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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Tumor Microenvironment".

Deadline for manuscript submissions: closed (31 August 2021) | Viewed by 36487

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Prof. Dr. Takami Sato

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Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, 1015 Walnut Street, 1024 Curtis Building, Philadelphia, PA 19107, USA
Interests: uveal melanoma; cancer immunology; immunotherapy; liver-directed treatment; tumor microenvironment; mouse models
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Dear Colleagues,

Uveal melanoma (UM) is the most common intraocular malignant tumor in adults. Primary UMs are effectively treated by plaque radiotherapy or enucleation; however, 30–50% of UM patients ultimately succumb to systemic recurrence, especially liver metastasis.

Two major mutations are present in the majority of metastatic UMs: (1) activating mutations in the alpha subunits of heterotrimeric G proteins (GNAQ or GNA11) and related genes (PLCB4, CYSLTR2) and (2) mutations affecting deubiquitinating enzymes (BAP1) or RNA splicing factors (SF3B1). Various inhibitors have been tested in attempts to block signals from mutant GNAQ/GNA11 to downstream pathways, including the MEK-ERK1/2 and AKT-PI3K pathways, with marginal clinical benefit. Furthermore, the microenvironment of metastatic UM in the liver is detrimental to antitumor immune responses and contributes to poor responses to immune checkpoint blockades.

This Special Issue will highlight the biological characteristics of metastatic UM and its microenvironment, covering both basic and clinical aspects to develop a strategy to improve the outcome of metastatic UM patients.

Prof. Takami Sato
Guest Editor

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Keywords

uveal melanoma
metastasis
liver
tumor microenvironment
tumor–microenvironment interaction
dormancy
research model
signal inhibitor
immunotherapy

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Research

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14 pages, 916 KiB

Open AccessArticle

Prognostic Values of G-Protein Mutations in Metastatic Uveal Melanoma

by Mizue Terai, Ayako Shimada, Inna Chervoneva, Liam Hulse, Meggie Danielson, Jeff Swensen, Marlana Orloff, Philip B. Wedegaertner, Jeffrey L. Benovic, Andrew E. Aplin and Takami Sato

Cancers 2021, 13(22), 5749; https://doi.org/10.3390/cancers13225749 - 17 Nov 2021

Cited by 14 | Viewed by 2639

Abstract

Uveal melanoma is the most common primary ocular malignancy in adults, characterized by gene mutations in G protein subunit alpha q (GNAQ) and G protein subunit alpha 11 (GNA11). Although they are considered to be driver mutations, their role in MUM remains elusive. We investigated key somatic mutations of MUM and their impact on patients’ survival after development of systemic metastasis (Met-to-Death). Metastatic lesions from 87 MUM patients were analyzed by next generation sequencing (NGS). GNA11 (41/87) and GNAQ (39/87) mutations were most predominantly seen in MUM. Most GNA11 mutations were Q209L (36/41), whereas GNAQ mutations comprised Q209L (14/39) and Q209P (21/39). Epigenetic pathway mutations BAP1 (42/66), SF3B1 (11/66), FBXW7 (2/87), PBRM1 (1/66), and SETD2 (1/66) were found. No specimen had the EIF1AX mutation. Interestingly, Met-to-Death was longer in patients with GNAQ Q209P compared to GNAQ/GNA11 Q209L mutations, suggesting the difference in mutation type in GNAQ/GNA11 might determine the prognosis of MUM. Structural alterations of the GNAQ/GNA11 protein and their impact on survival of MUM patients should be further investigated. Full article

(This article belongs to the Special Issue Metastatic Uveal Melanoma)

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15 pages, 1946 KiB

Open AccessArticle

Radiological Patterns of Uveal Melanoma Liver Metastases in Correlation to Genetic Status

by Serdar Yavuzyigitoglu, Michael C. Y. Tang, Miguel Jansen, Kaspar W. Geul, Roy S. Dwarkasing, Jolanda Vaarwater, Wojtek Drabarek, Robert M. Verdijk, Dion Paridaens, Nicole C. Naus, Erwin Brosens, Annelies de Klein and Emine Kilic

Cancers 2021, 13(21), 5316; https://doi.org/10.3390/cancers13215316 - 22 Oct 2021

