Melanoma Subtypes Research Articles

Clinical Impact of Immune Checkpoint Inhibitor (ICI) Response, DNA Damage Repair (DDR) Gene Mutations and Immune-Cell Infiltration in Metastatic Melanoma Subtypes.

Molecular and histopathological analysis of melanoma subtypes has revealed distinct epidemiological, genetic, and clinical features. However, immunotherapy for advanced metastatic melanoma patients does not differ based on subtype. Response to immune checkpoint inhibitors (ICI) has been shown to vary, therefore, predictive biomarkers are needed in the design of precision treatments. Targeted sequencing and histopathological analysis (CD8 and CD20 immunohistochemistry) were performed on subtypes of metastatic melanoma (cutaneous melanoma (CM, n = 10); head and neck melanoma (HNM, n = 7); uveal melanoma (UM, n = 4); acral lentiginous melanoma (AM, n = 1) and mucosal melanoma (MM, n = 1) treated with ICI). Progression-free survival (PFS) was significantly associated with high CD8 expression (p = 0.025) and mutations in DNA damage repair (DDR) pathway genes (p = 0.012) in all subtypes but not with CD20 expression. Our study identified that immune cell infiltration and DDR gene mutations may have an impact in response to ICI treatment in metastatic melanoma but differs among subtypes. Therefore, a comprehensive understanding of the immune infiltration cells’ role and DDR gene mutations in metastatic melanoma may identify prognostic biomarkers.

Redefining the treatment of metastatic uveal melanoma with immunotherapy – A case report

Cancer immunotherapy originated in the early 1900s with the understanding of cancer immune surveillance and host immune defense mechanisms against cancer cells. Immunotherapy has provided a ray of hope in patients with uveal melanoma, a subtype of melanoma that has a poor prognosis once it has metastasized. Metastatic uveal melanoma (MUM) lacks a standard protocol for the treatment. Systemic chemotherapy has not shown any potential benefit. Moreover, its high toxicity has limited its use. Immunotherapy has changed the approach to treating these patients and has significantly prolonged the overall survival as well as the quality of life. We, hereby, present an interesting case of a patient presenting with MUM after an unusually long time from the primary treatment and showing an exceptional response to immunotherapy.

Variation in second cancer risk by melanoma subtype among survivors

To the Editor: The incidence of melanoma in the United States is increasing, with 100,000 new cases projected in 2022.1,2 Survivors of cutaneous melanoma (CM) are at an increased risk of developing second primary cancers (SPCs), including melanoma, breast cancer, prostate cancer, and non-Hodgkin lymphoma.3,4 Variation in SPC risk according to CM subtype has not been systematically evaluated using population data.

Selected Articles from This Issue

Interleukin-15 (IL-15) regulates the generation, persistence, and differentiation of natural killer (NK) and CD8 T cells. To expand its role in cancer immunotherapy, Chen and colleagues designed a multitumor model treated with the combination of intratumoral anti-CD40, parenteral IL-15 and anti-PD-1. Anti-CD40 given intratumorally not only reduced dosing requirements and toxicity, but it also stimulated the antitumor activity of the distal tumors, suggestive of an abscopal effect. IL-15 with intratumoral anti-CD40 was additive/synergistic, and the inclusion of the anti-PD-1 was additive to the combination. Thus, this treatment shows promise for patients with solid tumors or resistance to anti-PD-1 therapy.Cancer-associated fibroblasts (CAF) are a heterogenous cell population with a complex immunoregulatory role, which has not been well defined in head and neck squamous cell carcinoma (HNSCC). Leveraging protein activity inference tools to analyze scRNA-sequencing of HNSCC patients, pre- and post-nivolumab, Obradovic and colleagues identified distinct subpopulations of head and neck CAF (HNCAF). Enrichment of a T-cell stimulating population (tsCAF) was found to associate with treatment response and ex vivo assays confirmed this CAF subset reduces CD8 T-cell exhaustion. Analysis of an independent HNSCC cohort treated with pembrolizumab validated this tsCAF subset as a potential biomarker of response.Approximately 30% of MSI-H/dMMR tumors do not respond to immune checkpoint inhibitors (ICI), highlighting the importance of identifying predictive biomarkers or molecular profiling correlated with resistance to these agents. Here, Chida and colleagues performed transcriptomic profiling of MSI-H/dMMR gastrointestinal tumors treated with PD-1 blockade. The study revealed that nonresponders had the enrichment of epithelial mesenchymal transition, angiogenesis, hypoxia, mTORC1, KRAS, Wnt/β-catenin, TGF-β, and various metabolism-related signaling pathways, which have been associated with an immunosuppressive tumor microenvironment. Meanwhile, the IFN-γ pathway was upregulated in responders. High expression of VEGF-A might predict a negative response to ICI in this population.Acral melanoma is a rare subtype of melanoma that arises on non-sun exposed skin of the hands, feet, and nailbeds. Patients with acral melanoma have lower response rates to immunotherapy than those with nonacral cutaneous melanoma, suggesting unique microenvironmental features. In their study, Li and colleagues performed comprehensive single cell analysis of a cohort of acral melanoma specimens and found them to harbor fewer effector CD8 T cells and NK cells and a complete absence of γδ T cells compared to non-acral cutaneous melanoma. VISTA, TIGIT, and adenosine signaling were identified as targetable immune checkpoints in acral melanoma.

