• E-cadherin
• Histone deacetylase 6
• Skin cancer
• Tumor progression
• β-catenin

• Humans
• Melanoma/drug therapy
• Melanoma/pathology
• Melanoma/metabolism
• Histone Deacetylase 6/antagonists & inhibitors
• Histone Deacetylase 6/metabolism
• Apoptosis/drug effects
• Cell Movement/drug effects
• Cell Proliferation/drug effects
• Histone Deacetylase Inhibitors/pharmacology
• Cell Line, Tumor
• Temozolomide/pharmacology
• Hydroxamic Acids/pharmacology
• Dacarbazine/pharmacology
• Dacarbazine/analogs & derivatives
• Drug Resistance, Neoplasm/drug effects
• Drug Synergism
• Cadherins/metabolism

• 88887.799640/2022-00 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
• 88881.708989/2022-01 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
• APQ-02291-18 Fundação de Amparo à Pesquisa do Estado de Minas Gerais

• MAFG
• MITF
• melanoma
• mouse model
• phenotype switching
• transcription factor

• T32 CA113275 NCI NIH HHS
• R01 CA244236 NCI NIH HHS
• P30 CA076292 NCI NIH HHS
• R21 CA256141 NCI NIH HHS
• R01 CA259046 NCI NIH HHS

• Ornstein-Uhlenbeck processes
• WNT signaling
• adaptation
• clonal evolution
• gene expression
• immunotherapy response
• melanoma
• single-cell analysis

• Dermatology
• Melanoma

• Humans
• Histones/genetics
• Histones/metabolism
• Melanoma/pathology
• Cell Dedifferentiation/genetics
• Acetylation
• Cell Line, Tumor
• Chromatin/genetics

• R01 CA259295 NCI NIH HHS
• F30 CA253988 NCI NIH HHS
• R01 CA154683 NCI NIH HHS
• T32 GM146636 NIGMS NIH HHS
• UL1 TR004419 NCATS NIH HHS
• P30 CA196521 NCI NIH HHS
• S10 OD026880 NIH HHS
• P30 AR079200 NIAMS NIH HHS
• S10 OD018522 NIH HHS
• National Institutes of Health

• Cancer
• Genetic regulation
• Immune resistance
• Immunotherapy
• Targeted therapy
• Tumor immunity

• Humans
• Phosphatidylinositol 3-Kinases/metabolism
• Proteomics
• Neoplasms/genetics
• Neoplasms/therapy
• Neoplasms/metabolism
• Immunotherapy
• Signal Transduction
• Tumor Microenvironment

• Mary Louise Andrews Award for Cancer Research Virginia Academy of Science

• MITF
• Wnt/β-catenin
• anti-PD-1 immunotherapy
• ferroptosis
• melanoma

• Humans
• beta Catenin/metabolism
• Ferroptosis
• Wnt Proteins/metabolism
• Melanoma/pathology
• Wnt Signaling Pathway
• Immunotherapy
• Microphthalmia-Associated Transcription Factor/metabolism

Cancer is characterized by an abnormal growth of the cells in an uncontrolled manner. These cells have the potential to invade and can eventually turn into malignancy, leading to highly fatal forms of tumor. Small subpopulations of cancer cells that are long-lived with the potential of excessive self-renewal and tumor formation are called cancer stem cells (CSCs) or cancer-initiating cells or tumor stem cells. CSCs can be found in tissues, such as breast, brain, lung, liver, ovary, and testis; however, their origin is still a matter of debate. These cells can differentiate and possess self-renewal capacity maintained by numerous intracellular signal transduction pathways, such as the Wnt/β-catenin signaling, Notch signaling, transforming growth factor-β signaling, and Hedgehog signaling. They can also contribute to numerous malignancies and are an important reason for tumor recurrence and metastasis because they are resistant to the known therapeutic strategies that mainly target the bulk of the tumor cells. This review contains collected and compiled information after analyzing published works of the last three decades. The goal was to gather information of recent breakthroughs related to CSCs, strategies to target CSCs' niche (e.g., nanotechnology with tumor biology), and their signaling pathways for cancer therapy. Moreover, the role of metformin, an antidiabetic drug, acting as a chemotherapeutic agent on CSCs by inhibiting cellular transformation and its selective killing is also addressed.

