
|
|
12
|
Patel SB, McCormack C, Hodge JC. Non-fusion mutations in endometrial stromal sarcomas: what is the potential impact on tumourigenesis through cell cycle dysregulation? J Clin Pathol 2020; 73:830-835. [PMID: 32385140 DOI: 10.1136/jclinpath-2020-206432] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Revised: 03/30/2020] [Accepted: 04/23/2020] [Indexed: 12/13/2022]
Abstract
Targeted next-generation sequencing using the 50-gene Ion AmpliSeq Cancer Hotspot Panel v2 identified two significant point mutations in endometrial stromal sarcomas (ESS). Case 1 is a uterine mass from a quadragenarian woman with a karyotype lacking any known ESS rearrangements but demonstrated to have a CTNNB1-activating mutation (c.133T>C, p.[Ser45Pro]). Analysis of a uterine mass from case 2, a sexagenarian woman, revealed biallelic CDKN2A-inactivating mutations (c.172C>T, p.[Arg58Ter] and a deletion). Break-apart studies to identify YWHAE, JAZF1 and PHF1 rearrangements were negative in both tumours. We propose a model in which these point mutations may affect cell proliferation, converging at Wnt signalling and G1-S checkpoint control, that independently or in concert with a rare gene fusion result in ESS tumour development or progression.
Collapse
Affiliation(s)
- Snehal B Patel
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA.,Molecular Diagnostics Section, Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.,Strata Oncology, Ann Arbor, MI, United States
| | - Colin McCormack
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA.,Baylor Scott & White Medical Center-Temple, Temple, TX, United States
| | - Jennelle C Hodge
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA .,Department of Medical and Molecular Genetics, Indiana University, Indianapolis, IN, USA.,Department of Pediatrics, University of California Los Angeles, Los Angeles, CA, United States
| |
Collapse
|
|
13
|
Wnt Signaling in Neural Crest Ontogenesis and Oncogenesis. Cells 2019; 8:cells8101173. [PMID: 31569501 PMCID: PMC6829301 DOI: 10.3390/cells8101173] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Revised: 09/23/2019] [Accepted: 09/25/2019] [Indexed: 02/06/2023] Open
Abstract
Neural crest (NC) cells are a temporary population of multipotent stem cells that generate a diverse array of cell types, including craniofacial bone and cartilage, smooth muscle cells, melanocytes, and peripheral neurons and glia during embryonic development. Defective neural crest development can cause severe and common structural birth defects, such as craniofacial anomalies and congenital heart disease. In the early vertebrate embryos, NC cells emerge from the dorsal edge of the neural tube during neurulation and then migrate extensively throughout the anterior-posterior body axis to generate numerous derivatives. Wnt signaling plays essential roles in embryonic development and cancer. This review summarizes current understanding of Wnt signaling in NC cell induction, delamination, migration, multipotency, and fate determination, as well as in NC-derived cancers.
Collapse
|
|
14
|
Molecular background of skin melanoma development and progression: therapeutic implications. Postepy Dermatol Alergol 2019; 36:129-138. [PMID: 31320844 PMCID: PMC6627250 DOI: 10.5114/ada.2019.84590] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Accepted: 02/18/2018] [Indexed: 12/19/2022] Open
Abstract
Melanoma is the most aggressive skin cancer with an increasing number of cases worldwide and curable mostly in its early stage. The improvement in patients' survival in advanced melanoma has been achieved only recently, due to development of new biological drugs for targeted therapies and immunotherapy. Further progress in the treatment of melanoma is clearly dependent on the better understanding of its complex biology. This review describes the most important molecular mechanisms and genetic events underlying skin melanoma development and progression, depicts the way of action of newly developed drugs and indicates new potential therapeutic targets.
Collapse
|
|
15
|
Krajnović T, Drača D, Kaluđerović GN, Dunđerović D, Mirkov I, Wessjohann LA, Maksimović-Ivanić D, Mijatović S. The hop-derived prenylflavonoid isoxanthohumol inhibits the formation of lung metastasis in B16-F10 murine melanoma model. Food Chem Toxicol 2019; 129:257-268. [PMID: 31034931 DOI: 10.1016/j.fct.2019.04.046] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2018] [Revised: 04/13/2019] [Accepted: 04/25/2019] [Indexed: 12/22/2022]
Abstract
Isoxanthohumol (IXN), a prenylflavonoid from hops and beer, gained increasing attention as a potential chemopreventive agent. In the present study, IXN antimetastatic potential in vitro against the highly invasive melanoma cell line B16-F10 and in vivo in a murine metastatic model was investigated. Melanoma cell viability was diminished in a dose-dependent manner following the treatment with IXN. This decrease was a consequence of autophagy and caspase-dependent apoptosis. Additionally, the dividing potential of highly proliferative melanoma cells was dramatically affected by this isoflavanone, which was in correlation with an abrogated cell colony forming potential, indicating changes in their metastatic features. Concordantly, IXN promoted strong suppression of the processes that define metastasis- cell adhesion, invasion, and migration. Further investigation at the molecular level revealed that the abolished metastatic potential of a melanoma subclone was due to disrupted integrin signaling. Importantly, these results were reaffirmed in vivo where IXN inhibited the development of lung metastatic foci in tumor-challenged animals. The results of the present study may highlight the beneficial effects of IXN on melanoma as the most aggressive type of skin cancer and will hopefully shed a light on the possible use of this prenylflavonoid in the treatment of metastatic malignancies.
Collapse
Affiliation(s)
- Tamara Krajnović
- Department of Immunology, Institute for Biological Research "Siniša Stanković", University of Belgrade, Bulevar despota Stefana 142, 11060, Belgrade, Serbia.
| | - Dijana Drača
- Department of Immunology, Institute for Biological Research "Siniša Stanković", University of Belgrade, Bulevar despota Stefana 142, 11060, Belgrade, Serbia.
| | - Goran N Kaluđerović
- Department of Bioorganic Chemistry, Leibniz-Institute of Plant Biochemistry, Weinberg 3, D 06120, Halle (Saale), Germany.
| | - Duško Dunđerović
- Institute of Pathology, School of Medicine, University of Belgrade, dr Subotića 1, 11000, Belgrade, Serbia.
| | - Ivana Mirkov
- Department of Immunology, Institute for Biological Research "Siniša Stanković", University of Belgrade, Bulevar despota Stefana 142, 11060, Belgrade, Serbia.
| | - Ludger A Wessjohann
- Department of Bioorganic Chemistry, Leibniz-Institute of Plant Biochemistry, Weinberg 3, D 06120, Halle (Saale), Germany.
| | - Danijela Maksimović-Ivanić
- Department of Immunology, Institute for Biological Research "Siniša Stanković", University of Belgrade, Bulevar despota Stefana 142, 11060, Belgrade, Serbia.
| | - Sanja Mijatović
- Department of Immunology, Institute for Biological Research "Siniša Stanković", University of Belgrade, Bulevar despota Stefana 142, 11060, Belgrade, Serbia.
| |
Collapse
|
|
16
|
Leonardi GC, Falzone L, Salemi R, Zanghì A, Spandidos DA, McCubrey JA, Candido S, Libra M. Cutaneous melanoma: From pathogenesis to therapy (Review). Int J Oncol 2018; 52:1071-1080. [PMID: 29532857 PMCID: PMC5843392 DOI: 10.3892/ijo.2018.4287] [Citation(s) in RCA: 253] [Impact Index Per Article: 36.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2017] [Accepted: 02/08/2018] [Indexed: 02/07/2023] Open
Abstract
In less than 10 years, melanoma treatment has been revolutionized with the approval of tyrosine kinase inhibitors and immune checkpoint inhibitors, which have been shown to have a significant impact on the prognosis of patients with melanoma. The early steps of this transformation have taken place in research laboratories. The mitogen‑activated protein kinase (MAPK) pathway, phosphoinositol‑3‑kinase (PI3K) pathway promote the development of melanoma through numerous genomic alterations on different components of these pathways. Moreover, melanoma cells deeply interact with the tumor microenvironment and the immune system. This knowledge has led to the identification of novel therapeutic targets and treatment strategies. In this review, the epidemiological features of cutaneous melanoma along with the biological mechanisms involved in its development and progression are summarized. The current state‑of‑the‑art of advanced stage melanoma treatment strategies and the currently available evidence of the use of predictive and prognostic biomarkers are also discussed.
Collapse
Affiliation(s)
- Giulia C. Leonardi
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania
| | - Luca Falzone
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania
| | - Rossella Salemi
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania
| | - Antonino Zanghì
- Department of Medical and Surgical Sciences and Advanced Technology 'G.F. Ingrassia', University of Catania, 95125 Catania, Italy
| | - Demetrios A. Spandidos
- Laboratory of Clinical Virology, Medical School, University of Crete, 71003 Heraklion, Crete, Greece
| | - James A. McCubrey
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC 27858, USA
| | - Saverio Candido
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania
| | - Massimo Libra
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania
- Research Center of Tumor Prevention, Diagnosis and Cure (CRS PreDiCT), University of Catania, 95123 Catania, Italy
| |
Collapse
|
|
17
|
Kovacs D, Migliano E, Muscardin L, Silipo V, Catricalà C, Picardo M, Bellei B. The role of Wnt/β-catenin signaling pathway in melanoma epithelial-to-mesenchymal-like switching: evidences from patients-derived cell lines. Oncotarget 2017; 7:43295-43314. [PMID: 27175588 PMCID: PMC5190024 DOI: 10.18632/oncotarget.9232] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2015] [Accepted: 04/10/2016] [Indexed: 12/13/2022] Open
Abstract
Deregulations or mutations of WNT/β-catenin signaling have been associated to both tumour formation and progression. However, contradictory results concerning the role of β-catenin in human melanoma address an open question on its oncogenic nature and prognostic value in this tumour. Changes in WNT signaling pathways have been linked to phenotype switching of melanoma cells between a highly proliferative/non-invasive and a slow proliferative/metastatic condition. We used a novel panel of cell lines isolated from melanoma specimens, at initial passages, to investigate phenotype differences related to the levels and activity of WNT/β-catenin signaling pathway. This in vitro cell system revealed a marked heterogeneity that comprises, in some cases, two distinct tumour-derived subpopulations of cells presenting a different activation level and cellular distribution of β-catenin. In cells derived from the same tumor, we demonstrated that the prevalence of LEF1 (high β-catenin expressing cells) or TCF4 (low β-catenin expressing cells) as β-catenin partner for DNA binding, is associated to the expression of two distinct profiles of WNT-responsive genes. Interestingly, melanoma cells expressing relative low level of β-catenin and an invasive markers signature were associated to the TNF-α-induced pro-inflammatory pathway and to the chemotherapy resistance, suggesting that the co-existence of melanoma subpopulations with distinct biological properties could influence the impact of chemo- and immunotherapy.