Actionable Mutation Profile of Sun-Protected Melanomas in South America.

Melanomas that arise in sun-protected sites, including acral and oral mucosal melanomas, are likely under the control of unique, specific mechanisms that lead to mutagenesis through various pathways. In this study, we examined somatic mutations in tumors by targeted sequencing using a custom Ion Ampliseq Panel, comprising hotspots of 14 genes that are frequently mutated in solid tumors. Tumor DNA was extracted from 9 formalin fixation, paraffin-embedded sun-protected melanomas (4 primary oral mucosal melanomas and 5 acral lentiginous melanomas), and we identified mutations in the NRAS , PIK3CA , EGFR , HRAS , ERBB2 , and ROS1 genes. This study reveals new actionable mutations that are potential targets in the treatment of photo-protected melanomas. Additional studies on more of these melanoma subtypes could confirm our findings and identify new mutations.

Survival and tumor characteristics of patients presenting with single primary versus second primary melanoma lesions

Patients with single primary melanomas have an increased risk of developing subsequent melanomas. Secondary tumors diagnosed within and after three months are termed "synchronous" and "asynchronous," respectively. Compare the tumor distributions and survival characteristics of patients with second primary melanoma subtypes to patients with single primary melanomas. Retrospective cohort study. Data were collected from an institutional database from 14,029 patients with a diagnosis of a primary melanoma seen between 1970 and 2004. The synchronous and asynchronous cohorts demonstrated significantly improved survival probabilities compared to the single primary cohort (p=.04 and .002, respectively). Single primaries (2.2mm, SD=2.3) were significantly thicker than the first identified synchronous (2.0mm, SD=1.7) and the first identified asynchronous lesions (1.7mm, SD= 1.3). Synchronous lesions were more likely to be anatomically concordant compared to asynchronous lesions (55.7% vs 38.2%, p<.001). Our limitations include the single center study design as well as incomplete records for second primary melanoma Breslow depth and histopathology. Patients with second primary melanomas demonstrated a significant survival advantage and thinner lesions compared to single primary melanomas. Our reported tumor distributions support the role of FBSE's, with attention to the region of initial diagnosis.

Classification and Staging of Melanoma in the Head and Neck.