• APC
• Wnt/β-catenin signaling
• cancer
• clinical trials
• mutations
• pharmacological agents

WNT signalling is important for development in all metazoans and is associated with various human diseases. The ubiquitin–proteasome system (UPS) and regulatory endoplasmic reticulum-associated degradation (ERAD) have been implicated in the production of WNT proteins. Here, we investigated how the WNT secretory factor EVI (also known as WLS) is ubiquitylated, recognised by ERAD components and subsequently removed from the secretory pathway. We performed a focused immunoblot-based RNAi screen for factors that influence EVI/WLS protein stability. We identified the VCP-binding proteins FAF2 and UBXN4 as novel interaction partners of EVI/WLS and showed that ERLIN2 links EVI/WLS to the ubiquitylation machinery. Interestingly, we also found that EVI/WLS is ubiquitylated and degraded in cells irrespective of their level of WNT production. This K11, K48 and K63-linked ubiquitylation is mediated by the E2 ubiquitin-conjugating enzymes UBE2J2, UBE2K and UBE2N, but is independent of the E3 ubiquitin ligases HRD1 (also known as SYVN1) and GP78 (also known as AMFR). Taken together, our study identifies factors that link the UPS to the WNT secretory pathway and provides mechanistic details of the fate of an endogenous substrate of regulatory ERAD in mammalian cells.

This article has an associated First Person interview with the first author of the paper.

Summary: The WNT secretory factor EVI/WLS is ubiquitylated and linked to ER-associated degradation by multiple proteins, providing insight into the link between WNT signalling and the ubiquitin–proteasome system.

• ERAD
• EVI/WLS
• Proteolysis
• Ubiquitination/Ubiquitylation
• Wnt signaling

Tumor cells invade and spread via either a mesenchymal or an amoeboid mode of migration. Amoeboid tumor cells have a rounded morphology and pronounced RhoA activity. Here, we investigate how WNT5A signaling, a tumor promotor in melanoma, relates to Rho GTPase activity and amoeboid migration. We compared melanoma cells with low (HTB63 cells) and high (WM852 cells) WNT5A expression. HTB63 cells exhibited an amoeboid morphology and had higher RhoA activity but lower invasiveness than WM852 cells in a three‐dimensional (3D) collagen matrix. We next explored the relationships between WNT5A, morphology, and invasive behavior. WNT5A knockdown impaired Rho GTPase Cdc42 activity, resulting in reduced invasion of amoeboid and mesenchymal melanoma cells. Interestingly, knockdown of WNT5A or inhibition of its secretion in WM852 cells expressing wild‐type BRAF also led to increased RhoA activity via decreased RND3 expression, resulting in predominantly amoeboid morphology. In contrast, such treatments had the opposite effects on RND3 expression and RhoA activity in HTB63 cells expressing the active BRAF^V600 mutation. However, treatment of HTB63 cells with a BRAF inhibitor made them respond to WNT5A knockdown in a similar manner as WM852 cells expressing wild‐type BRAF. We next found that dual targeting of WNT5A and RhoA more effectively reduced melanoma cell invasion than targeting either protein individually. Taken together, our results suggest that low WNT5A signaling in melanoma cells promotes a rounded amoeboid type of invasion, which quite likely serves as a compensatory response to decreased WNT5A/Cdc42‐driven invasion. This phenomenon partially explains the enduring melanoma cell invasion observed after impaired WNT5A signaling and has therapeutic implications. Our results suggest that dual targeting of WNT5A and RhoA signaling is a more effective strategy for controlling the invasion of BRAF wild‐type and BRAF^V600 mutated melanomas treated with a BRAF inhibitor than targeting either of the proteins individually.

• WNT5A signaling
• amoeboid
• melanoma invasion
• rho GTPase

• Animals
• Carbamates/pharmacology
• Cell Line, Tumor
• Cell Proliferation/physiology
• Dishevelled Proteins/metabolism
• Drug Resistance, Neoplasm
• G1 Phase/physiology
• GTP Phosphohydrolases/genetics
• Heterografts
• Homeodomain Proteins/genetics
• Homeodomain Proteins/metabolism
• Humans
• Intracellular Signaling Peptides and Proteins/genetics
• Intracellular Signaling Peptides and Proteins/physiology
• Melanoma/drug therapy
• Melanoma/genetics
• Melanoma/mortality
• Melanoma/pathology
• Membrane Proteins/genetics
• Mice
• Molecular Targeted Therapy
• Mutation
• Neoplasm Transplantation
• Proto-Oncogene Proteins B-raf/antagonists & inhibitors
• Proto-Oncogene Proteins B-raf/genetics
• RNA, Small Interfering/metabolism
• S Phase/physiology
• Skin Neoplasms/drug therapy
• Skin Neoplasms/genetics
• Skin Neoplasms/mortality
• Skin Neoplasms/pathology
• Sulfonamides/pharmacology
• Tumor Stem Cell Assay
• Wnt Signaling Pathway/physiology