Cited by 3 | Viewed by 3074

Abstract

This study reports the role played by the mutation status of Uveal Melanoma (UM) in relation to hepatic metastatic patterns as seen on imaging modalities. Radiological images were obtained from 123 patients treated at the Erasmus Medical Center Rotterdam or the Rotterdam Eye Hospital. Radiological images were derived from either computed tomography or magnetic resonance imaging. Hepatic metastatic patterns were classified by counting the number of metastases found in the liver. Miliary metastatic pattern (innumerable small metastases in the entire liver) was analyzed separately. Mutation status was determined in 85 patients. Median disease-free survival (DFS) and survival with metastases differed significantly between each of the metastatic patterns (respectively, p = 0.009, p < 0.001), both in favor of patients with less hepatic metastases. The mutation status of the primary tumor was not correlated with any hepatic tumor profiles (p = 0.296). Of the patients who had a solitary metastasis (n = 18), 11 originated from a primary BAP1-mutated tumors and one from a primary SF3B1-mutated tumor. Of the patients who had a miliary metastasis pattern (n = 24), 17 had a primary BAP1-mutated tumor and two had a primary SF3B1-mutated tumor. Chromosome 8p loss was significantly more in patients with more metastases (p = 0.045). Moreover, the primary UMs of patients with miliary metastases harbored more chromosome 8p and 1p loss, compared to patients with single solitary metastasis (p = 0.035 and p = 0.026, respectively). In conclusion, our study shows that there is an inverse correlation of the number of metastasis with the DFS and metastasized survival, indicating separate growth patterns. We also revealed that the number and type of metastases is irrelevant to the prognostic mutation status of the tumor, showing that both BAP1- and SF3B1-mutated UM can result in solitary and miliary metastases, indicating that other processes lay ground to the different metastatic patterns. Full article

(This article belongs to the Special Issue Metastatic Uveal Melanoma)

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12 pages, 1210 KiB

Open AccessArticle

LAG3 and Its Ligands Show Increased Expression in High-Risk Uveal Melanoma

by Zahra Souri, Annemijn P. A. Wierenga, Wilma G. M. Kroes, Pieter A. van der Velden, Robert M. Verdijk, Michael Eikmans, Gregorius P. M. Luyten and Martine J. Jager

Cancers 2021, 13(17), 4445; https://doi.org/10.3390/cancers13174445 - 3 Sep 2021

Cited by 30 | Viewed by 4609

Abstract

Uveal melanoma (UM) is a rare ocular malignancy which originates in the uveal tract, and often gives rise to metastases. Potential targets for immune checkpoint inhibition are lymphocyte-activation gene 3 (LAG3) and its ligands. We set out to analyse the distribution of these molecules in UM. The expression of mRNA was determined using an Illumina array in 64 primary UM from Leiden. The T lymphocyte fraction was determined by digital droplet PCR. In a second cohort of 15 cases from Leiden, mRNA expression was studied by Fluidigm qPCR, while a third cohort consisted of 80 UM from TCGA. In the first Leiden cohort, LAG3 expression was associated with the presence of epithelioid cells (p = 0.002), monosomy of chromosome 3 (p = 0.004), and loss of BAP1 staining (p = 0.001). In this Leiden cohort as well as in the TCGA cohort, LAG3 expression correlated positively with the expression of its ligands: LSECtin, Galectin-3, and the HLA class II molecules HLA-DR, HLA-DQ, and HLA-DP (all p < 0.001). Furthermore, ligands Galectin-3 and HLA class II were increased in monosomy 3 tumours and the expression of LAG3 correlated with the presence of an inflammatory phenotype (T cell fraction, macrophages, HLA-A and HLA-B expression: all p < 0.001). High expression levels of LAG3 (p = 0.01), Galectin-3 (p = 0.001), HLA-DRA1 (p = 0.002), HLA-DQA1 (p = 0.04), HLA-DQB2 (p = 0.03), and HLA-DPA1 (p = 0.007) were associated with bad survival. We conclude that expression of the LAG ligands Galectin-3 and HLA class II strongly correlates with LAG3 expression and all are increased in UM with Monosomy 3/BAP1 loss. The distribution suggests a potential benefit of monoclonal antibodies against LAG3 or Galectin-3 as adjuvant treatment in patients with high-risk UM. Full article

(This article belongs to the Special Issue Metastatic Uveal Melanoma)