Collapse
Affiliation(s)
- Daniela Kovacs
- Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatologic Institute, IRCCS, Rome, Italy
| | - Emilia Migliano
- Department of Plastic and Reconstructive Surgery, San Gallicano Dermatologic Institute, IRCCS, Rome, Italy
| | - Luca Muscardin
- Dermatopathological Laboratory, San Gallicano Dermatologic Institute, IRCCS, Rome, Italy
| | - Vitaliano Silipo
- Department of Oncologic Dermatology, San Gallicano Dermatologic Institute, IRCCS, Rome, Italy
| | - Caterina Catricalà
- Department of Oncologic Dermatology, San Gallicano Dermatologic Institute, IRCCS, Rome, Italy
| | - Mauro Picardo
- Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatologic Institute, IRCCS, Rome, Italy
| | - Barbara Bellei
- Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatologic Institute, IRCCS, Rome, Italy
| |
Collapse
|
|
18
|
Kundu A, Khouri MG, Aryana S, Firestone GL. 1-Benzyl-indole-3-carbinol is a highly potent new small molecule inhibitor of Wnt/β-catenin signaling in melanoma cells that coordinately inhibits cell proliferation and disrupts expression of microphthalmia-associated transcription factor isoform-M. Carcinogenesis 2017; 38:1207-1217. [PMID: 29028954 DOI: 10.1093/carcin/bgx103] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2016] [Accepted: 09/19/2017] [Indexed: 11/15/2022] Open
Abstract
1-Benzyl-indole-3-carbinol (1-benzyl-I3C), a synthetic analogue of the crucifer-derived natural phytochemical I3C, displayed significantly wider sensitivity and anti-proliferative potency in melanoma cells than the natural compound. Unlike I3C, which targets mainly oncogenic BRAF-expressing cells, 1-benzyl-I3C effectively inhibited proliferation of melanoma cells with a more extensive range of mutational profiles, including those expressing wild-type BRAF. In both cultured melanoma cell lines and in vivo in melanoma cell-derived tumor xenografts, 1-benzyl-I3C disrupted canonical Wnt/β-catenin signaling that resulted in the downregulation of β-catenin protein levels with a concomitant increase in levels of the β-catenin destruction complex components such as glycogen synthase kinase-3β (GSK-3β) and Axin. Concurrent with the inhibition of Wnt/β-catenin signaling, 1-benzyl-I3C strongly downregulated expression of the melanoma master regulator, microphthalmia-associated transcription factor isoform-M (MITF-M) by inhibiting promoter activity through the consensus lymphoid enhancer factor-1 (LEF-1)/T-cell transcription factor (TCF) DNA-binding site. Chromatin immunoprecipitation revealed that 1-benzyl-I3C downregulated interactions of endogenous LEF-1 with the MITF-M promoter. 1-Benzyl-I3C ablated Wnt-activated LEF-1-dependent reporter gene activity in a TOP FLASH assay that was rescued by expression of a constitutively active form of the Wnt co-receptor low-density lipoprotein receptor-related protein (LRP6), indicating that 1-benzyl-I3C disrupts Wnt/β-catenin signaling at or upstream of LRP6. In oncogenic BRAF-expressing melanoma cells, combinations of 1-benzyl-I3C and Vemurafenib, a clinically employed BRAF inhibitor, showed strong anti-proliferative effects. Taken together, our observations demonstrate that 1-benzyl-I3C represents a new and highly potent indolecarbinol-based small molecule inhibitor of Wnt/β-catenin signaling that has intriguing translational potential, alone or in combination with other anti-cancer agents, to treat human melanoma.
Collapse
Affiliation(s)
- Aishwarya Kundu
- Department of Molecular and Cell Biology and the Cancer Research Laboratory, University of California at Berkeley, USA
| | - Michelle G Khouri
- Department of Molecular and Cell Biology and the Cancer Research Laboratory, University of California at Berkeley, USA
| | - Sheila Aryana
- Department of Molecular and Cell Biology and the Cancer Research Laboratory, University of California at Berkeley, USA
| | | |
Collapse
|
|
19
|
Stueven NA, Schlaeger NM, Monte AP, Hwang SPL, Huang CC. A novel stilbene-like compound that inhibits melanoma growth by regulating melanocyte differentiation and proliferation. Toxicol Appl Pharmacol 2017; 337:30-38. [PMID: 29042215 DOI: 10.1016/j.taap.2017.10.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2017] [Revised: 10/12/2017] [Accepted: 10/13/2017] [Indexed: 02/07/2023]
Abstract
Melanoma is the most aggressive form of skin cancer. Current challenges to melanoma therapy include the adverse effects from immunobiologics, resistance to drugs targeting the MAPK pathway, intricate interaction of many signal pathways, and cancer heterogeneity. Thus combinational therapy with drugs targeting multiple signaling pathways becomes a new promising therapy. Here, we report a family of stilbene-like compounds called A11 that can inhibit melanoma growth in both melanoma-forming zebrafish embryos and mouse melanoma cells. The growth inhibition by A11 is a result of mitosis reduction but not apoptosis enhancement. Meanwhile, A11 activates both MAPK and Akt signaling pathways. Many A11-treated mouse melanoma cells exhibit morphological changes and resemble normal melanocytes. Furthermore, we found that A11 causes down-regulation of melanocyte differentiation genes, including Pax3 and MITF. Together, our results suggest that A11 could be a new melanoma therapeutic agent by inhibiting melanocyte differentiation and proliferation.
Collapse
Affiliation(s)
- Noah A Stueven
- Biology Department, University of Wisconsin-River Falls, River Falls, WI 54022, United States
| | - Nicholas M Schlaeger
- Biology Department, University of Wisconsin-River Falls, River Falls, WI 54022, United States
| | - Aaron P Monte
- Department of Chemistry and Biochemistry, University of Wisconsin-La Crosse, La Crosse, WI 54601, United States
| | - Sheng-Ping L Hwang
- Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 115, Taiwan
| | - Cheng-Chen Huang
- Biology Department, University of Wisconsin-River Falls, River Falls, WI 54022, United States.
| |
Collapse
|
|
20
|
Szczepaniak Sloane RA, Gopalakrishnan V, Reddy SM, Zhang X, Reuben A, Wargo JA. Interaction of molecular alterations with immune response in melanoma. Cancer 2017; 123:2130-2142. [PMID: 28543700 DOI: 10.1002/cncr.30681] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2016] [Revised: 02/10/2017] [Accepted: 02/21/2017] [Indexed: 01/01/2023]
Abstract
Major advances have been made in melanoma treatment with the use of molecularly targeted therapies and immunotherapies, and numerous regimens are now approved by the US Food and Drug Administration for patients with stage IV disease. However, therapeutic resistance remains an issue to both classes of agents, and reliable biomarkers of therapeutic response and resistance are lacking. Mechanistic insights are being gained through preclinical studies and translational research, offering potential strategies to enhance responses and survival in treated patients. A comprehensive understanding of the immune effects of common mutations at play in melanoma is critical, as is an appreciation of the molecular mechanisms contributing to therapeutic resistance to immunotherapy. These mechanisms and the interplay between them are discussed herein. Cancer 2017;123:2130-42. © 2017 American Cancer Society.
Collapse
Affiliation(s)
| | | | - Sangeetha M Reddy
- Department of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Xue Zhang
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Alexandre Reuben
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jennifer A Wargo
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.,Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| |
Collapse
|
|
21
|
Shi Q, Liu H, Han P, Li C, Wang Y, Wu W, Zhu D, Amos CI, Fang S, Lee JE, Han J, Wei Q. Genetic Variants in WNT2B and BTRC Predict Melanoma Survival. J Invest Dermatol 2017; 137:1749-1756. [PMID: 28499756 PMCID: PMC5548422 DOI: 10.1016/j.jid.2017.04.023] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Revised: 04/01/2017] [Accepted: 04/23/2017] [Indexed: 12/12/2022]
Abstract
Cutaneous melanoma (CM) is the most lethal skin cancer. The Wnt pathway has an impact on development, invasion, and metastasis of CM, thus likely affecting CM prognosis. Using data from a published genome-wide association study from The University of Texas MD Anderson Cancer Center, we assessed the associations of 19,830 common single-nucleotide polymorphisms (SNPs) in 151 Wnt pathway autosomal genes with CM-specific survival and then validated significant SNPs in another genome-wide association study from Harvard University. In the single-locus analysis, 1,855 SNPs were significantly associated with CM-specific survival at P < 0.05, of which 547 SNPs were still considered noteworthy after the correction by the false-positive report probability. In the replication, two SNPs remained significantly associated with CM-specific survival after multiple comparison correction. By performing functional prediction and stepwise selection, we identified two independent SNPs (i.e., WNT2B rs1175649 G>T and BTRC rs61873997 G>A) that showed a predictive role in CM-specific survival, with an effect-allele-attributed hazards ratio (adjusted hazards ratio) of 1.99 (95% confidence interval = 1.41-2.81, P = 8.10 × 10-5) and 0.61 (0.46-0.80, 3.12×10-4), respectively. Collectively, these variants in the Wnt pathway genes may be biomarkers for outcomes of patients with CM, if validated by larger studies.
Collapse
Affiliation(s)
- Qiong Shi
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China; Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina, USA; Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA
| | - Hongliang Liu
- Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina, USA; Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA
| | - Peng Han
- Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina, USA; Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA; Department of Otorhinolaryngology Head and Neck Surgery, First Affiliated Hospital, Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi, China
| | - Chunying Li
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Yanru Wang
- Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina, USA; Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA
| | - Wenting Wu
- Department of Epidemiology, Fairbanks School of Public Health, Indiana University Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis, Indiana, USA
| | - Dakai Zhu
- Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire, USA
| | - Christopher I Amos
- Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire, USA
| | - Shenying Fang
- Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA
| | - Jeffrey E Lee
- Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA
| | - Jiali Han
- Department of Epidemiology, Fairbanks School of Public Health, Indiana University Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis, Indiana, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
| | - Qingyi Wei
- Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina, USA; Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA.
| |
Collapse
|
|
22
|
Melanocytic nevi and melanoma: unraveling a complex relationship. Oncogene 2017; 36:5771-5792. [PMID: 28604751 DOI: 10.1038/onc.2017.189] [Citation(s) in RCA: 132] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Revised: 05/09/2017] [Accepted: 05/10/2017] [Indexed: 12/11/2022]
Abstract
Approximately 33% of melanomas are derived directly from benign, melanocytic nevi. Despite this, the vast majority of melanocytic nevi, which typically form as a result of BRAFV600E-activating mutations, will never progress to melanoma. Herein, we synthesize basic scientific insights and data from mouse models with common observations from clinical practice to comprehensively review melanocytic nevus biology. In particular, we focus on the mechanisms by which growth arrest is established after BRAFV600E mutation. Means by which growth arrest can be overcome and how melanocytic nevi relate to melanoma are also considered. Finally, we present a new conceptual paradigm for understanding the growth arrest of melanocytic nevi in vivo termed stable clonal expansion. This review builds upon the canonical hypothesis of oncogene-induced senescence in growth arrest and tumor suppression in melanocytic nevi and melanoma.