• R01 GM131101 NIGMS NIH HHS

• Animals
• Antigens, CD/metabolism
• Arginase/metabolism
• Cell Line, Tumor
• Female
• Lung Neoplasms/secondary
• Lymphocytes, Tumor-Infiltrating/metabolism
• Male
• Melanoma/metabolism
• Melanoma/secondary
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Myeloid-Derived Suppressor Cells/immunology
• Myeloid-Derived Suppressor Cells/metabolism
• Neoplasm Invasiveness
• Programmed Cell Death 1 Receptor/metabolism
• T-Lymphocytes, Regulatory/metabolism
• Transforming Growth Factor beta1/metabolism
• Tumor Microenvironment
• Wnt-5a Protein/metabolism
• Lymphocyte Activation Gene 3 Protein

• P01 CA140043 NCI NIH HHS
• P30 CA006973 NCI NIH HHS
• P30 CA010815 NCI NIH HHS
• R01 NS107342 NINDS NIH HHS
• R01 CA207935 NCI NIH HHS
• R01 NS114478 NINDS NIH HHS
• R00 CA208012 NCI NIH HHS
• P01 CA114046 NCI NIH HHS
• R01 CA174746 NCI NIH HHS
• R01 CA232256 NCI NIH HHS

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.

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.

• cancer associated fibroblast
• melanoma
• melanomagenesis
• tumor microenvironment

Secreted frizzled-related proteins (SFRP) are glycoproteins containing a so-called frizzled-like cysteine-rich domain. This domain enables them to bind to Wnt ligands or frizzled (FzD) receptors, making potent regulators of Wnt signaling. As Wnt signaling is often altered in cancer, it is not surprising that Wnt regulators such as SFRP proteins are often differentially expressed in the tumor microenvironment, both in a metastatic and non-metastatic setting. Indeed, SFRP2 is shown to be specifically upregulated in the tumor vasculature of several types of cancer. Several studies investigated the functional role of SFRP2 in the tumor vasculature, showing that SFRP2 binds to FzD receptors on the surface of tumor endothelial cells. This activates downstream Wnt signaling and which is, thereby, stimulating angiogenesis. Interestingly, not the well-known canonical Wnt signaling pathway, but the noncanonical Wnt/Ca²⁺ pathway seems to be a key player in this event. In tumor models, the pro-angiogenic effect of SFRP2 could be counteracted by antibodies targeting SFRP2, without the occurrence of toxicity. Since tumor angiogenesis is an important process in tumorigenesis and metastasis formation, specific tumor endothelial markers such as SFRP2 show great promise as targets for anti-cancer therapies. This review discusses the role of SFRP2 in noncanonical Wnt signaling and tumor angiogenesis, and highlights its potential as anti-angiogenic therapeutic target in cancer.

• Angiogenesis
• Cancer
• SFRP2
• Therapeutic target
• Tumor vasculature
• Wnt signaling

• cancer stem cells
• melanoma
• rho signalling

• Animals
• Cell Transformation, Neoplastic
• Female
• Frizzled Receptors/genetics
• Frizzled Receptors/metabolism
• Humans
• Male
• Melanoma/genetics
• Melanoma/metabolism
• Melanoma/pathology
• Mice
• Mice, SCID
• Microfilament Proteins/genetics
• Microfilament Proteins/metabolism
• Myosin Type II/genetics
• Myosin Type II/metabolism
• Neoplasm Invasiveness
• Signal Transduction
• Wnt Proteins/genetics
• Wnt Proteins/metabolism
• rho GTP-Binding Proteins/genetics
• rho GTP-Binding Proteins/metabolism
• rho-Associated Kinases/genetics
• rho-Associated Kinases/metabolism