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14 pages, 2828 KiB

Open AccessArticle

In Uveal Melanoma, Angiopoietin-2 but Not Angiopoietin-1 Is Increased in High-Risk Tumors, Providing a Potential Druggable Target

by Anna M.W. ten Voorde, Annemijn P.A. Wierenga, Rogier J. Nell, Pieter A. van der Velden, Gregorius P.M. Luyten, Robert M. Verdijk and Martine J. Jager

Cancers 2021, 13(16), 3986; https://doi.org/10.3390/cancers13163986 - 7 Aug 2021

Cited by 3 | Viewed by 2212

Abstract

Uveal melanoma (UM) metastasize haematogeneously, and tumor blood vessel density is an important prognostic factor. We hypothesized that proangiogenic factors such as angiopoietin-1 (ANG-1) and angiopoietin-2 (ANG-2), two targetable cytokines, might play a role in tumor development and metastatic behavior. mRNA levels of ANG-1 and ANG-2 were determined in 64 tumors using an Illumina HT-12 v4 mRNA chip and compared to clinical, pathologic, and genetic tumor parameters. Tissue expression was also determined by immunohistochemistry (IHC). Samples of aqueous humor were collected from 83 UM-containing enucleated eyes and protein levels that were determined in a multiplex proximity extension assay. High tissue gene expression of ANG-2, but not of ANG-1, was associated with high tumor thickness, high largest basal diameter, involvement of the ciliary body, and with UM-related death (ANG-2 mRNA p < 0.001; ANG-2 aqueous protein p < 0.001). The presence of the ANG-2 protein in aqueous humor correlated with its mRNA expression in the tumor (r = 0.309, p = 0.03). IHC showed that ANG-2 was expressed in macrophages as well as tumor cells. The presence of ANG-2 in the tumor and in aqueous humor, especially in high-risk tumors, make ANG-2 a potential targetable cytokine in uveal melanoma. Full article

(This article belongs to the Special Issue Metastatic Uveal Melanoma)

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11 pages, 1415 KiB

Open AccessArticle

Immune Checkpoint Blockade for Metastatic Uveal Melanoma: Patterns of Response and Survival According to the Presence of Hepatic and Extrahepatic Metastasis

by Elias A. T. Koch, Anne Petzold, Anja Wessely, Edgar Dippel, Anja Gesierich, Ralf Gutzmer, Jessica C. Hassel, Sebastian Haferkamp, Bettina Hohberger, Katharina C. Kähler, Harald Knorr, Nicole Kreuzberg, Ulrike Leiter, Carmen Loquai, Friedegund Meier, Markus Meissner, Peter Mohr, Claudia Pföhler, Farnaz Rahimi, Dirk Schadendorf, Beatrice Schell, Max Schlaak, Patrick Terheyden, Kai-Martin Thoms, Beatrice Schuler-Thurner, Selma Ugurel, Jens Ulrich, Jochen Utikal, Michael Weichenthal, Fabian Ziller, Carola Berking, Markus V. Heppt and on behalf of the German Dermatologic Cooperative Oncology Group (DeCOG, Committee Ocular Melanoma) Show full author list Hide full author list

Cancers 2021, 13(13), 3359; https://doi.org/10.3390/cancers13133359 - 4 Jul 2021

Cited by 21 | Viewed by 4421

Abstract

Background: Since there is no standardized and effective treatment for advanced uveal melanoma (UM), the prognosis is dismal once metastases develop. Due to the availability of immune checkpoint blockade (ICB) in the real-world setting, the prognosis of metastatic UM has improved. However, it is unclear how the presence of hepatic and extrahepatic metastasis impacts the response and survival after ICB. Methods: A total of 178 patients with metastatic UM treated with ICB were included in this analysis. Patients were recruited from German skin cancer centers and the German national skin cancer registry (ADOReg). To investigate the impact of hepatic metastasis, two cohorts were compared: patients with liver metastasis only (cohort A, n = 55) versus those with both liver and extra-hepatic metastasis (cohort B, n = 123). Data were analyzed in both cohorts for response to treatment, progression-free survival (PFS), and overall survival (OS). The survival and progression probabilities were calculated with the Kaplan–Meier method. Log-rank tests, χ² tests, and t-tests were performed to detect significant differences between both cohorts. Results: The median OS of the overall population was 16 months (95% CI 13.4–23.7) and the median PFS, 2.8 months (95% CI 2.5–3.0). The median OS was longer in cohort B than in cohort A (18.2 vs. 6.1 months; p = 0.071). The best objective response rate to dual ICB was 13.8% and to anti-PD-1 monotherapy 8.9% in the entire population. Patients with liver metastases only had a lower response to dual ICB, yet without significance (cohort A 8.7% vs. cohort B 16.7%; p = 0.45). Adverse events (AE) occurred in 41.6%. Severe AE were observed in 26.3% and evenly distributed between both cohorts. Conclusion: The survival of this large cohort of patients with advanced UM was more favorable than reported in previous benchmark studies. Patients with both hepatic and extrahepatic metastasis showed more favorable survival and higher response to dual ICB than those with hepatic metastasis only. Full article