Collapse
|
|
23
|
Bertrand JU, Petit V, Hacker E, Berlin I, Hayward NK, Pouteaux M, Sage E, Whiteman DC, Larue L. UVB represses melanocyte cell migration and acts through β-catenin. Exp Dermatol 2017; 26:875-882. [DOI: 10.1111/exd.13318] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/08/2017] [Indexed: 12/20/2022]
Affiliation(s)
- Juliette U. Bertrand
- Institut Curie; PSL Research University; INSERM U1021; Normal and Pathological Development of Melanocytes; Orsay France
- Univ Paris-Sud; Univ Paris-Saclay; CNRS UMR 3347; Orsay France
- Equipe Labellisée Ligue Contre le Cancer; Orsay France
| | - Valérie Petit
- Institut Curie; PSL Research University; INSERM U1021; Normal and Pathological Development of Melanocytes; Orsay France
- Univ Paris-Sud; Univ Paris-Saclay; CNRS UMR 3347; Orsay France
- Equipe Labellisée Ligue Contre le Cancer; Orsay France
| | - Elke Hacker
- Queensland Institute of Medical Research; Brisbane QLD Australia
| | - Irina Berlin
- Institut Curie; PSL Research University; INSERM U1021; Normal and Pathological Development of Melanocytes; Orsay France
- Univ Paris-Sud; Univ Paris-Saclay; CNRS UMR 3347; Orsay France
- Equipe Labellisée Ligue Contre le Cancer; Orsay France
| | | | - Marie Pouteaux
- Institut Curie; PSL Research University; INSERM U1021; Normal and Pathological Development of Melanocytes; Orsay France
- Univ Paris-Sud; Univ Paris-Saclay; CNRS UMR 3347; Orsay France
- Equipe Labellisée Ligue Contre le Cancer; Orsay France
| | - Evelyne Sage
- Institut Curie; PSL Research University; INSERM U1021; Normal and Pathological Development of Melanocytes; Orsay France
- Univ Paris-Sud; Univ Paris-Saclay; CNRS UMR 3347; Orsay France
- Equipe Labellisée Ligue Contre le Cancer; Orsay France
| | | | - Lionel Larue
- Institut Curie; PSL Research University; INSERM U1021; Normal and Pathological Development of Melanocytes; Orsay France
- Univ Paris-Sud; Univ Paris-Saclay; CNRS UMR 3347; Orsay France
- Equipe Labellisée Ligue Contre le Cancer; Orsay France
| |
Collapse
|
|
24
|
Shim JH, Shin HT, Park J, Park JH, Lee JH, Yang JM, Kim DH, Jang KT, Lee DY. Mutational profiling of acral melanomas in Korean populations. Exp Dermatol 2017; 26:883-888. [DOI: 10.1111/exd.13321] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/06/2017] [Indexed: 12/12/2022]
Affiliation(s)
- Joon Ho Shim
- Department of Dermatology; Samsung Medical Center; Sungkyunkwan University School of Medicine; Seoul Korea
- Samsung Genome Institute; Samsung Medical Center; Seoul Korea
| | - Hyun-Tae Shin
- Samsung Genome Institute; Samsung Medical Center; Seoul Korea
| | - Jiho Park
- Department of Health Sciences and Technology; Samsung Advanced Institute for Health Sciences and Technology; Sungkyunkwan University; Seoul Korea
| | - Ji-Hye Park
- Department of Dermatology; Samsung Medical Center; Sungkyunkwan University School of Medicine; Seoul Korea
| | - Jong-Hee Lee
- Department of Dermatology; Samsung Medical Center; Sungkyunkwan University School of Medicine; Seoul Korea
- Department of Medical Device Management & Research; Samsung Advanced Institute for Health Sciences and Technology; Sungkyunkwan University; Seoul Korea
| | - Jun-Mo Yang
- Department of Dermatology; Samsung Medical Center; Sungkyunkwan University School of Medicine; Seoul Korea
| | - Duk-Hwan Kim
- Department of Molecular Cell Biology; Samsung Biomedical Research Institute; Sungkyunkwan University School of Medicine; Suwon Korea
| | - Kee-Taek Jang
- Department of Pathology; Samsung Medical Center; Sungkyunkwan University School of Medicine; Seoul Korea
| | - Dong-Youn Lee
- Department of Dermatology; Samsung Medical Center; Sungkyunkwan University School of Medicine; Seoul Korea
| |
Collapse
|
|
25
|
Olvedy M, Tisserand JC, Luciani F, Boeckx B, Wouters J, Lopez S, Rambow F, Aibar S, Thienpont B, Barra J, Köhler C, Radaelli E, Tartare-Deckert S, Aerts S, Dubreuil P, van den Oord JJ, Lambrechts D, De Sepulveda P, Marine JC. Comparative oncogenomics identifies tyrosine kinase FES as a tumor suppressor in melanoma. J Clin Invest 2017; 127:2310-2325. [PMID: 28463229 DOI: 10.1172/jci91291] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2016] [Accepted: 03/02/2017] [Indexed: 01/11/2023] Open
Abstract
Identification and functional validation of oncogenic drivers are essential steps toward advancing cancer precision medicine. Here, we have presented a comprehensive analysis of the somatic genomic landscape of the widely used BRAFV600E- and NRASQ61K-driven mouse models of melanoma. By integrating the data with publically available genomic, epigenomic, and transcriptomic information from human clinical samples, we confirmed the importance of several genes and pathways previously implicated in human melanoma, including the tumor-suppressor genes phosphatase and tensin homolog (PTEN), cyclin dependent kinase inhibitor 2A (CDKN2A), LKB1, and others. Importantly, this approach also identified additional putative melanoma drivers with prognostic and therapeutic relevance. Surprisingly, one of these genes encodes the tyrosine kinase FES. Whereas FES is highly expressed in normal human melanocytes, FES expression is strongly decreased in over 30% of human melanomas. This downregulation correlates with poor overall survival. Correspondingly, engineered deletion of Fes accelerated tumor progression in a BRAFV600E-driven mouse model of melanoma. Together, these data implicate FES as a driver of melanoma progression and demonstrate the potential of cross-species oncogenomic approaches combined with mouse modeling to uncover impactful mutations and oncogenic driver alleles with clinical importance in the treatment of human cancer.
Collapse
Affiliation(s)
- Michael Olvedy
- Laboratory for Molecular Cancer Biology, Center for Cancer Biology, Vlaams Instituut voor Biotechnologie (VIB), Leuven, Belgium.,Laboratory for Molecular Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium
| | - Julie C Tisserand
- INSERM, Aix Marseille University, CNRS, Institut Paoli-Calmettes, CRCM, Equipe Labellisée Ligue Contre le Cancer, Marseille, France
| | - Flavie Luciani
- Laboratory for Molecular Cancer Biology, Center for Cancer Biology, Vlaams Instituut voor Biotechnologie (VIB), Leuven, Belgium.,Laboratory for Molecular Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium
| | - Bram Boeckx
- Laboratory for Translational Genetics, Center for Cancer Biology, VIB, Leuven, Belgium.,Laboratory for Translational Genetics, and
| | - Jasper Wouters
- Laboratory of Computational Biology, Department of Human Genetics, KU Leuven, Leuven, Belgium.,Laboratory of Computational Biology, and
| | - Sophie Lopez
- INSERM, Aix Marseille University, CNRS, Institut Paoli-Calmettes, CRCM, Equipe Labellisée Ligue Contre le Cancer, Marseille, France
| | - Florian Rambow
- Laboratory for Molecular Cancer Biology, Center for Cancer Biology, Vlaams Instituut voor Biotechnologie (VIB), Leuven, Belgium.,Laboratory for Molecular Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium
| | - Sara Aibar
- Laboratory of Computational Biology, Department of Human Genetics, KU Leuven, Leuven, Belgium.,Laboratory of Computational Biology, and
| | - Bernard Thienpont
- Laboratory for Translational Genetics, Center for Cancer Biology, VIB, Leuven, Belgium.,Laboratory for Translational Genetics, and
| | - Jasmine Barra
- Laboratory for Molecular Cancer Biology, Center for Cancer Biology, Vlaams Instituut voor Biotechnologie (VIB), Leuven, Belgium.,Laboratory for Molecular Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium
| | - Corinna Köhler
- Laboratory for Molecular Cancer Biology, Center for Cancer Biology, Vlaams Instituut voor Biotechnologie (VIB), Leuven, Belgium.,Laboratory for Molecular Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium
| | - Enrico Radaelli
- Mouse Histopathology Core Facility, VIB Center for Brain & Disease Research, Leuven, Belgium
| | - Sophie Tartare-Deckert
- Centre Méditerranéen de Médecine Moléculaire (C3M), INSERM, U1065, Université Côte d'Azur, Nice, France
| | - Stein Aerts
- Laboratory of Computational Biology, Department of Human Genetics, KU Leuven, Leuven, Belgium.,Laboratory of Computational Biology, and
| | - Patrice Dubreuil
- INSERM, Aix Marseille University, CNRS, Institut Paoli-Calmettes, CRCM, Equipe Labellisée Ligue Contre le Cancer, Marseille, France
| | - Joost J van den Oord
- Laboratory of Translational Cell and Tissue Research, Department of Pathology, KU Leuven and UZ Leuven, Leuven, Belgium
| | - Diether Lambrechts
- Laboratory for Translational Genetics, Center for Cancer Biology, VIB, Leuven, Belgium.,Laboratory for Translational Genetics, and
| | - Paulo De Sepulveda
- INSERM, Aix Marseille University, CNRS, Institut Paoli-Calmettes, CRCM, Equipe Labellisée Ligue Contre le Cancer, Marseille, France
| | - Jean-Christophe Marine
- Laboratory for Molecular Cancer Biology, Center for Cancer Biology, Vlaams Instituut voor Biotechnologie (VIB), Leuven, Belgium.,Laboratory for Molecular Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium
| |
Collapse
|
|
26
|
Massi D, Romano E, Rulli E, Merelli B, Nassini R, De Logu F, Bieche I, Baroni G, Cattaneo L, Xue G, Mandalà M. Baseline β-catenin, programmed death-ligand 1 expression and tumour-infiltrating lymphocytes predict response and poor prognosis in BRAF inhibitor-treated melanoma patients. Eur J Cancer 2017; 78:70-81. [PMID: 28412591 DOI: 10.1016/j.ejca.2017.03.012] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2016] [Revised: 02/17/2017] [Accepted: 03/13/2017] [Indexed: 11/16/2022]
Abstract
BACKGROUND The activation of oncogenic Wnt/β-catenin pathway in melanoma contributes to a lack of T-cell infiltration. Whether baseline β-catenin expression in the context of tumour-infiltrating lymphocytes (TILs) and programmed death ligand-1 (PD-L1) overexpression correlates with prognosis of metastatic melanoma patients (MMPs) treated with mitogen-activated protein kinase, MAPK inhibitor (MAPKi) monotherapy, however, has not been fully clarified. PATIENTS AND METHODS Sixty-four pre-treatment formalin-fixed and paraffin embedded melanoma samples from MMP treated with a BRAF inhibitor (n = 39) or BRAF and MEK inhibitors (n = 25) were assessed for presence of β-catenin, PD-L1, cluster of differentiation (CD)8, CD103 and forkhead box protein P3 (FOXP3) expression by immunohistochemistry, and results were correlated with clinical outcome. Quantitative assessment of mRNA transcripts associated with Wnt/β-catenin pathway and immune response was performed in 51 patients. RESULTS We found an inverse correlation between tumoural β-catenin expression and the level of CD8, CD103 or forkhead box protein P3 (FOXP3) positivity in the tumour microenvironment (TME). By multivariate analysis, PD-L1 <5% (odds ratio, OR 0.12, 95% confidence interval, CI 0.03-0.53, p = 0.005) and the presence of CD8+ T cells (OR 18.27, 95%CI 2.54-131.52, p = 0.004) were significantly associated with a higher probability of response to MAPKi monotherapy. Responding patients showed a significantly increased expression of mRNA transcripts associated with adaptive immunity and antigen presentation. By multivariate analysis, progression-free survival (PFS) (hazards ratio (HR) = 0.25 95%CI 0.10-0.61, p = 0.002) and overall survival (OS) (HR = 0.24 95%CI 0.09-0.67, p = 0.006) were longer in patients with high density of CD8+ T cells and β-catenin <10% than those without CD8+ T cells infiltration and β-catenin ≥10%. CONCLUSION Our findings provide evidence that in the context of MAPKi monotherapy, immune subsets in the (TME) and gene signature predict prognosis in MMPs.