• 21153 Cancer Research UK
• FC001112 Wellcome Trust
• FC001112 Medical Research Council
• FC001112 Cancer Research UK
• Wellcome Trust
• C10355/A15587 Cancer Research UK
• 24478 Cancer Research UK
• WT 203148/Z/16/Z Wellcome Trust
• C33043/A12065 Cancer Research UK
• C48390/A21153 Cancer Research UK
• FC001112 Arthritis Research UK
• C97993H Medical Research Council
• MR/L023091/1 Medical Research Council
• IS-BRC-1215-20006 Department of Health
• C33043/A24478 Cancer Research UK
• C30122/A15774 Cancer Research UK
• C30122/A11527 Cancer Research UK
• Cancer Research UK (CRUK)
• EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 Marie Skłodowska-Curie Actions (H2020 Excellent Science - Marie Skłodowska-Curie Actions)

• WNT
• WNT5A
• immune evasion
• melanoma
• signal transduction crosstalk
• β-catenin

• Animals
• Cell Polarity/genetics
• Cell Proliferation/genetics
• Humans
• Melanoma/genetics
• Mutation/genetics
• Wnt Signaling Pathway/genetics

• EMT
• OSCC
• PMD
• WNT
• biomarker

• Wnt5A
• aged microenvironment
• melanoma
• slow-cycling phenotype
• therapy resistance
• tumor microenvironment
• wild-type 53

• BRAF
• immunotherapy
• melanoma
• targeted therapy

• Wnt
• cancer
• targeted cancer therapy
• β-catenin

• AKT signaling
• WNT1-inducible signaling pathway protein 1 (WISP1/CCN4)
• Wnt signaling
• cancer
• epithelial-mesenchymal transition (EMT)
• invasion
• melanoma
• metastasis
• secreted protein
• tumor microenvironment

Melanoma, one of the most aggressive neoplasms, is characterized by rapid cell proliferation. Transducin-like Enhancer of Split (TLE) is an important regulator of cell proliferation via Histone deacetylase (HDAC) recruitment. Given that HDAC activity is associated with melanoma progression, we examined the relationship between TLE3, a TLE family member, and melanoma. TLE3 expression was increased during the progression of human patient melanoma (p < 0.05). Overexpression of Tle3 in B16 murine melanoma cells led to an increase in cell proliferation (p < 0.01) as well as the number of cyclinD1-positive cells. in vivo injection of mice with B16 cells overexpressing Tle3 resulted in larger tumor formation than in mice injected with control cells (p < 0.05). In contrast, siRNA-mediated knockdown of Tle3 in B16 cells or TLE3 in HMV-II human melanoma cells decreased proliferation (p < 0.01). Treatment of B16 cells with trichostatin A (2.5 μM), a class I and II HDAC inhibitor, prevented the effect s of Tle3 on proliferation. In conclusion, these data indicate that Tle3 is required, at least in part, for proliferation in the B16 mouse melanoma model.

• HDAC inhibitors
• malignant melanoma
• transcriptional co-repressor
• trichostatin A

Secreted frizzled-related protein 5 (SFRP5) plays a key role in the development and progression of multiple tumors. However, the role and underlying mechanisms of SFRP5 in melanoma cells remain unknown.

We used immunohistochemistry and Western blot analysis to detect the expression of SFRP5 in melanoma tissues and melanoma cells, respectively. Furthermore, both in vitro and in vivo assays were used to determine the effect of SFRP5 on malignant behavior in melanoma cells.

We found that SFRP5 was markedly downregulated in melanoma tissues and cell lines. The SFRP5 overexpression exhibited no effect on the proliferation and apoptosis of melanoma cells but markedly suppressed the migration and invasion of melanoma cells in vitro. Regarding mechanisms, the SFRP5 overexpression inhibited the migration and invasion of melanoma cells by suppressing the epithelial–mesenchymal transition process and decreasing the matrix metalloproteinase-2/9 expression through the Wnt signaling pathway. Finally, in a xenograft animal model, we illustrated that the SFRP5 overexpression suppressed the tumor growth by decreasing angiogenesis and declined lung metastasis.

This study suggests that SFRP5 expression could be potentially useful in the invasion and metastasis of melanoma and serve as a putative promising target for human melanoma therapy.