The rates of melanoma continue to rise, with recent estimates have shown that 18% to 22% of new melanoma cases occur within the head and neck in the United States each year. The mainstay of treatment of nonmetastatic primary melanomas of the head and neck includes the surgical resection and management of regional disease as indicated. Thorough knowledge of the classification and staging of melanoma is paramount to evaluate prognosis, determine the appropriate surgical intervention, and assess eligibility for adjuvant therapy and clinic trials. The traditional clinicopathologic classification of melanoma is based on morphologic aspects of the growth phase and distinguishes 4 of the most common subtypes as defined by the World Health Organization: superficial spreading, nodular, acral lentiginous, and lentigo maligna melanoma. The data used to derive the AJCC TNM Categories are based on superficial spreading melanoma and nodular subtypes. Melanoma is diagnosed histopathologically following initial biopsy that will assist with classifying the tumor to guide treatment. Classification is based on tumor thickness and ulceration (T stage, Breslow Staging), Regional Lymph Node Involvement (N Stage), and presence of metastasis (M Stage). Tumor thickness (Breslow thickness) and ulceration are 2 independent prognostic factors that have been shown to be the strongest predictors of survival and outcome. Clark level of invasion and mitotic rate are no longer incorporated into the current AJCC staging system, but still have shown to be important prognostic factors for cutaneous melanoma. For patients with metastatic (Stage IV) disease Lactate Dehydrogenase remains an independent predictor of survival. The Maxillofacial surgeon must remain up to date on the most current management strategies in this patient population. Classification systems and staging provide the foundation for clinical decision making and prognostication for the Maxillofacial surgeon when caring for these patients.

Whole-slide multispectral imaging reveals the immune subtypes of melanoma associated with the tumor microenvironment: An automated 7-color mIF assay

Abstract Immunotherapy and precision medicine are rapidly developing approaches to cancer therapy. Biomarkers that detect the tumor and tumor microenvironment allow for the development of strategies that accelerate the advancement of treatments to enhance a patient’s immune system. Akoya’s MOTiF™ PD-1/PD-L1 Auto Melanoma Kit is a validated, multiplex immunoassay enabling detection of the 6 most clinically relevant immuno-oncology and spatial biomarkers: FoxP3, PD-L1, Sox10/S100, PD-1, CD8 and CD68. In this study, the MOTiF™ PD-1/PD-L1 panel was used to analyze the tumor microenvironment and specifically assess immune phenotypes within melanoma samples from 3 patients. This study demonstrates a fully optimized and end-to-end workflow solution for biomarker discovery in melanoma. We demonstrate the utility of Akoya’s MOTiF™ PD-1/PD-L1 Melanoma panel kit in studying the cellular diversity while retaining spatial context. Stained slides were analyzed using the InForm® and PhenoptrReports image analysis platforms to identify phenotypes and better understand spatial relationships between cell phenotypes. The MOTiF™ PD-1/PD-L1 panel kit provides reproducibility across different patient samples. This data provides insight into the innate and adaptive immune landscape for targeted design of new immunotherapies as well as improved efficacy and reduced toxicity in the treatment of melanoma.

Tumor-intrinsic factors dictate beneficial effect of microbiota-based therapies

Abstract Gut microbiota impacts antitumor immunity and recent studies have shown that manipulating microbiota via fecal transplant can rescue immune checkpoint blockade (ICB) response in refractory melanoma patients. However, not all patients benefited from this approach. We hypothesize that tumor-intrinsic factors (e.g. neoantigen load and immune microenvironment) contribute to the microbiota effect on anticancer response. To test this, we performed preclinical microbiota manipulation studies using dietary intervention. Mice fed high-fiber diet (FD) had improved spontaneous tumor control and response to ICB. Mechanistically, FD-induced changes in microbiota composition skewed the tumor innate immune repertoire towards an antitumor profile marked by increased dendritic cell infiltration. Downstream of the innate compartment, FD reduced the proportion of intratumoral Tregs and exhausted CD8+ T cells. We further assessed the effects of FD across 8 tumor models including EL4 lymphoma, MC38 colon carcinoma, and 6 melanomas (M1–M6) that mimic the variety of human melanoma subtypes. Although FD had a beneficial effect overall, not all models responded to the same extent, and were accompanied by different changes in the tumor immune profile. FD delayed tumor initiation for EL4 and M4, reduced growth rate for M3 and M5, both delayed initiation and reduced growth rate for MC38, M2, and M6, but had no significant effects for M1. Additionally, we found that increasing tumor immunogenicity resulted in a synergistic effect with FD. Our data suggests that tumor-intrinsic factors influence the beneficial effect of microbiota on antitumor immunity. Identifying these factors will help refine the use of microbiota-based therapies in the clinic. This research was supported by the Intramural Research Program of the NIH (CCR-NCI). This research was supported by the Intramural Research Program of the NIH (CCR-NCI).