Collapse
Affiliation(s)
- Daniela Massi
- Division of Pathological Anatomy, Department of Surgery and Translational Medicine, University of Florence, Italy
| | - Emanuela Romano
- Department of Oncology, Center for Cancer Immunotherapy, INSERM U932, Institut Curie, PSL Research University, Paris, France
| | - Eliana Rulli
- Department of Oncology, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy
| | - Barbara Merelli
- Unit of Medical Oncology, Department of Oncology and Hematology, Papa Giovanni XXIII Hospital, Bergamo, Italy
| | - Romina Nassini
- Unit of Clinical Pharmacology and Oncology, Department of Health Sciences, University of Florence, Italy
| | - Francesco De Logu
- Unit of Clinical Pharmacology and Oncology, Department of Health Sciences, University of Florence, Italy
| | - Ivan Bieche
- Pharmacogenomics Unit, Department of Genetics, Institut Curie, 26 rue d'Ulm, Paris 75005, France
| | - Gianna Baroni
- Division of Pathological Anatomy, Department of Surgery and Translational Medicine, University of Florence, Italy
| | - Laura Cattaneo
- Division of Pathological Anatomy, Papa Giovanni XXIII Hospital, Bergamo, Italy
| | - Gongda Xue
- Department of Biomedicine, University Hospital of Basel, Basel, Switzerland
| | - Mario Mandalà
- Unit of Medical Oncology, Department of Oncology and Hematology, Papa Giovanni XXIII Hospital, Bergamo, Italy.
| |
Collapse
|
|
27
|
Liu H, Zhu M, Li Z, Wang Y, Xing R, Lu Y, Xue W. Depletion of p42.3 gene inhibits proliferation and invasion in melanoma cells. J Cancer Res Clin Oncol 2017; 143:639-648. [PMID: 28093638 DOI: 10.1007/s00432-016-2328-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2016] [Accepted: 12/22/2016] [Indexed: 01/18/2023]
Abstract
PURPOSE The p42.3 gene is identified recently, and the upregulated expression has been characterized in a variety of human cancers and embryonic tissues but not yet in malignant melanoma. In this study, we explored the role of p42.3 gene in the development of melanoma. METHODS The expression of p42.3 was detected by immunohistochemistry staining of 261 cases of patient lesions, including nevi and melanoma, and its correlation with clinical pathological characteristics and prognosis was analyzed. Furthermore, a series of in vitro assays were used to investigate the biological function of p42.3 in melanoma cells. RESULTS Immunohistochemistry staining showed an elevated expression level of p42.3 in melanoma compared to nevi (P = 0.001). Statistical analysis indicated that this high level was well correlated with patients' clinical stage (P = 0.045), but not with gender, age, clinical type, mitotic rate, and overall survival (P > 0.05). Moreover, in vitro assays showed knockdown p42.3 gene expression could inhibit the biological profiling, including proliferation, migration, and invasion of melanoma cells, and also affect PI3K/Akt pathway, MAPK pathway, and β-catenin. CONCLUSIONS This study suggests that p42.3, acting like an oncogene, is involved in the malignant transformation process of melanoma and may serve as a biomarker for diagnostic and treatment purposes.
Collapse
Affiliation(s)
- Hui Liu
- Department of Pathology, Peking University Cancer Hospital and Institute, Beijing, 100142, China
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Laboratory of Molecular Oncology, Peking University Cancer Hospital and Institute, Beijing, 100142, China
| | - Min Zhu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Laboratory of Molecular Oncology, Peking University Cancer Hospital and Institute, Beijing, 100142, China
| | - Zhongwu Li
- Department of Pathology, Peking University Cancer Hospital and Institute, Beijing, 100142, China
| | - Yan Wang
- Department of Pathology, Peking University Cancer Hospital and Institute, Beijing, 100142, China
| | - Rui Xing
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Laboratory of Molecular Oncology, Peking University Cancer Hospital and Institute, Beijing, 100142, China
| | - Youyong Lu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Laboratory of Molecular Oncology, Peking University Cancer Hospital and Institute, Beijing, 100142, China.
| | - Weicheng Xue
- Department of Pathology, Peking University Cancer Hospital and Institute, Beijing, 100142, China.
| |
Collapse
|
|
28
|
Brown K, Yang P, Salvador D, Kulikauskas R, Ruohola-Baker H, Robitaille AM, Chien AJ, Moon RT, Sherwood V. WNT/β-catenin signaling regulates mitochondrial activity to alter the oncogenic potential of melanoma in a PTEN-dependent manner. Oncogene 2017; 36:3119-3136. [PMID: 28092677 PMCID: PMC5467017 DOI: 10.1038/onc.2016.450] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Revised: 09/23/2016] [Accepted: 10/12/2016] [Indexed: 12/23/2022]
Abstract
Aberrant regulation of WNT/β-catenin signaling has a crucial role in the onset and progression of cancers, where the effects are not always predictable depending on tumor context. In melanoma, for example, models of the disease predict differing effects of the WNT/β-catenin pathway on metastatic progression. Understanding the processes that underpin the highly context-dependent nature of WNT/β-catenin signaling in tumors is essential to achieve maximal therapeutic benefit from WNT inhibitory compounds. In this study, we have found that expression of the tumor suppressor, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), alters the invasive potential of melanoma cells in response to WNT/β-catenin signaling, correlating with differing metabolic profiles. This alters the bioenergetic potential and mitochondrial activity of melanoma cells, triggered through regulation of pro-survival autophagy. Thus, WNT/β-catenin signaling is a regulator of catabolic processes in cancer cells, which varies depending on the metabolic requirements of tumors.
Collapse
Affiliation(s)
- K Brown
- School of Pharmacy, University of East Anglia, Norwich Research Park, Norwich, UK
| | - P Yang
- Department of Pharmacology, Howard Hughes Medical Institute, Institute for Stem Cell and Regenerative Medicine, Seattle, WA, USA
| | - D Salvador
- Division of Cancer Research, Jacqui Wood Cancer Centre, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK
| | - R Kulikauskas
- Department of Pharmacology, Howard Hughes Medical Institute, Institute for Stem Cell and Regenerative Medicine, Seattle, WA, USA
| | - H Ruohola-Baker
- Department of Biochemistry, University of Washington, Seattle, WA, USA
| | - A M Robitaille
- Department of Pharmacology, Howard Hughes Medical Institute, Institute for Stem Cell and Regenerative Medicine, Seattle, WA, USA
| | - A J Chien
- Department of Pharmacology, Howard Hughes Medical Institute, Institute for Stem Cell and Regenerative Medicine, Seattle, WA, USA.,Division of Dermatology, University of Washington, Seattle, WA, USA
| | - R T Moon
- Department of Pharmacology, Howard Hughes Medical Institute, Institute for Stem Cell and Regenerative Medicine, Seattle, WA, USA
| | - V Sherwood
- School of Pharmacy, University of East Anglia, Norwich Research Park, Norwich, UK.,Division of Cancer Research, Jacqui Wood Cancer Centre, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK
| |
Collapse
|
|
29
|
Serini S, Zinzi A, Ottes Vasconcelos R, Fasano E, Riillo MG, Celleno L, Trombino S, Cassano R, Calviello G. Role of β-catenin signaling in the anti-invasive effect of the omega-3 fatty acid DHA in human melanoma cells. J Dermatol Sci 2016; 84:149-159. [PMID: 27600927 DOI: 10.1016/j.jdermsci.2016.06.010] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Revised: 06/21/2016] [Accepted: 06/23/2016] [Indexed: 01/08/2023]
Abstract
BACKGROUND We previously found that docosahexaenoic acid (DHA), a dietary polyunsaturated fatty acid present at high level in fatty fish, inhibited cell growth and induced differentiation of melanoma cells in vitro by increasing nuclear β-catenin content. An anti-neoplastic role of nuclear β-catenin was suggested in melanoma, and related to the presence in the melanocyte lineage of the microphtalmia transcription factor (MITF), which interferes with the transcription of β-catenin/TCF/LEF pro-invasive target genes. OBJECTIVE In the present work we investigated if DHA could inhibit the invasive potential of melanoma cells, and if this effect could be related to DHA-induced alterations of the Wnt/β-catenin signaling, including changes in MITF expression. METHODS WM115 and WM266-4 human melanoma, and B16-F10 murine melanoma cell lines were used. Cell invasion was evaluated by Wound Healing and Matrigel transwell assays. Protein expression was analyzed by Western Blotting and β-catenin phosphorylation by immunoprecipitation. The role of MITF in the anti-invasive effect of DHA was analyzed by siRNA gene silencing. RESULTS We found that DHA inhibited anchorage-independent cell growth, reduced their migration/invasion in vitro and down-regulated several Matrix Metalloproteinases (MMP: MMP-2, MT1-MMP and MMP-13), known to be involved in melanoma invasion. We related these effects to the β-catenin increased nuclear expression and PKA-dependent phosphorylation, as well as to the increased expression of MITF. CONCLUSION The data obtained further support the potential role of dietary DHA as suppressor of melanoma progression to invasive malignancy through its ability to enhance MITF expression and PKA-dependent nuclear β-catenin phosphorylation.