• SFRP5
• Wnt signaling
• invasion
• melanoma
• migration

• CD133
• CD44
• Cancer initiation
• Cancer stem cell
• DCLK1
• Metastasis
• PROM1
• Signal transduction
• Therapeutic resistance
• Tumor development

Although most melanoma cases may be treated by surgical intervention upon early diagnosis, a significant portion of patients can still be refractory, presenting low survival rates within 5 years after the discovery of the illness. As a hallmark, melanomas are highly prone to evolve into metastatic sites. Moreover, melanoma tumors are highly resistant to most available drug therapies and their incidence have increased over the years, therefore leading to public health concerns about the development of novel therapies. Therefore, researches are getting deeper in unveiling the mechanisms by which melanoma initiation can be triggered and sustained. In this context, important progress has been achieved regarding the roles and the impact of cellular signaling pathways in melanoma. This knowledge has provided tools for the development of therapies based on the intervention of signal(s) promoted by these cascades. In this review, we summarize the importance of major signaling pathways (mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K)-Akt, Wnt, nuclear factor κ-light-chain-enhancer of activated B cell (NF-κB), Janus kinase (JAK)-signal transducer and activator of transcription (STAT), transforming growth factor β (TGF-β) and Notch) in skin homeostasis and melanoma progression. Available and developing melanoma therapies interfering with these signaling cascades are further discussed.

• intracellular signaling
• melanoma
• melanomagenesis
• skin cancer

• FOXQ1
• N-cadherin
• carcinoma
• differentiation
• epithelial-to-mesenchymal transition
• invasion
• melanoma
• metastasis
• β-catenin

β-catenin/CTNNB1 is an intracellular scaffold protein that interacts with adhesion molecules (E-cadherin/CDH1, N-cadherin/CDH2, VE-cadherin/CDH5 and α-catenins), transmembrane-type mucins (MUC1/CD227 and MUC16/CA125), signaling regulators (APC, AXIN1, AXIN2 and NHERF1/EBP50) and epigenetic or transcriptional regulators (BCL9, BCL9L, CREBBP/CBP, EP300/p300, FOXM1, MED12, SMARCA4/BRG1 and TCF/LEF). Gain-of-function CTTNB1 mutations are detected in bladder cancer, colorectal cancer, gastric cancer, liver cancer, lung cancer, pancreatic cancer, prostate cancer and uterine cancer, whereas loss-of-function CTNNB1 mutations are also detected in human cancer. ABCB1, ALDH1A1, ASCL2, ATF3, AXIN2, BAMBI, CCND1, CD44, CLDN1, CTLA4, DKK1, EDN1, EOMES, FGF18, FGF20, FZD7, IL10, JAG1, LEF1, LGR5, MITF, MSX1, MYC, NEUROD1, NKD1, NODAL, NOTCH2, NOTUM, NRCAM, OPN, PAX3, PPARD, PTGS2, RNF43, SNAI1, SP5, TCF7, TERT, TNFRSF19, VEGFA and ZNRF3 are representative β-catenin target genes. β-catenin signaling is involved in myofibroblast activation and subsequent pulmonary fibrosis, in addition to other types of fibrosis. β-catenin and NF-κB signaling activation are involved in field cancerization in the stomach associated with Helicobacter pylori (H. pylori) infection and in the liver associated with hepatitis C virus (HCV) infection and other etiologies. β-catenin-targeted therapeutics are functionally classified into β-catenin inhibitors targeting upstream regulators (AZ1366, ETC-159, G007-LK, GNF6231, ipafricept, NVP-TNKS656, rosmantuzumab, vantictumab, WNT-C59, WNT974 and XAV939), β-catenin inhibitors targeting protein-protein interactions (CGP049090, CWP232228, E7386, ICG-001, LF3 and PRI-724), β-catenin inhibitors targeting epigenetic regulators (PKF118-310), β-catenin inhibitors targeting mediator complexes (CCT251545 and cortistatin A) and β-catenin inhibitors targeting transmembrane-type transcriptional outputs, including CD44v6, FZD7 and LGR5. Eradicating H. pylori and HCV is the optimal approach for the first-line prevention of gastric cancer and hepatocellular carcinoma (HCC), respectively. However, β-catenin inhibitors may be applicable for the prevention of organ fibrosis, second-line HCC prevention and treating β-catenin-driven cancer. The multi-layered prevention and treatment strategy of β-catenin-related human diseases is necessary for the practice of personalized medicine and implementation of precision medicine.