Antigen mimicry as an effective strategy to induce CSPG4-targeted immunity in dogs with oral melanoma: a veterinary trial

BackgroundMelanoma is the most lethal form of skin cancer in humans. Conventional therapies have limited efficacy, and overall response is still unsatisfactory considering that immune checkpoint inhibitors induce lasting clinical...

Lentigo Maligna of the head and neck: A retrospective study assessing surgical excision margins in a South African population

BackgroundLentigo maligna (LM) is a subtype of melanoma in situ that occurs on sun-damaged skin and is associated with significant subclinical extension beyond the clinical margins of the lesion.ObjectivesThis study aimed to determine if the standard recommended tumor excision margins for LM are adequate to achieve a 97% clearance rate and if any patient or tumor characteristics warranted wider margins.MethodsThis study is a retrospective chart review of all patients who were diagnosed with LM of the head and neck and treated with staged excision.ResultsThe study included 64 patients. With a 6 mm surgical excision margin, only 60.9% of LM were completely excised. A 9 mm margin resulted in complete clearance of 71.9% of LM cases, and a 12 mm margin resulted in complete clearance in 90.6%. A surgical excision margin of 18 mm would have been required to excise 96.7% of tumors completely. Recurrent tumors (P = .01) and tumor size larger than 20 mm were associated with wider surgical excision margins (P = .154).ConclusionThis study of LM in a South African population corroborates that the standard surgical excision margins recommended by international melanoma guidelines for LM are inadequate to achieve a 97% clearance rate.

Specific Anatomic Transcriptomes Drive Oncogenesis in Melanoma.

Positional identity is crucial for determining the specificity of oncogenes in melanoma subtypes.

Malignant and in situ subtypes of melanoma are associated with basal and squamous cell carcinoma and its precancerous lesions

Patients with cutaneous malignant melanoma (CMM) are at increased risk of non-melanoma skin cancers (NMSCs) and possibly precancerous lesions. To analyse the association between CMM and not only NMSCs but also precursor lesions, actinic keratosis (AK) and Bowen disease (BD). The Finnish Cancer Registry data was used to calculate the age-standardized incidence ratio during 2000-2013 for basal (BCC) and squamous (SCC) cell carcinoma in patients with CMM. All tissue material collected from 70,420 subjects during 2000-2013 and reposited in the Biobank of Eastern Finland was used to calculate the age-standardized prevalence of BCC, SCC, BD and AK in CMM patients. In both genders, the age-standardized incidence ratio of BCC and SCC was increased in CMM patients. The age-standardized prevalence of NMSCs and precursor lesions was higher in patients with CMM than in those without CMM, and was higher in CMM patients with immunosuppression (IS) than in those without IS. The association of M-Snomed subtypes, lentigo maligna (LM), melanoma in situ (MIS) and malignant melanoma (MM) with AK and/or BD was stronger than with BCC. LM revealed the highest association with the combination of AKBD-SCC. Male subjects showed a higher age-standardized prevalence of CMM, MM and BCC than females, but the opposite was observed for AK. Melanoma increases the risk of NMSCs, and IS may enhance this risk. Both malignant and in situ subtypes of melanoma associate with not only BCC and SCC, but also precancerous lesions.