Collapse
Affiliation(s)
- Simona Serini
- Institute of General Pathology, Università Cattolica del S. Cuore, Rome, Italy
| | - Antonio Zinzi
- Department of Pharmacy, Health and Nutritional Sciences, Università della Calabria, Arcavacata di Rende, Cosenza, Italy
| | - Renata Ottes Vasconcelos
- Instituto de Ciências Biológicas, Universidade Federal do Rio Grande-FURG, Rio Grande, RS, Brazil
| | - Elena Fasano
- Institute of General Pathology, Università Cattolica del S. Cuore, Rome, Italy
| | - Maria Greca Riillo
- Department of Pharmacy, Health and Nutritional Sciences, Università della Calabria, Arcavacata di Rende, Cosenza, Italy
| | - Leonardo Celleno
- Institute of Dermatology, Università Cattolica del S. Cuore, Rome, Italy; Research Center for Biotechnology Applied to Cosmetology, Università Cattolica del S. Cuore, Rome, Italy
| | - Sonia Trombino
- Department of Pharmacy, Health and Nutritional Sciences, Università della Calabria, Arcavacata di Rende, Cosenza, Italy
| | - Roberta Cassano
- Department of Pharmacy, Health and Nutritional Sciences, Università della Calabria, Arcavacata di Rende, Cosenza, Italy
| | - Gabriella Calviello
- Institute of General Pathology, Università Cattolica del S. Cuore, Rome, Italy; Research Center for Biotechnology Applied to Cosmetology, Università Cattolica del S. Cuore, Rome, Italy.
| |
Collapse
|
|
30
|
Aktary Z, Bertrand JU, Larue L. The WNT-less wonder: WNT-independent β-catenin signaling. Pigment Cell Melanoma Res 2016; 29:524-40. [PMID: 27311806 DOI: 10.1111/pcmr.12501] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2016] [Accepted: 06/14/2016] [Indexed: 12/18/2022]
Abstract
β-catenin is known as an Armadillo protein that regulates gene expression following WNT pathway activation. However, WNT-independent pathways also activate β-catenin. During the establishment of the melanocyte lineage, β-catenin plays an important role. In the context of physiopathology, β-catenin is activated genetically or transiently in various cancers, including melanoma, where it can be found in the nucleus of tumors. In this review, we discuss alternative pathways that activate β-catenin independent of WNTs and highlight what is known regarding these pathways in melanoma. We also discuss the role of β-catenin as a transcriptional regulator in various cell types, with emphasis on the different transcription factors it associates with independent of WNT induction. Finally, the role of WNT-independent β-catenin in melanocyte development and melanomagenesis is also discussed.
Collapse
Affiliation(s)
- Zackie Aktary
- Normal and Pathological Development of Melanocytes, INSERM U1021, Institut Curie, PSL Research University, Orsay, France.,CNRS UMR 3347, Univ Paris-Sud, Univ Paris-Saclay, Orsay, France.,Equipe Labellisée Ligue Contre le Cancer, Orsay, France
| | - Juliette U Bertrand
- Normal and Pathological Development of Melanocytes, INSERM U1021, Institut Curie, PSL Research University, Orsay, France.,CNRS UMR 3347, Univ Paris-Sud, Univ Paris-Saclay, Orsay, France.,Equipe Labellisée Ligue Contre le Cancer, Orsay, France
| | - Lionel Larue
- Normal and Pathological Development of Melanocytes, INSERM U1021, Institut Curie, PSL Research University, Orsay, France. .,CNRS UMR 3347, Univ Paris-Sud, Univ Paris-Saclay, Orsay, France. .,Equipe Labellisée Ligue Contre le Cancer, Orsay, France.
| |
Collapse
|
|
31
|
Naspi A, Zingariello M, Sancillo L, Panasiti V, Polinari D, Martella M, Rosa Alba R, Londei P. IGFBP-3 inhibits Wnt signaling in metastatic melanoma cells. Mol Carcinog 2016; 56:681-693. [PMID: 27377812 PMCID: PMC5213668 DOI: 10.1002/mc.22525] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2015] [Revised: 06/17/2016] [Accepted: 07/01/2016] [Indexed: 12/27/2022]
Abstract
In previous works, we have shown that insulin‐like growth factor‐binding protein‐3 (IGFBP‐3), a tissue and circulating protein able to bind to IGFs, decreases drastically in the blood serum of patients with diffuse metastatic melanoma. In agreement with the clinical data, recombinant IGFBP‐3 was found to inhibit the motility and invasiveness of cultured metastatic melanoma cells and to prevent growth of grafted melanomas in mice. The present work was aimed at identifying the signal transduction pathways underlying the anti‐tumoral effects of IGFBP‐3. We show that the anti‐tumoral effect of IGFBP‐3 is due to inhibition of the Wnt pathway and depends upon the presence of CD44, a receptor protein known to modulate Wnt signaling. Once it has entered the cell, IGFBP‐3 binds the Wnt signalosome interacting specifically with its component GSK‐3β. As a consequence, the β‐catenin destruction complex dissociates from the LRP6 Wnt receptor and GSK‐3β is activated through dephosphorylation, becoming free to target cytoplasmic β‐catenin which is degraded by the proteasomal pathway. Altogether, the results suggest that IGFBP‐3 is a novel and effective inhibitor of Wnt signaling. As IGFBP‐3 is a physiological protein which has no detectable toxic effects either on cultured cells or live mice, it might qualify as an interesting new therapeutic agent in melanoma, and potentially many other cancers with a hyperactive Wnt signaling. © 2016 The Authors. Molecular Carcinogenesis Published by Wiley Periodicals, Inc.
Collapse
Affiliation(s)
- Antimo Naspi
- Department of Cellular Biotechnologies and Haematology, Istituto Pasteur Fondazione Cenci-Bolognetti, Sapienza University of Rome, Rome, Italy
| | - Maria Zingariello
- Laboratory of Microscopic and Ultrastructural Anatomy, School of Medicine, Campus Bio-Medico University of Rome, Rome, Italy
| | - Laura Sancillo
- Department of Medicine and Aging Sciences, Section of Human Morphology, University G. D'Annunzio, Chieti, Italy
| | - Vincenzo Panasiti
- Plastic and Reconstructive Surgery Unit, Campus Bio-Medico University of Rome, Rome, Italy
| | - Dorina Polinari
- Department of Cellular Biotechnologies and Haematology, Istituto Pasteur Fondazione Cenci-Bolognetti, Sapienza University of Rome, Rome, Italy
| | - Marianna Martella
- Department of Cellular Biotechnologies and Haematology, Istituto Pasteur Fondazione Cenci-Bolognetti, Sapienza University of Rome, Rome, Italy
| | - Rana Rosa Alba
- Department of Medicine and Aging Sciences, Section of Human Morphology, University G. D'Annunzio, Chieti, Italy
| | - Paola Londei
- Department of Cellular Biotechnologies and Haematology, Istituto Pasteur Fondazione Cenci-Bolognetti, Sapienza University of Rome, Rome, Italy
| |
Collapse
|
|
32
|
Yaguchi T, Kawakami Y. Cancer-induced heterogeneous immunosuppressive tumor microenvironments and their personalized modulation. Int Immunol 2016; 28:393-9. [PMID: 27401477 DOI: 10.1093/intimm/dxw030] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2016] [Accepted: 06/16/2016] [Indexed: 02/06/2023] Open
Abstract
Although recent cancer immunotherapy strategies, including immune-checkpoint blockade (i.e. blocking PD-1, PD-L1 or CTLA-4), have shown durable clinical effects in some (but not all) patients with various advanced cancers, further understanding of human immunopathology, particularly in tumor microenvironments, is essential to improve this type of therapy. The major hurdle for immunotherapy is the immunosuppression that is found in cancer patients. There are two types of immunosuppression: one is induced by gene alterations in cancer; the other is local adaptive immunosuppression, triggered by tumor-specific T cells in tumors. The former is caused by multiple mechanisms via various immunosuppressive molecules and via cells triggered by gene alterations, including activated oncogenes, in cancer cells. The various immunosuppressive mechanisms involve signaling cascades that vary among cancer types, subsets within cancer types and individual cancers. Therefore, personalized immune-interventions are necessary to appropriately target oncogene-induced signaling that modulates anti-cancer immune responses, on the basis of genetic and immunological analysis of each patient. Further understanding of human cancer immunopathology may lead to real improvement of current cancer immunotherapies.
Collapse
Affiliation(s)
- Tomonori Yaguchi
- Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Yutaka Kawakami
- Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| |
Collapse
|
|
33
|
Wnt/β-catenin signaling in melanoma: Preclinical rationale and novel therapeutic insights. Cancer Treat Rev 2016; 49:1-12. [PMID: 27395773 DOI: 10.1016/j.ctrv.2016.06.009] [Citation(s) in RCA: 81] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2016] [Revised: 06/20/2016] [Accepted: 06/21/2016] [Indexed: 01/25/2023]
Abstract
WNT signaling regulates embryonic development and tissue homeostasis in the adult stage. Evolutionarily, activation of the WNT pathway is triggered by a large family of cytokines and activates a broad spectrum of downstream targets through two independent branches mediated by β-catenin (defined as canonical pathway) or PLC and small GTPase (defined as non-canonical pathway), respectively. Recent studies revealed the crucial role of WNT in the maintenance of cell metabolism and stemness as well as its deregulation in tumourigenesis and malignant transformation through oncogenic reprogramming, which contributes to cancer cell proliferation and differentiation, survival, stress response and resistance. In addition, multiple functional mutations discovered in human tumours have been reported to cause malignancy, indicating this pathway as a novel therapeutic target in oncology. Notably, emerging data highlights its involvement in the crosstalk between immune and cancer cells. However, contradictory effects have been also observed in different pre-clinical models when strategic(???) inhibitors are tested. In this review, we address the multifaceted regulatory mechanisms of WNT signaling in cancer, with a particular focus on current melanoma therapy, which has witnessed dramatic improvement in the last five years.
Collapse
|
|
34
|
Sunamura N, Ohira T, Kataoka M, Inaoka D, Tanabe H, Nakayama Y, Oshimura M, Kugoh H. Regulation of functional KCNQ1OT1 lncRNA by β-catenin. Sci Rep 2016; 6:20690. [PMID: 26868975 PMCID: PMC4751614 DOI: 10.1038/srep20690] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2015] [Accepted: 01/11/2016] [Indexed: 01/12/2023] Open
Abstract
Long noncoding RNAs (lncRNAs) have been implicated in many biological processes through epigenetic mechanisms. We previously reported that KCNQ1OT1, an imprinted antisense lncRNA in the human KCNQ1 locus on chromosome 11p15.5, is involved in cis-limited silencing within an imprinted KCNQ1 cluster. Furthermore, aberration of KCNQ1OT1 transcription was observed with a high frequency in colorectal cancers. However, the molecular mechanism of the transcriptional regulation and the functional role of KCNQ1OT1 in colorectal cancer remain unclear. Here, we show that the KCNQ1OT1 transcriptional level was significantly increased in human colorectal cancer cells in which β-catenin was excessively accumulated in the nucleus. Additionally, overexpression of β-catenin resulted in an increase in KCNQ1OT1 lncRNA-coated territory. On the other hand, knockdown of β-catenin resulted in significant decrease of KCNQ1OT1 lncRNA-coated territory and an increase in the mRNA expression of the SLC22A18 and PHLDA2 genes that are regulated by KCNQ1OT1. We showed that β-catenin can promote KCNQ1OT1 transcription through direct binding to the KCNQ1OT1 promoter. Our evidence indicates that β-catenin signaling may contribute to development of colorectal cancer by functioning as a novel lncRNA regulatory factor via direct targeting of KCNQ1OT1.