• KLF4
• embryonic stem cells
• melanoma
• miR-183~96~182 cluster
• microRNA

We reported that knockdown of the antisense noncoding mitochondrial RNAs (ASncmtRNAs) induces apoptotic death of several human tumor cell lines, but not normal cells, suggesting this approach for selective therapy against different types of cancer. In order to translate these results to a preclinical scenario, we characterized the murine noncoding mitochondrial RNAs (ncmtRNAs) and performed in vivo knockdown in syngeneic murine melanoma models. Mouse ncmtRNAs display structures similar to the human counterparts, including long double-stranded regions arising from the presence of inverted repeats. Knockdown of ASncmtRNAs with specific antisense oligonucleotides (ASO) reduces murine melanoma B16F10 cell proliferation and induces apoptosis in vitro through downregulation of pro-survival and metastasis markers, particularly survivin. For in vivo studies, subcutaneous B16F10 melanoma tumors in C57BL/6 mice were treated systemically with specific and control antisense oligonucleotides (ASO). For metastasis studies, tumors were resected, followed by systemic administration of ASOs and the presence of metastatic nodules in lungs and liver was assessed. Treatment with specific ASO inhibited tumor growth and metastasis after primary tumor resection. In a metastasis-only assay, mice inoculated intravenously with cells and treated with the same ASO displayed reduced number and size of melanoma nodules in the lungs, compared to controls. Our results suggest that ASncmtRNAs could be potent targets for melanoma therapy. To our knowledge, the ASncmtRNAs are the first potential non-nuclear targets for melanoma therapy.

• antisense therapy
• melanoma
• metastasis
• mitochondria
• noncoding RNA

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.

• WNT/β-catenin
• melanoma heterogeneity
• metastases
• proliferation

Cutaneous melanoma represents the most fatal skin cancer due to its high metastatic capacity. According to the “phenotype switching” model, the aggressive nature of melanoma cells results from their intrinsic potential to dynamically switch from a high-proliferative/low-invasive to a low-proliferative/high-invasive state. Here we identify the low affinity neurotrophin receptor CD271 as a key effector of phenotype switching in melanoma. CD271 plays a dual role in this process by decreasing proliferation, while simultaneously promoting invasiveness. Dynamic modification of CD271 expression allows tumor cells to grow at low levels of CD271, to reduce growth and invade when CD271 expression is high, and to re-expand at a distant site upon decrease of CD271 expression. Mechanistically, the cleaved intracellular domain of CD271 controls proliferation, while the interaction of CD271 with the neurotrophin receptor Trk-A modulates cell adhesiveness through dynamic regulation of a set of cholesterol synthesis genes relevant for patient survival.

The aggressive nature of melanoma cells relies on their ability to switch from a high-proliferative/low-invasive to a low-proliferative/high-invasive state; however, the mechanisms governing this switch are unclear. Here, using in vivo models of human melanoma, the authors show that CD271 is a key regulator of phenotype switching and metastasis formation.

Melanoma is a cancer that exhibits one of the most aggressive and heterogeneous features. The incidence rate escalates. A high number of clones harboring various mutations contribute to an exceptional level of intratumor heterogeneity of melanoma. It also refers to metastases which may originate from different subclones of primary lesion. Such component of the neoplasm biology is termed intertumor and intratumor heterogeneity. These levels of tumor heterogeneity hinder accurate diagnosis and effective treatment. The increasing number of research on the topic reflects the need for understanding limitation or failure of contemporary therapies. Majority of analyses concentrate on mutations in cancer-related genes. Novel high-throughput techniques reveal even higher degree of variations within a lesion. Consolidation of theories and researches indicates new routes for treatment options such as targets for immunotherapy. The demand for personalized approach in melanoma treatment requires extensive knowledge on intratumor and intertumor heterogeneity on the level of genome, transcriptome/proteome, and epigenome. Thus, achievements in exploration of melanoma variety are described in details. Particularly, the issue of tumor heterogeneity or homogeneity given BRAF mutations is discussed.