(This article belongs to the Special Issue Metastatic Uveal Melanoma)

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12 pages, 2393 KiB

Open AccessArticle

Prognostic Implications of MRI Melanin Quantification and Cytogenetic Abnormalities in Liver Metastases of Uveal Melanoma

by Toulsie Ramtohul, Khadija Ait Rais, Sophie Gardrat, Raymond Barnhill, Sergio Román-Román, Nathalie Cassoux, Manuel Rodrigues, Pascale Mariani, Leanne De Koning, Gaëlle Pierron and Vincent Servois

Cancers 2021, 13(11), 2728; https://doi.org/10.3390/cancers13112728 - 31 May 2021

Cited by 10 | Viewed by 2508

Abstract

To evaluate the prognostic implications of melanin quantification assessed by magnetic resonance imaging (MRI) with respect to the clinical, pathological, and genetic features of liver metastases of uveal melanoma (LMUM). This single-center retrospective cohort study included 63 patients eligible for margin-free resection of LMUM between 2007 and 2018. Comparative genomic hybridization of resected liver metastases on microarrays was performed for genetic risk classification. Metastases exhibiting monosomy 3 with any type of gain of chromosome 8 (M3/8g) were considered high-genetic-risk. MRI melanin quantification using the mean T1 signal (mT1s) in liver metastases was assessed quantitatively on preoperative imaging examination and compared to that of gross pathological evaluation. The association between MRI melanin quantification and overall survival (OS) was assessed by multivariate analysis using the Cox proportional hazards model. Gross pathological assessment of melanin content and MRI melanin quantification were strongly correlated (r = 0.8, p < 0.001). Independent prognostic factors associated with OS were disease-free interval ≤ 24 months (HR = 3.1; 95% CI, 1.6–6.0; p < 0.001), high-genetic-risk (HR = 2.2; 95% CI, 1.1–4.8; p = 0.04), mT1s > 1.1 (HR = 2.3; 95% CI, 1.2–4.7; p = 0.019), and complete hepatic resection (HR = 0.3; 95% CI, 0.2–0.7; p = 0.004). In patients with high-genetic-risk, mT1s showed a significant association with OS (HR = 3.7; 95% CI, 1.5–9.3; p = 0.006). The median OS was 17.5 months vs. 27 months for >1.1 and ≤1.1 mT1s tumors, respectively (p = 0.003). We showed that the level of pigmentation in M3/8g LMUM identified two subsets that were correlated with distinct clinical outcomes. Full article

(This article belongs to the Special Issue Metastatic Uveal Melanoma)

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17 pages, 8514 KiB

Open AccessArticle

Dual Targeting of CDK4/6 and cMET in Metastatic Uveal Melanoma

by Masahiro Ohara, Kengo Saito, Ken Kageyama, Mizue Terai, Hanyin Cheng, Andrew E. Aplin and Takami Sato

Cancers 2021, 13(5), 1104; https://doi.org/10.3390/cancers13051104 - 4 Mar 2021

Cited by 9 | Viewed by 3079

Abstract

Uveal melanoma (UM) is the most common cancer of the eye in adults. Up to 50% of UM patients subsequently develop metastases, especially in the liver. It has been reported that the retinoblastoma (RB) pathway is deregulated in more than 90% of UM despite the rarity of mutations in the RB1 gene itself. CDK4/6 inhibition (CDK4/6i) is a rational strategy for treatment of UM. In this report, we investigated the antiproliferative activity of a selective CDK4/6 inhibitor on metastatic UM. A CDK4/6 inhibitor suppressed UM cell lines growth in in vitro and in vivo experiments. Hepatocyte growth factor (HGF) decreased the effect of CDK4/6 inhibitor on metastatic UM cell lines. When CDK4/6i was combined with cMET inhibitor, enhanced growth suppression was observed in metastatic UM tumors grown in human-HGF knock-in xenograft mouse models. HGF is enriched in the liver and the majority of liver metastases from UM express activated forms of cMET; therefore, signaling through cMET could contribute to the resistance mechanisms against CDK4/6i, especially in UM patients with hepatic metastasis. Together, these results provide a rationale for the use of cMET inhibitor in combination with a CDK4/6 inhibitor for the treatment of metastatic UM. Full article