Collapse
Affiliation(s)
- Naohiro Sunamura
- Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science, Tottori University, 86 Nishi-Cho, Yonago, Tottori 683-8503, Japan
| | - Takahito Ohira
- Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science, Tottori University, 86 Nishi-Cho, Yonago, Tottori 683-8503, Japan
| | - Miki Kataoka
- Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science, Tottori University, 86 Nishi-Cho, Yonago, Tottori 683-8503, Japan
| | - Daigo Inaoka
- Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science, Tottori University, 86 Nishi-Cho, Yonago, Tottori 683-8503, Japan
| | - Hideyuki Tanabe
- Department of Evolutionary Studies of Biosystems Science, School of Advanced Sciences, SOKENDAI (The Graduate University for Advanced Studies), Shonan Village, Hayama, Kanagawa 240-0193, Japan
| | - Yuji Nakayama
- Division of Functional Genomics, Research Center for Bioscience and Technology, Tottori University, 86 Nishi-Cho, Yonago, Tottori 683-8503, Japan
| | - Mitsuo Oshimura
- Chromosome Engineering Research Center, Tottori University, 86 Nishi-Cho, Yonago, Tottori 683-8503, Japan
| | - Hiroyuki Kugoh
- Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science, Tottori University, 86 Nishi-Cho, Yonago, Tottori 683-8503, Japan.,Chromosome Engineering Research Center, Tottori University, 86 Nishi-Cho, Yonago, Tottori 683-8503, Japan
| |
Collapse
|
|
35
|
Roads to melanoma: Key pathways and emerging players in melanoma progression and oncogenic signaling. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2016; 1863:770-84. [PMID: 26844774 DOI: 10.1016/j.bbamcr.2016.01.025] [Citation(s) in RCA: 137] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/10/2015] [Revised: 01/27/2016] [Accepted: 01/29/2016] [Indexed: 12/16/2022]
Abstract
Melanoma has markedly increased worldwide during the past several decades in the Caucasian population and is responsible for 80% of skin cancer deaths. Considering that metastatic melanoma is almost completely resistant to most current therapies and is linked with a poor patient prognosis, it is crucial to further investigate potential molecular targets. Major cell-autonomous drivers in the pathogenesis of this disease include the classical MAPK (i.e., RAS-RAF-MEK-ERK), WNT, and PI3K signaling pathways. These pathways play a major role in defining the progression of melanoma, and some have been the subject of recent pharmacological strategies to treat this belligerent disease. This review describes the latest advances in the understanding of melanoma progression and the major molecular pathways involved. In addition, we discuss the roles of emerging molecular players that are involved in melanoma pathogenesis, including the functional role of the melanoma tumor antigen, p97/MFI2 (melanotransferrin).
Collapse
|
|
36
|
Krajnović T, Kaluđerović GN, Wessjohann LA, Mijatović S, Maksimović-Ivanić D. Versatile antitumor potential of isoxanthohumol: Enhancement of paclitaxel activity in vivo. Pharmacol Res 2016; 105:62-73. [PMID: 26784390 DOI: 10.1016/j.phrs.2016.01.011] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2015] [Revised: 12/18/2015] [Accepted: 01/13/2016] [Indexed: 01/19/2023]
Abstract
Isoxanthohumol (IXN), a prenylated flavonoid from hops, exhibits diverse biological activities, e.g. antitumor, antiinflammatory, antioxidant and antiangiogenic. In this study, the effect of IXN is evaluated on two melanoma cell lines with dissimilar molecular background, B16 and A375. The treatment of both cell lines with IXN resulted in dose-dependent decrease of cell viability. Abolished viability was in correlation with changed morphology and loss of dividing potential indicating phenotypical alteration of both tested cell lines. While modified B16 cells underwent the process of non-classic differentiation followed by tyrosinase activity without enhancement of melanin content, inhibition of Notch 1, β-catenin and Oct-3/4 was observed in A375 cells indicating loss of their pluripotent characteristics. In parallel with this, distinct subpopulations in both cell cultures entered the process of programmed cell death-apoptosis in a caspase independent manner. The described changes in cultures upon exposure to IXN could be connected with the suppression of reactive oxygen (ROS) and nitrogen species (RNS) induced by the drug. Despite the differences in which IXN promoted modifications in the upper part of the PI3K/Akt and MEK-ERK signaling pathways between B16 and A375 cells, p70S6K and its target S6 protein in both types of melanoma cells, after transient activation, became inhibited. In addition to direct input of IXN on cell viability, this study for the first time shows that IXN strongly sensitizes melanoma cells to the treatment with paclitaxel in vivo, in concordance with data obtained in vitro on B16 cells as well as their highly invasive F10 subclone.
Collapse
Affiliation(s)
- Tamara Krajnović
- Institute for Biological Research "Siniša Stanković", University of Belgrade, Bulevar Despota Stefana 142, 11060 Belgrade, Serbia.
| | - Goran N Kaluđerović
- Department of Bioorganic Chemistry, Leibniz-Institute of Plant Biochemistry, Weinberg 3, Halle (Saale), D 06120 Halle, Germany.
| | - Ludger A Wessjohann
- Department of Bioorganic Chemistry, Leibniz-Institute of Plant Biochemistry, Weinberg 3, Halle (Saale), D 06120 Halle, Germany.
| | - Sanja Mijatović
- Institute for Biological Research "Siniša Stanković", University of Belgrade, Bulevar Despota Stefana 142, 11060 Belgrade, Serbia.
| | - Danijela Maksimović-Ivanić
- Institute for Biological Research "Siniša Stanković", University of Belgrade, Bulevar Despota Stefana 142, 11060 Belgrade, Serbia.
| |
Collapse
|
|
37
|
Abstract
Many cancers have similar aberrations in various signaling cascades with crucial roles in cellular proliferation, differentiation, and morphogenesis. Dysregulation of signal cascades that play integral roles during early cellular development is well known to be a central feature of many malignancies. One such signaling cascade is the Wnt/β-catenin pathway, which has a profound effect on stem cell proliferation, migration, and differentiation. This pathway is dysregulated in numerous cell types, underscoring its global oncogenetic potential. This review highlights regulators and downstream effectors of this receptor cascade and addresses the increasingly apparent crosstalk of Wnt with other tumorigenic signaling pathways. As understanding of the genetic and epigenetic changes unique to these malignancies increases, identifying the regulatory mechanisms unique to the Wnt/β-catenin pathway and similarly aberrant receptor pathways will be imperative.
Collapse
Affiliation(s)
- Saint-Aaron L Morris
- Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
| | - Suyun Huang
- Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA; Program in Cancer Biology, The University of Texas Graduate School of Biomedical Sciences, 6767 Bertner Avenue, Mitchell Building BSRB S3.8344, Houston, TX 77030, USA
| |
Collapse
|
|
38
|
Vaid M, Singh T, Prasad R, Katiyar SK. Bioactive proanthocyanidins inhibit growth and induce apoptosis in human melanoma cells by decreasing the accumulation of β-catenin. Int J Oncol 2015; 48:624-34. [PMID: 26676402 PMCID: PMC4725457 DOI: 10.3892/ijo.2015.3286] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2015] [Accepted: 10/23/2015] [Indexed: 11/22/2022] Open
Abstract
Melanoma is a highly aggressive form of skin cancer with poor survival rate. Aberrant activation of Wnt/β-catenin has been observed in nearly one-third of human melanoma cases thereby indicating that targeting Wnt/β-catenin signaling could be a promising strategy against melanoma development. In the present study, we determined chemotherapeutic effect of grape seed proanthocyanidins (GSPs) on the growth of melanoma cells and validated their protective effects in vivo using a xenograft mouse model, and assessed if β-catenin is the target of GSP chemotherapeutic effect. Our in vitro data show that treatment of A375 and Hs294t human melanoma cells with GSPs inhibit the growth of melanoma cells, which was associated with the reduction in the levels of β-catenin. Administration of dietary GSPs (0.2 and 0.5%, w/w) in supplementation with AIN76A control diet significantly inhibited the growth of melanoma tumor xenografts in nude mice. Furthermore, dietary GSPs inhibited the xenograft growth of Mel928 (β-catenin-activated), while did not inhibit the xenograft growth of Mel1011 (β-catenin-inactivated) cells. These observations were further verified by siRNA knockdown of β-catenin and forced overexpression of β-catenin in melanoma cells using a cell culture model.
Collapse
Affiliation(s)
- Mudit Vaid
- Department of Dermatology, University of Alabama at Birmingham, AL 35294, USA
| | - Tripti Singh
- Department of Dermatology, University of Alabama at Birmingham, AL 35294, USA
| | - Ram Prasad
- Department of Dermatology, University of Alabama at Birmingham, AL 35294, USA
| | - Santosh K Katiyar
- Department of Dermatology, University of Alabama at Birmingham, AL 35294, USA
| |
Collapse
|
|
39
|
Jiang J, Yu C, Chen M, Zhang H, Tian S, Sun C. Reduction of miR-29c enhances pancreatic cancer cell migration and stem cell-like phenotype. Oncotarget 2015; 6:2767-78. [PMID: 25605017 PMCID: PMC4413616 DOI: 10.18632/oncotarget.3089] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2014] [Accepted: 12/25/2014] [Indexed: 12/31/2022] Open
Abstract
The hallmarks of pancreatic cancer are limitless replicative potential as well as tissue invasion and metastasis, leading to an extremely aggressive disease with shockingly high lethality. However, the molecular mechanisms underlying these characteristics remain largely unclear. Herein, we report the results of a differential miRNA expression screen that compared pancreatic cancer tissues and normal pancreatic tissues, where the pancreatic cancer tissues had highly downregulated miR-29c with relative Wnt cascade hyperactivation. MiR-29c directly suppressed the following Wnt upstream regulators: frequently rearranged in advanced T-cell lymphomas 2 (FRAT2), low-density lipoprotein receptor-related protein 6 (LRP6), Frizzled-4 (FZD4) and Frizzled-5 (FZD5). Furthermore, transforming growth factor-β (TGF-β) inhibited miR-29c expression, leading to Wnt activation. Significantly, our results were consistent with an important correlation between miR-29c levels and TGF-β hyperactivation and the activated Wnt cascade in human pancreatic cancer specimens. These findings reveal a novel mechanism for Wnt hyperactivation in pancreatic cancer and may suggest a new target for clinical intervention in pancreatic cancer.
Collapse
Affiliation(s)
- Jianxin Jiang
- Department of Hepatobiliary Surgery, Affiliated Hospital of Guiyang Medical College, Guiyang, Guizhou, China
| | - Chao Yu
- Department of Hepatobiliary Surgery, Affiliated Hospital of Guiyang Medical College, Guiyang, Guizhou, China
| | - Meiyuan Chen
- Department of Hepatobiliary Surgery, Affiliated Hospital of Guiyang Medical College, Guiyang, Guizhou, China
| | - Hao Zhang
- Department of Hepatobiliary Surgery, Affiliated Hospital of Guiyang Medical College, Guiyang, Guizhou, China
| | - Se Tian
- Department of Hepatobiliary Surgery, Affiliated Hospital of Guiyang Medical College, Guiyang, Guizhou, China
| | - Chengyi Sun
- Department of Hepatobiliary Surgery, Affiliated Hospital of Guiyang Medical College, Guiyang, Guizhou, China
| |
Collapse
|
|
40
|
Xu H, Gong L, Xia Y, Qu L, Li Q, Pang L, Si J, Li Z. Frizzled-7 promoter is highly active in tumors and promoter-driven Shiga-like toxin I inhibits hepatocellular carcinoma growth. Oncotarget 2015; 6:39908-23. [PMID: 26498690 PMCID: PMC4741869 DOI: 10.18632/oncotarget.5516] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2015] [Accepted: 10/06/2015] [Indexed: 01/02/2023] Open
Abstract
Frizzled-7 protein plays a significant role in the formation of several malignant tumors. Up regulation of the Frizzled-7 in cancer cell lines is associated with nuclear accumulation of wild-type β-catenin from the Wnt/β-catenin pathway which is frequently activated in tumors. To analyze activity of the Frizzled-7 promoter in tumor cells, we constructed two recombinant plasmid vectors in which the Frizzled-7 promoter was used to drive the expression of green fluorescent protein (GFP) and Shiga-like toxin I (Stx1) (pFZD7-GFP/Stx1) genes. The Frizzled-7 protein was found to be expressed in the cancer cell lines but not in the normal cell lines. The GFP expression was restricted to the cancer cell lines and xenografts in the BALB/C mice but not to normal cell lines. Moreover, cell proliferation and tumor growth decreased significantly after transfection with the pFZD7-Stx1. Results from this study will help determine a highly effective strategy for gene therapy of tumors.