Cancer stem cells (CSCs), which have the potential for self-renewal, differentiation and de-differentiation, undergo epigenetic, epithelial-mesenchymal, immunological and metabolic reprogramming to adapt to the tumor microenvironment and survive host defense or therapeutic insults. Intra-tumor heterogeneity and cancer-cell plasticity give rise to therapeutic resistance and recurrence through clonal replacement and reactivation of dormant CSCs, respectively. WNT signaling cascades cross-talk with the FGF, Notch, Hedgehog and TGFβ/BMP signaling cascades and regulate expression of functional CSC markers, such as CD44, CD133 (PROM1), EPCAM and LGR5 (GPR49). Aberrant canonical and non-canonical WNT signaling in human malignancies, including breast, colorectal, gastric, lung, ovary, pancreatic, prostate and uterine cancers, leukemia and melanoma, are involved in CSC survival, bulk-tumor expansion and invasion/metastasis. WNT signaling-targeted therapeutics, such as anti-FZD1/2/5/7/8 monoclonal antibody (mAb) (vantictumab), anti-LGR5 antibody-drug conjugate (ADC) (mAb-mc-vc-PAB-MMAE), anti-PTK7 ADC (PF-06647020), anti-ROR1 mAb (cirmtuzumab), anti-RSPO3 mAb (rosmantuzumab), small-molecule porcupine inhibitors (ETC-159, WNT-C59 and WNT974), tankyrase inhibitors (AZ1366, G007-LK, NVP-TNKS656 and XAV939) and β-catenin inhibitors (BC2059, CWP232228, ICG-001 and PRI-724), are in clinical trials or preclinical studies for the treatment of patients with WNT-driven cancers. WNT signaling-targeted therapeutics are applicable for combination therapy with BCR-ABL, EGFR, FLT3, KIT or RET inhibitors to treat a subset of tyrosine kinase-driven cancers because WNT and tyrosine kinase signaling cascades converge to β-catenin for the maintenance and expansion of CSCs. WNT signaling-targeted therapeutics might also be applicable for combination therapy with immune checkpoint blockers, such as atezolizumab, avelumab, durvalumab, ipilimumab, nivolumab and pembrolizumab, to treat cancers with immune evasion, although the context-dependent effects of WNT signaling on immunity should be carefully assessed. Omics monitoring, such as genome sequencing and transcriptome tests, immunohistochemical analyses on PD-L1 (CD274), PD-1 (PDCD1), ROR1 and nuclear β-catenin and organoid-based drug screening, is necessary to determine the appropriate WNT signaling-targeted therapeutics for cancer patients.

• alzheimer's disease
• angiogenesis
• cancer stem cells
• epithelial-to-mesenchymal transition
• fgf
• myeloid-derived suppressor cells
• notch
• regulatory t cells
• tumor microenvironment
• wnt5a

• Animals
• Colorectal Neoplasms, Hereditary Nonpolyposis/genetics
• Colorectal Neoplasms, Hereditary Nonpolyposis/metabolism
• Colorectal Neoplasms, Hereditary Nonpolyposis/therapy
• Endometrial Neoplasms/genetics
• Endometrial Neoplasms/metabolism
• Endometrial Neoplasms/therapy
• Female
• Humans
• Intellectual Disability/metabolism
• Intellectual Disability/therapy
• Male
• Mutation
• Neoplasm Proteins/genetics
• Neoplasm Proteins/metabolism
• Prostatic Neoplasms/genetics
• Prostatic Neoplasms/metabolism
• Prostatic Neoplasms/therapy
• Wnt Signaling Pathway/genetics

• MITF
• RAC
• RHO
• PDE5A
• TGFβ
• WNT5A
• co-operative invasion
• invasion
• melanoma
• phenotype switching

• Animals
• Antineoplastic Agents/therapeutic use
• Cell Differentiation
• Gene Expression Regulation, Neoplastic/drug effects
• Humans
• Melanoma/drug therapy
• Melanoma/metabolism
• Melanoma/pathology
• Molecular Targeted Therapy
• Neoplasm Invasiveness
• Neoplasm Metastasis
• Neoplasm Proteins/antagonists & inhibitors
• Phenotype
• Signal Transduction/drug effects
• Skin Neoplasms/drug therapy
• Skin Neoplasms/metabolism
• Skin Neoplasms/pathology