(This article belongs to the Special Issue Metastatic Uveal Melanoma)

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Review

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17 pages, 1137 KiB

Open AccessReview

Targeting Oncogenic Gα_q/11 in Uveal Melanoma

by Dominic Lapadula and Jeffrey L. Benovic

Cancers 2021, 13(24), 6195; https://doi.org/10.3390/cancers13246195 - 9 Dec 2021

Cited by 12 | Viewed by 3673

Abstract

Uveal melanoma is the most common intraocular cancer in adults and arises from the transformation of melanocytes in the uveal tract. While treatment of the primary tumor is often effective, 36–50% of patients develop metastatic disease primarily to the liver. While various strategies have been used to treat the metastatic disease, there remain no effective treatments that improve survival. Significant insight has been gained into the pathways that are altered in uveal melanoma, with mutually exclusive activating mutations in the GNAQ and GNA11 genes being found in over 90% of patients. These genes encode the alpha subunits of the hetetrotrimeric G proteins, G_q and G₁₁, and mutations result in activation of several important signaling pathways, including phospholipase C and activation of the transcription factor YAP. In this review, we discuss current efforts to target various signaling pathways in the treatment of uveal melanoma including recent efforts to target G_q and G₁₁ in mouse models. While selective targeting of G_q and G₁₁ provides a potential therapeutic strategy to treat uveal melanoma, it is evident that improved inhibitors and methods of delivery are needed. Full article

(This article belongs to the Special Issue Metastatic Uveal Melanoma)

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25 pages, 1192 KiB

Open AccessEditor’s ChoiceReview

Genetic Landscape and Emerging Therapies in Uveal Melanoma

by Rino S. Seedor, Marlana Orloff and Takami Sato

Cancers 2021, 13(21), 5503; https://doi.org/10.3390/cancers13215503 - 2 Nov 2021

Cited by 22 | Viewed by 5199

Abstract

Despite successful treatment of primary uveal melanoma, up to 50% of patients will develop systemic metastasis. Metastatic disease portends a poor outcome, and no adjuvant or metastatic therapy has been FDA approved. The genetic landscape of uveal melanoma is unique, providing prognostic and potentially therapeutic insight. In this review, we discuss our current understanding of the molecular and cytogenetic mutations in uveal melanoma, and the importance of obtaining such information. Most of our knowledge is based on primary uveal melanoma and a better understanding of the mutational landscape in metastatic uveal melanoma is needed. Clinical trials targeting certain mutations such as GNAQ/GNA11, BAP1, and SF3B1 are ongoing and promising. We also discuss the role of liquid biopsies in uveal melanoma in this review. Full article

(This article belongs to the Special Issue Metastatic Uveal Melanoma)

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15 pages, 2766 KiB

Open AccessReview

The Role of HGF/MET Signaling in Metastatic Uveal Melanoma

by Ryota Tanaka, Mizue Terai, Eric Londin and Takami Sato

Cancers 2021, 13(21), 5457; https://doi.org/10.3390/cancers13215457 - 30 Oct 2021

Cited by 22 | Viewed by 3467

Abstract

Hepatocyte growth factor (HGF)/mesenchymal-epithelial transition factor (MET) signaling promotes tumorigenesis and tumor progression in various types of cancer, including uveal melanoma (UM). The roles of HGF/MET signaling have been studied in cell survival, proliferation, cell motility, and migration. Furthermore, HGF/MET signaling has emerged as a critical player not only in the tumor itself but also in the tumor microenvironment. Expression of MET is frequently observed in metastatic uveal melanoma and is associated with poor prognosis. It has been reported that HGF/MET signaling pathway activation is the major mechanism of treatment resistance in metastatic UM (MUM). To achieve maximal therapeutic benefit in MUM patients, it is important to understand how MET signaling drives cellular functions in uveal melanoma cells. Here, we review the HGF/MET signaling biology and the role of HGF/MET blockades in uveal melanoma. Full article

(This article belongs to the Special Issue Metastatic Uveal Melanoma)

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