Differences by Anatomical Site of Non-Acral Lentiginous Melanomas of the Lower Limb

Background: Acral location of melanomas is associated with poor survival. It can be due, at least in part, to the fact that acral lentiginous melanoma, a distinct melanoma subtype, has a particular biological profile and a bad clinical behavior. However, since almost 50% of acral melanomas are not of acral lentiginous melanoma subtype, the worse clinical behavior could also be attributable to the intrinsic characteristics of the location. Objective: This study aimed to investigate if melanomas of the lower limb excluding acral lentiginous melanoma differ by location. Methods: This retrospective, observational study recruited patients from an oncology referral center in Spain. We included 285 patients with superficial spreading and nodular melanomas of the lower limb. We compare melanomas by site, clinical and pathological characteristics, and the differences by location of disease-free and melanoma-specific survival by the Kaplan-Meier method and Cox proportional hazard method. Results: Patients with melanomas on the foot, compared to those on the rest of the limb, were older and reported having suffered less sunburns; the melanoma more frequently appeared in areas that had been rarely sun exposed, were more frequently of nodular type, presented thicker tumors, with more ulceration, less regression, and more advanced stage of the disease. Foot location increased the risk of relapse and decreased melanoma-specific survival. Conclusion: Melanoma development in foot is less related to sun exposure and is associated with pathological features that can account for the worse prognosis and poorer survival.

Prognostic value of ulceration varies across Breslow thicknesses and clinical stages in acral melanoma: a retrospective study.

SummaryBackgroundUlceration is regarded as an adverse prognostic factor and is used together with tumour thickness to subcategorize patients with cutaneous melanoma. However, the prognostic impact of ulceration in acral melanoma (AM) is controversial.ObjectivesTo assess the prognostic impact of ulceration in AM and the variability across different Breslow thicknesses and clinical stages.MethodsA multicentre retrospective study of patients diagnosed with AM between January 2000 and December 2017. Differences in melanoma‐specific survival (MSS) between patients with and without ulceration were assessed using the multivariable Cox proportional hazards model and log‐rank test.ResultsAmong 1053 enrolled patients, 62.6% had ulceration. After a median follow‐up of 61 months, patients with ulceration had a lower median MSS than those without: 66.1 months, 95% confidence interval (CI) 60.0–86.0 vs. not reached; hazard ratio 1.41, 95% CI 1.09–1.82; P = 0.012. Among patients with thin (≤ 1 mm) melanoma, the survival curves of patients with vs. without ulceration clearly separated over time (P < 0.001). No association between ulceration and MSS was observed for melanomas of thickness > 1 mm (subgroups of T2, T3 and T4; all P‐values > 0.05) or patients with stage III disease (hazard ratio 1.09, 95% CI 0.71–1.68, P = 0.39).ConclusionsUlceration is an independent negative prognostic factor for patients with AM, but the impact varies across Breslow thicknesses and clinical stages. Ulceration has a significant effect on prognosis for patients with thin (≤ 1 mm) melanoma, but there was no association between ulceration and survival in intermediate/thick AM or stage III AM. What is already known about this topic? Ulceration status is used together with Breslow tumour thickness to subcategorize patients into different stages according to the America Joint Committee on Cancer melanoma staging system.As one distinctive subtype of cutaneous melanoma, acral melanoma (AM) is characterized by poor survival outcomes due to delayed diagnosis and a high prevalence of negative prognostic and genetic features.The prognostic impact of ulceration in AM is still controversial. What does this study add? This was the first large‐scale study to assess the prognostic and staging values of ulceration in patients with AM.Ulceration has a significant effect on prognosis for patients with thin (≤1 mm) melanoma, but no association between ulceration and survival was found in intermediate/thick or stage III AM.These findings should be considered when using ulceration‐based staging systems.

Digital melanoma in Caucasians: a descriptive and survival study according to sublocation.

Digital melanoma is an uncommon form of acral melanoma that is anatomically restricted to the finger. The aim of this study is to provide specific epidemiological and clinical information about this subtype of melanoma, as well as to identify differences in recurrence and survival depending on the anatomical sublocation. We describe a group of 45 Caucasian patients with digital melanoma divided into three groups: nail unit melanoma (group A), finger skin melanoma (group B), and those melanomas that involve both nail and adjacent skin (group C). The mean tumor thickness was 4.66 mm, and the most common histological subtype is acral lentiginous melanoma. Group C was more frequent in older men and was thicker and more frequently ulcerated (P < 0.05). In addition, patients in group C developed distant metastases more frequently and had a significantly lower median disease-free survival (26.60 months) compared with group A (69.47 months) and group B (89.81 months) (P < 0.05). According to our results, digital melanoma limited to nail apparatus or finger skin was associated with a better prognosis, while those affecting both nail apparatus and skin showed lower melanoma-specific survival.