• 16416 Cancer Research UK
• C11591/A16416 Cancer Research UK

• Axin
• Cytomegalovirus
• Epstein-Barr virus
• Glycogen synthase kinase-3
• Herpes simplex virus-1
• Herpesvirus
• Kaposi’s sarcoma-associated herpesvirus
• Varicella zoster virus
• Wnt/β-catenin

• Germ cells
• Planar cell polarity proteins
• Seminiferous epithelial cycle
• Sertoli cells
• Spermatogenesis
• Testis
• Wnt/PCP signaling

• Animals
• Cell Polarity
• Humans
• Male
• Models, Biological
• Proteins/metabolism
• Signal Transduction
• Spermatogenesis
• Testis/cytology
• Testis/metabolism

• R01 HD056034 NICHD NIH HHS
• U54 HD029990 NICHD NIH HHS

The proto-oncogene LIM-domain only 2 (lmo2) was traditionally considered to be a pivotal transcriptional regulator in hematopoiesis and leukemia. Recently, the cytosolic localization of LMO2 was revealed in multiple epithelial tissues and a variety of solid tumors. However, the function of LMO2 in these epithelia and solid tumors remains largely unclear. The Wnt signaling pathway is a crucial determinant of development, and abnormalities in several key segments of this pathway contribute to oncogenesis. The current study demonstrated that LMO2 participates in the regulation of canonical Wnt signaling in the cytoplasm by binding to Dishevelled-1/2 (DVL-1/2) proteins. These interactions occurred at the PDZ domain of Dishevelled, and LMO2 subsequently attenuated the activation of the key factor β-catenin in the canonical Wnt signaling pathway. Meanwhile, significantly decreased expression of LMO2 was detected in breast and colorectal cancers, and the downregulation of LMO2 in these cells increased cell proliferation and reduced apoptosis. Taken together, the data in this study revealed a novel crosstalk between LMO2 and the Wnt signaling pathway during tumorigenesis and suggested that LMO2 might be a tumor suppressor in certain solid tumors, in contrast to its traditional oncogenic role in the hematopoietic system.

Although the clinical landscape of melanoma is improving rapidly, metastatic melanoma remains a deadly disease. Age remains one of the greatest risk factors for melanoma, and patients older than 55 have a much poorer prognosis than younger individuals, even when the data are controlled for grade and stage. The reasons for this disparity have not been fully uncovered, but there is some recent evidence that Wnt signalling may have a role. Wnt signalling is known to have roles both in cancer progression as well as in organismal ageing. In melanoma, the interplay of Wnt signalling pathways is complex, with different members of the Wnt family guiding different aspects of invasion and proliferation. Here, we will briefly review the current literature addressing the roles of different Wnt pathways in melanoma pathogenesis, provide an overview of Wnt signalling during ageing, and discuss the intersection between melanoma and ageing in terms of Wnt signalling.

• CD103
• Cancer
• Dendritic cells
• Immunology
• PGE2
• β-catenin

Ultraviolet (UV) radiation is involved in almost all skin cancer cases, but on the other hand, it stimulates the production of pre-vitamin D3, whose active metabolite, 1,25-dihydroxyvitamin D3 (1,25VD3), plays important physiological functions on binding with its receptor (vitamin D receptor, VDR). UV-induced DNA damages in the form of cyclobutane pyrimidine dimers or (6-4)-pyrimidine-pyrimidone photoproducts are frequently found in skin cancer and its precursors. Therefore, removing these lesions is essential for the prevention of skin cancer. As UV-induced DNA damages are repaired by nucleotide excision repair (NER), the interaction of 1,25VD3 with NER components can be important for skin cancer transformation. Several studies show that 1,25VD3 protects DNA against damage induced by UV, but the exact mechanism of this protection is not completely clear. 1,25VD3 was also shown to affect cell cycle regulation and apoptosis in several signaling pathways, so it can be considered as a potential modulator of the cellular DNA damage response, which is crucial for mutagenesis and cancer transformation. 1,25VD3 was shown to affect DNA repair and potentially NER through decreasing nitrosylation of DNA repair enzymes by NO overproduction by UV, but other mechanisms of the interaction between 1,25VD3 and NER machinery also are suggested. Therefore, the array of NER gene functioning could be analyzed and an appropriate amount of 1.25VD3 could be recommended to decrease UV-induced DNA damage important for skin cancer transformation.

• DNA damage
• DNA repair
• UV radiation
• melanoma
• nucleotide excision repair
• skin cancer