Collapse
Affiliation(s)
- Hongpan Xu
- Department of Laboratory Medicine, the Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210011, China
| | - Lailing Gong
- Department of Laboratory Medicine, the Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210011, China
| | - Yanyan Xia
- Department of Laboratory Medicine, the Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210011, China
| | - Lili Qu
- Department of Laboratory Medicine, the Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210011, China
| | - Qiwen Li
- Department of Laboratory Medicine, the Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210011, China
| | - Lu Pang
- Department of Laboratory Medicine, the Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210011, China
| | - Jin Si
- Department of Laboratory Medicine, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu 210008, China
| | - Zhiyang Li
- Department of Laboratory Medicine, the Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210011, China
| |
Collapse
|
|
41
|
Vaid M, Singh T, Prasad R, Kappes JC, Katiyar SK. Therapeutic intervention of proanthocyanidins on the migration capacity of melanoma cells is mediated through PGE2 receptors and β-catenin signaling molecules. Am J Cancer Res 2015; 5:3325-3338. [PMID: 26807314 PMCID: PMC4697680] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2015] [Accepted: 10/02/2015] [Indexed: 06/05/2023] Open
Abstract
Melanoma is a highly aggressive form of skin cancer and a leading cause of death from skin diseases mainly due to its propensity to metastasis. Due to metastatic tendency, melanoma is often associated with activation of Wnt/β-catenin signaling mechanism. Blocking β-catenin activation may be a good strategy to block melanoma-associated mortality. We have shown earlier that grape seed proanthocyanidins (GSPs) inhibit melanoma cell migration via targeting cyclooxygenase-2 (COX-2) overexpression. Here we explored further whether inhibition of inflammatory mediators-mediated activation of β-catenin by GSPs is associated with the inhibition of melanoma cell migration. Our study revealed that PGE2 receptors (EP2 and EP4) agonists promote melanoma cell migration while PGE2 receptor antagonist suppressed the migration capacity of melanoma cells. GSPs treatment inhibit butaprost (EP2 agonist) or Cay10580 (EP4 agonist) induced migration of melanoma cells. Western blot analysis revealed that GSPs reduced cellular accumulation of β-catenin, and decreased the expressions of matrix metalloproteinase (MMP)-2, MMP-9 and MITF, downstream targets of β-catenin in melanoma cells. GSPs also reduced the protein expressions of PI3K and p-Akt in the same set of experiment. To verify that β-catenin is a specific molecular target of GSPs, we compared the effect of GSPs on cell migration of β-catenin-activated (Mel1241) and β-catenin-inactivated (Mel1011) melanoma cells. GSPs inhibit cell migration of Mel1241 cells but not of Mel1011 cells. Additionally, in vivo bioluminescence imaging data indicate that dietary administration of GSPs (0.5%, w/w) in supplementation with AIN76A control diet inhibited the migration/extravasation of intravenously injected melanoma cells in lungs of immune-compromised nude mice, and that this effect of GSPs was associated with an inhibitory effect on the activation of β-catenin and its downstream targets, such as MMPs, in lungs as a target organ.
Collapse
Affiliation(s)
- Mudit Vaid
- Department of Dermatology, University of Alabama at BirminghamBirmingham, AL 35294, USA
| | - Tripti Singh
- Department of Dermatology, University of Alabama at BirminghamBirmingham, AL 35294, USA
- Birmingham Veterans Affairs Medical CenterBirmingham, AL 35233, USA
| | - Ram Prasad
- Department of Dermatology, University of Alabama at BirminghamBirmingham, AL 35294, USA
- Birmingham Veterans Affairs Medical CenterBirmingham, AL 35233, USA
| | - John C Kappes
- Department of Medicine, University of Alabama at BirminghamBirmingham, AL 35294, USA
- Department of Pathology, University of Alabama at BirminghamBirmingham, AL 35294, USA
- Department of Comprehensive Cancer Center, University of Alabama at BirminghamBirmingham, AL 35294, USA
- Birmingham Veterans Affairs Medical CenterBirmingham, AL 35233, USA
| | - Santosh K Katiyar
- Department of Dermatology, University of Alabama at BirminghamBirmingham, AL 35294, USA
- Department of Comprehensive Cancer Center, University of Alabama at BirminghamBirmingham, AL 35294, USA
- Birmingham Veterans Affairs Medical CenterBirmingham, AL 35233, USA
| |
Collapse
|
|
42
|
Prasad CP, Mohapatra P, Andersson T. Therapy for BRAFi-Resistant Melanomas: Is WNT5A the Answer? Cancers (Basel) 2015; 7:1900-24. [PMID: 26393652 PMCID: PMC4586801 DOI: 10.3390/cancers7030868] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2015] [Revised: 09/09/2015] [Accepted: 09/14/2015] [Indexed: 12/18/2022] Open
Abstract
In recent years, scientists have advocated the use of targeted therapies in the form of drugs that modulate genes and proteins that are directly associated with cancer progression and metastasis. Malignant melanoma is a dreadful cancer type that has been associated with the rapid dissemination of primary tumors to multiple sites, including bone, brain, liver and lungs. The discovery that approximately 40%–50% of malignant melanomas contain a mutation in BRAF at codon 600 gave scientists a new approach to tackle this disease. However, clinical studies on patients have shown that although BRAFi (BRAF inhibitors) trigger early anti-tumor responses, the majority of patients later develop resistance to the therapy. Recent studies have shown that WNT5A plays a key role in enhancing the resistance of melanoma cells to BRAFi. The focus of the current review will be on melanoma development, signaling pathways important to acquired resistance to BRAFi, and why WNT5A inhibitors are attractive candidates to be included in combinatorial therapies for melanoma.
Collapse
Affiliation(s)
- Chandra Prakash Prasad
- Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Clinical Research Centre, Skåne University Hospital, Malmö SE-20502, Sweden.
| | - Purusottam Mohapatra
- Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Clinical Research Centre, Skåne University Hospital, Malmö SE-20502, Sweden.
| | - Tommy Andersson
- Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Clinical Research Centre, Skåne University Hospital, Malmö SE-20502, Sweden.
| |
Collapse
|
|
43
|
Spranger S, Bao R, Gajewski TF. Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity. Nature 2015. [PMID: 25970248 DOI: 10.1038/nature14404.] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Melanoma treatment is being revolutionized by the development of effective immunotherapeutic approaches. These strategies include blockade of immune-inhibitory receptors on activated T cells; for example, using monoclonal antibodies against CTLA-4, PD-1, and PD-L1 (refs 3-5). However, only a subset of patients responds to these treatments, and data suggest that therapeutic benefit is preferentially achieved in patients with a pre-existing T-cell response against their tumour, as evidenced by a baseline CD8(+) T-cell infiltration within the tumour microenvironment. Understanding the molecular mechanisms that underlie the presence or absence of a spontaneous anti-tumour T-cell response in subsets of cases, therefore, should enable the development of therapeutic solutions for patients lacking a T-cell infiltrate. Here we identify a melanoma-cell-intrinsic oncogenic pathway that contributes to a lack of T-cell infiltration in melanoma. Molecular analysis of human metastatic melanoma samples revealed a correlation between activation of the WNT/β-catenin signalling pathway and absence of a T-cell gene expression signature. Using autochthonous mouse melanoma models we identified the mechanism by which tumour-intrinsic active β-catenin signalling results in T-cell exclusion and resistance to anti-PD-L1/anti-CTLA-4 monoclonal antibody therapy. Specific oncogenic signals, therefore, can mediate cancer immune evasion and resistance to immunotherapies, pointing to new candidate targets for immune potentiation.
Collapse
Affiliation(s)
- Stefani Spranger
- Department of Pathology, The University of Chicago, Chicago, Illinois 60637, USA
| | - Riyue Bao
- Center for Research Informatics, The University of Chicago, Chicago, Illinois 60637, USA
| | - Thomas F Gajewski
- 1] Department of Pathology, The University of Chicago, Chicago, Illinois 60637, USA [2] Department of Medicine, The University of Chicago, Chicago, Illinois 60637, USA
| |
Collapse
|
|
44
|
Spranger S, Bao R, Gajewski TF. Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity. Nature 2015; 523:231-5. [PMID: 25970248 DOI: 10.1038/nature14404] [Citation(s) in RCA: 2088] [Impact Index Per Article: 208.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2014] [Accepted: 03/05/2015] [Indexed: 12/12/2022]
Abstract
Melanoma treatment is being revolutionized by the development of effective immunotherapeutic approaches. These strategies include blockade of immune-inhibitory receptors on activated T cells; for example, using monoclonal antibodies against CTLA-4, PD-1, and PD-L1 (refs 3-5). However, only a subset of patients responds to these treatments, and data suggest that therapeutic benefit is preferentially achieved in patients with a pre-existing T-cell response against their tumour, as evidenced by a baseline CD8(+) T-cell infiltration within the tumour microenvironment. Understanding the molecular mechanisms that underlie the presence or absence of a spontaneous anti-tumour T-cell response in subsets of cases, therefore, should enable the development of therapeutic solutions for patients lacking a T-cell infiltrate. Here we identify a melanoma-cell-intrinsic oncogenic pathway that contributes to a lack of T-cell infiltration in melanoma. Molecular analysis of human metastatic melanoma samples revealed a correlation between activation of the WNT/β-catenin signalling pathway and absence of a T-cell gene expression signature. Using autochthonous mouse melanoma models we identified the mechanism by which tumour-intrinsic active β-catenin signalling results in T-cell exclusion and resistance to anti-PD-L1/anti-CTLA-4 monoclonal antibody therapy. Specific oncogenic signals, therefore, can mediate cancer immune evasion and resistance to immunotherapies, pointing to new candidate targets for immune potentiation.