Second Primary Malignancies in Patients With Melanoma Subtypes: Analysis of 120,299 Patients From the SEER Database (2000-2016).

PurposeEvaluate incidence of second primary malignancies (SPM) after non-acral cutaneous melanoma (NACM), acral lentiginous melanoma (ALM), mucosal melanoma (MM), and uveal melanoma (UM).Patients and MethodsFirst primary NACM, ALM, MM, and UM cases diagnosed 2000-2016 were extracted from SEER. Seer*Stat was used to calculate excess absolute risks (EAR) and standardized incidence ratios (SIR) of SPMs relative to a matched cohort from the general population. P-value of 0.05 determined significance.ResultsInclusion criteria was met by 109,385 patients with NACM, 2166 with ALM, 2498 with MM, and 6250 with UM. Increased incidence of malignancies occurred after NACM (SIR 1.51; 95%CI, 1.49-1.54), ALM (SIR 1.59; 95%CI, 1.40-1.81), MM (SIR 2.14; 95%CI, 1.85-2.45), and UM (SIR 1.24; 95%CI, 1.14-1.34) relative to the general population. Cutaneous melanoma occurred more frequently after NACM (SIR 9.54; 95%CI, 9.27-9.83), ALM (SIR 12.19; 95%CI, 9.70-15.14), MM (SIR 10.05; 95%CI, 7.18-13.68), and UM (SIR 2.91; 95%CI, 2.27-3.66). Patients with initial NACM (SIR 2.44; 95%CI, 1.64-3.51) and UM (SIR 44.34; 95%CI, 29.91-63.29) demonstrated increased incidence of eye and orbit melanoma. Renal malignancies occurred more frequently after NACM (SIR 1.24; 95%CI, 1.11-1.38), MM (SIR 3.54; 95%CI, 1.62-6.72) and UM (SIR 1.68; 95%CI, 1.09-2.48). Increased incidence of thyroid malignancies was observed after NACM (SIR 1.83; 95%CI, 1.61-2.06), ALM (SIR 3.74; 95%CI, 1.71-7.11), MM (SIR 4.40; 95%CI, 1.77-9.06), and UM (SIR 3.79; 95%CI, 2.52-5.47). Increased incidence of lymphoma was observed after NACM (SIR 1.20; 95%CI, 1.09-1.31) and ALM (SIR 2.06; 95%CI, 1.13-3.46).ConclusionPatients with NACM, ALM, MM, and UM have increased incidence of SPMs compared to that expected from the general population. Each of these melanoma subtypes had increased occurrence of cutaneous melanoma and thyroid cancer; some, but not all, had increased occurrence of renal malignancies, eye and orbit melanoma, and lymphoma.

Integrative Genomic Profiling Uncovers Therapeutic Targets of Acral Melanoma in Asian Populations.

Acral melanoma is the major subtype of melanoma seen in Asian patients with melanoma and is featured by its insidious onset and poor prognosis. The genomic study that elucidates driving mutational events is fundamental to the development of gene-targeted therapy. However, research on genomic profiles of acral melanoma in Asian patients is still sparse. We carried out whole-exome sequencing (WES) on 60 acral melanoma lesions (with 55 primary samples involved), targeted deep sequencing in a validation cohort of 48 cases, RNA sequencing in 37 acral melanoma samples (all from the 60 undergoing WES), and FISH in 233 acral melanoma specimens (54 of the 60 undergoing WES included). All the specimens were derived from Asian populations. BRAF, NRAS, and KIT were discerned as significantly mutated genes (SMG) in acral melanoma. The detected COSMIC signature 3 related to DNA damage repair, along with the high genomic instability score, implied corresponding pathogenesis of acral melanoma. Moreover, the copy number gains of EP300 were associated with the response of acral melanoma to targeted therapy of A485 (a p300 inhibitor) and immune checkpoint blockade treatment. In addition, the temporal order in mutational processes of the samples was reconstructed, and copy-number alterations were identified as early mutational events. Our study provided a detailed view of genomic instability, potential therapeutic targets, and intratumoral heterogeneity of acral melanoma, which might fuel the development of personalized strategies for treating acral melanoma in Asian populations.