Collapse
Affiliation(s)
- Stefani Spranger
- Department of Pathology, The University of Chicago, Chicago, Illinois 60637, USA
| | - Riyue Bao
- Center for Research Informatics, The University of Chicago, Chicago, Illinois 60637, USA
| | - Thomas F Gajewski
- 1] Department of Pathology, The University of Chicago, Chicago, Illinois 60637, USA [2] Department of Medicine, The University of Chicago, Chicago, Illinois 60637, USA
| |
Collapse
|
|
45
|
Angelova M, Ferris M, Swan KF, McFerrin HE, Pridjian G, Morris CA, Sullivan DE. Kaposi's sarcoma-associated herpesvirus G-protein coupled receptor activates the canonical Wnt/β-catenin signaling pathway. Virol J 2014; 11:218. [PMID: 25514828 PMCID: PMC4304609 DOI: 10.1186/s12985-014-0218-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2014] [Accepted: 11/27/2014] [Indexed: 12/12/2022] Open
Abstract
Background KSHV is a tumorigenic γ-herpesvirus that has been identified as the etiologic agent of Kaposi’s sarcoma (KS), a multifocal highly vascularized neoplasm that is the most common malignancy associated with acquired immunodeficiency syndrome (AIDS). The virus encodes a constitutively active chemokine receptor homologue, vGPCR that possesses potent angiogenic and tumorigenic properties, and is critical for KSHV pathobiology. To date, a number of signaling pathways have been identified as key in mediating vGPCR oncogenic potential. Findings In this study, we identify a novel pathway, the Wnt/β-catenin pathway, which is dysregulated by vGPCR expression in endothelial cells. Expression of vGPCR in endothelial cells enhances the nuclear accumulation of β-catenin, that correlates with an increase in β-catenin transcriptional activity. Activation of β-catenin signaling by vGPCR is dependent on the PI3K/Akt pathway, as treatment of vGPCR-expressing cells with a pharmacological inhibitor of PI3K, leads to a decreased activation of a β-catenin-driven reporter, a significant decrease in expression of β-catenin target genes, and reduced endothelial tube formation. Conclusions Given the critical role of Wnt/β-catenin signaling in angiogenesis and tumorigenesis, the findings from this study suggest a novel mechanism in KSHV-induced malignancies. Electronic supplementary material The online version of this article (doi:10.1186/s12985-014-0218-8) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Magdalena Angelova
- Department of Microbiology and Immunology, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA, USA.
| | - MaryBeth Ferris
- Department of Microbiology and Immunology, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA, USA.
| | - Kenneth F Swan
- Department of Obstetrics and Gynecology, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA, USA.
| | - Harris E McFerrin
- Biology Department, Xavier University, 1 Drexel Drive, New Orleans, LA, USA.
| | - Gabriella Pridjian
- Department of Obstetrics and Gynecology, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA, USA.
| | - Cindy A Morris
- Department of Microbiology and Immunology, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA, USA.
| | - Deborah E Sullivan
- Department of Microbiology and Immunology, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA, USA.
| |
Collapse
|
|
46
|
Sex disparities in melanoma outcomes: The role of biology. Arch Biochem Biophys 2014; 563:42-50. [DOI: 10.1016/j.abb.2014.06.018] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2014] [Revised: 06/16/2014] [Accepted: 06/18/2014] [Indexed: 02/06/2023]
|
|
47
|
Wang L, Guo J, Wang Q, Zhou J, Xu C, Teng R, Chen Y, Wei Q, Liu ZP. LZTFL1 suppresses gastric cancer cell migration and invasion through regulating nuclear translocation of β-catenin. J Cancer Res Clin Oncol 2014; 140:1997-2008. [PMID: 25005785 DOI: 10.1007/s00432-014-1753-9] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2014] [Accepted: 06/19/2014] [Indexed: 01/02/2023]
Abstract
PURPOSE Our previous work identified leucine zipper transcription factor-like 1 (LZTFL1) as a novel tumor suppressor gene, with its expression correlated with survival outcome in gastric cancer (GC) patients. This study focuses on the role of LZTFL1 in GC aggression and metastasis as well as its underlying molecular mechanisms. METHOD LZTFL1 immunohistochemical (IHC) staining on 311 paired normal/cancer tissue arrays were used to reconfirm the clinical significance of LZTFL1 expression. Transwell chamber assays were used to determine migration and invasive ability of GC cells. Gelatin zymography was employed to investigate the matrix metalloproteinases (MMPs) activity in tumor cells. Co-immunoprecipitation and Duolink in situ proximity ligation assay were used to analyze the interaction between LZTFL1 and β-catenin and the cellular localization of the interaction. RESULT IHC results indicated that patients with high LZTFL1 expression had a longer overall survival time (58 months, 95 % CI 28-128 months) than patients with low LZTFL1 expression (27 months, 95 % CI 23-35 months; p < 0.01). The expression level of LZTFL1 is associated with the degree of cell differentiation. LZTFL1 is necessary and sufficient to inhibit the expression of molecular markers associated with epithelial-mesenchymal transition (EMT) and cellular phenotypes associated with tumor cell EMT including the migration, invasion, and the expression and activities of MMPs of tumor cells. LZTFL1 binds β-catenin in the cytoplasm of the cell and inhibited its nuclear translocation. CONCLUSION LZTFL1 suppresses GC cell EMT by inhibiting β-catenin nuclear translocation. Re-expression of LZTFL1 in GC cells may be a potential therapeutic means to prevent GC metastasis.
Collapse
Affiliation(s)
- Linbo Wang
- Department of Surgical Oncology and Institute of Clinical Medicine, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | | | | | | | | | | | | | | | | |
Collapse
|
|
48
|
Abstract
Melanoma, the deadliest form of skin cancer, is an aggressive disease that is rising in incidence. Although melanoma is a historically treatment-resistant malignancy, in recent years unprecedented breakthroughs in targeted therapies and immunotherapies have revolutionized the standard of care for patients with advanced disease. Here, we provide an overview of recent developments in our understanding of melanoma risk factors, genomics, and molecular pathogenesis and how these insights have driven advances in melanoma treatment. In addition, we review benefits and limitations of current therapies and look ahead to continued progress in melanoma prevention and therapy. Remarkable achievements in the field have already produced a paradigm shift in melanoma treatment: Metastatic melanoma, once considered incurable, can now be treated with potentially curative rather than palliative intent.
Collapse
Affiliation(s)
- Jennifer A Lo
- Cutaneous Biology Research Center, Department of Dermatology and MGH Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - David E Fisher
- Cutaneous Biology Research Center, Department of Dermatology and MGH Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
| |
Collapse
|
|
49
|
Rosner K, Adsule S, Haynes B, Kirou E, Kato I, Mehregan DR, Shekhar MPV. Rad6 is a Potential Early Marker of Melanoma Development. Transl Oncol 2014; 7:S1936-5233(14)00044-8. [PMID: 24831578 PMCID: PMC4145396 DOI: 10.1016/j.tranon.2014.04.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2014] [Revised: 03/24/2014] [Accepted: 03/24/2014] [Indexed: 11/17/2022] Open
Abstract
Melanoma is the leading cause of death from skin cancer in industrialized countries. Several melanoma-related biomarkers and signaling pathways have been identified; however, their relevance to melanoma development/progression or to clinical outcome remains to be established. Aberrant activation of Wnt/β-catenin pathway is implicated in various cancers including melanoma. We have previously demonstrated Rad6, an ubiquitin-conjugating enzyme, as an important mediator of β-catenin stability in breast cancer cells. Similar to breast cancer, β-catenin-activating mutations are rare in melanomas, and since β-catenin signaling is implicated in melanoma, we examined the relationship between β-catenin levels/activity and expression of β-catenin transcriptional targets Rad6 and microphthalmia-associated transcription factor-M (Mitf-M) in melanoma cell models, and expression of Rad6, β-catenin, and Melan-A in nevi and cutaneous melanoma tissue specimens. Our data show that Rad6 is only weakly expressed in normal human melanocytes but is overexpressed in melanoma lines. Unlike Mitf-M, Rad6 overexpression in melanoma lines is positively associated with high molecular weight β-catenin protein levels and β-catenin transcriptional activity. Double-immunofluorescence staining of Rad6 and Melan-A in melanoma tissue microarray showed that histological diagnosis of melanoma is significantly associated with Rad6/Melan-A dual positivity in the melanoma group compared to the nevi group (P=.0029). In contrast to strong β-catenin expression in normal and tumor areas of superficial spreading malignant melanoma (SSMM), Rad6 expression is undetectable in normal areas and Rad6 expression increases coincide with increased Melan-A in the transformed regions of SSMM. These data suggest a role for Rad6 in melanoma pathogenesis and that Rad6 expression status may serve as an early marker for melanoma development.
Collapse
Affiliation(s)
- Karli Rosner
- Department of Dermatology, Wayne State University, 110, East Warren Avenue, Detroit, MI 48201; Center for Molecular Medicine and Genetics, Wayne State University, 110, East Warren Avenue, Detroit, MI 48201; Karmanos Cancer Institute, Wayne State University, 110, East Warren Avenue, Detroit, MI 48201.
| | - Shreelekha Adsule
- Department of Oncology, Wayne State University, 110, East Warren Avenue, Detroit, MI 48201
| | - Brittany Haynes
- Karmanos Cancer Institute, Wayne State University, 110, East Warren Avenue, Detroit, MI 48201; Department of Oncology, Wayne State University, 110, East Warren Avenue, Detroit, MI 48201
| | - Evangelia Kirou
- Department of Dermatology, Wayne State University, 110, East Warren Avenue, Detroit, MI 48201
| | - Ikuko Kato
- Karmanos Cancer Institute, Wayne State University, 110, East Warren Avenue, Detroit, MI 48201; Department of Oncology, Wayne State University, 110, East Warren Avenue, Detroit, MI 48201
| | - Darius R Mehregan
- Department of Dermatology, Wayne State University, 110, East Warren Avenue, Detroit, MI 48201
| | - Malathy P V Shekhar
- Karmanos Cancer Institute, Wayne State University, 110, East Warren Avenue, Detroit, MI 48201; Department of Oncology, Wayne State University, 110, East Warren Avenue, Detroit, MI 48201; Department of Pathology, Wayne State University, 110, East Warren Avenue, Detroit, MI 48201.
| |
Collapse
|
|
50
|
Melanoma Development and Progression Are Associated with Rad6 Upregulation and β -Catenin Relocation to the Cell Membrane. J Skin Cancer 2014; 2014:439205. [PMID: 24891954 PMCID: PMC4033428 DOI: 10.1155/2014/439205] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2014] [Revised: 04/02/2014] [Accepted: 04/15/2014] [Indexed: 12/21/2022] Open
Abstract
We have previously demonstrated that Rad6 and β -catenin enhance each other's expression through a positive feedback loop to promote breast cancer development/progression. While β -catenin has been implicated in melanoma pathogenesis, Rad6 function has not been investigated. Here, we examined the relationship between Rad6 and β -catenin in melanoma development and progression. Eighty-eight cutaneous tumors, 30 nevi, 29 primary melanoma, and 29 metastatic melanomas, were immunostained with anti- β -catenin and anti-Rad6 antibodies. Strong expression of Rad6 was observed in only 27% of nevi as compared to 100% of primary and 96% of metastatic melanomas. β -Catenin was strongly expressed in 97% of primary and 93% of metastatic melanomas, and unlike Rad6, in 93% of nevi. None of the tumors expressed nuclear β -catenin. β -Catenin was exclusively localized on the cell membrane of 55% of primary, 62% of metastatic melanomas, and only 10% of nevi. Cytoplasmic β -catenin was detected in 90% of nevi, 17% of primary, and 8% of metastatic melanoma, whereas 28% of primary and 30% of metastatic melanomas exhibited β -catenin at both locations. These data suggest that melanoma development and progression are associated with Rad6 upregulation and membranous redistribution of β -catenin and that β -catenin and Rad6 play independent roles in melanoma development.
Collapse
|