Risk factors for lymphatic and hematogenous metastasis after diagnosis of cutaneous Melanoma in Taiwan

Risk factors of lymphatic and hematogenous metastasis in cutaneous melanoma remained unclear in Asian population. This study aimed to identify clinical and histopathological factors to predict metastatic pathways in cutaneous melanoma in Taiwan. A total of 247 patients diagnosed as stage I and II melanoma, followed at National Taiwan University Hospital were included in this retrospective study from 1980 to 2020. Kaplan-Meier curves and Cox proportional hazards regression were utilized to identify risk factors. During a median follow-up of 143 months, 48 (19.4%) and 62 (25.1%) patients developed lymphatic and hematogenous metastasis respectively. In the univariate analysis, age> 70 years, greater Breslow thickness, ulceration, neurotropism, and NRAS mutation were significant risk factors for lymphatic metastasis in all subtypes of melanoma. Age >70 years, head and neck location, thickness, ulceration, higher mitotic rate, neurotropism, and NRAS mutation were significant predictors of hematogenous metastasis in all subtypes. In the multivariate analysis, greater thickness (HR for 2.0-4.0mm, 4.5; p=.009 and HR for >4.0mm, 5.7; p=.003) retained its significance as an independent risk factor for lymphatic metastasis in all subtypes of melanoma. Thickness (HR for >4.0mm, 5.7; p<.001) and ulceration (HR, 2.5; p=.001) were independent risk factors for hematogenous metastasis. Risk factors of metastasis not only differ between lymphatic and hematogenous pathways, but also differ between ethnics and melanoma subtypes. Better understanding the behavior of cutaneous melanoma may help guide further treatments and follow-up plans.

TRPM1 promotes tumor progression in acral melanoma by activating the Ca2+/CaMKIIδ/AKT pathway

IntroductionAcral melanoma is a predominant and aggressive subtype of melanoma in non-Caucasian populations. There is a lack of genotype-driven therapies for over 50% of patients. TRPM1 (transient receptor potential melastatin 1), a nonspecific cation channel, is mainly expressed in retinal bipolar neurons and skin. Nonetheless, the function of TRPM1 in melanoma progression is poorly understood. ObjectivesWe investigated the association between TRPM1 and acral melanoma progression and revealed the molecular mechanisms by which TRPM1 promotes tumor progression and malignancy. MethodsTRPM1 expression and CaMKII phosphorylation in tumor specimens were tested by immunohistochemistry analysis and scored by two independent investigators. The functions of TRPM1 and CaMKII were assessed using loss-of-function and gain-of-function approaches and examined by western blotting, colony formation, cell migration and invasion, and xenograft tumor growth assays. The effects of a CaMKII inhibitor, KN93, were evaluated using both in vitro cell and in vivo xenograft mouse models. ResultsWe revealed that TRPM1 protein expression was positively associated with tumor progression and shorter survival in patients with acral melanoma. TRPM1 promoted AKT activation and the colony formation, cell mobility, and xenograft tumor growth of melanoma cells. TRPM1 elevated cytosolic Ca2+ levels and activated CaMKIIδ (Ca2+/calmodulin-dependent protein kinase IIδ) to promote the CaMKIIδ/AKT interaction and AKT activation. The functions of TRPM1 in melanoma cells were suppressed by a CaMKII inhibitor, KN93. Significant upregulation of phospho-CaMKII levels in acral melanomas was related to increased expression of TRPM1. An acral melanoma cell line with high expression of TRPM1, CA11, was isolated from a patient to show the anti-tumor activity of KN93 in vitro and in vivo. ConclusionsTRPM1 promotes tumor progression and malignancy in acral melanoma by activating the Ca2+/CaMKIIδ/AKT pathway. CaMKII inhibition may be a potential therapeutic strategy for treating acral melanomas with high expression of TRPM1.