Objective Melanotic schwannoma (MS) is a rare peripheral nerve sheath tumor accompanied by melanin deposition and severe refractory pain. However, its molecular pathogenesis remains unclear. This study aimed to explore the histomorphological, transcriptomic, and proteomic characteristics of MS, and to identify key molecules related to melanin production, pain generation, and targeted therapy.
Methods Histomorphological characteristics of MS were observed by Luxol Fast Blue (LFB) staining and hematoxylin and eosin (HE) staining in tumor tissues from 3 MS patients. Combined transcriptomic and proteomic analyses were performed to screen differentially expressed genes and proteins. The expression levels of tyrosinase-related protein 1 (TYRP1), transient receptor potential ankyrin 1 (TRPA1), and Bruton’s tyrosine kinase (BTK) were validated by quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting, and immunofluorescence staining.
Results Histomorphological examination revealed typical melanin deposition and prominent compression of adjacent nerve fibers in MS. Transcriptomic and proteomic analyses showed activation of the melanin synthesis pathway and transient receptor potential (TRP) channel-related neuroinflammatory pathway. The expression of TYRP1 and TRPA1 was significantly upregulated, suggesting that these related pathways are associated with melanin production and neuropathic pain in MS. In addition, the expression of BTK, a known molecular target of targeted drugs, was significantly increased, suggesting that BTK inhibitors have potential therapeutic effects on MS.
Conclusion This study delineates the histomorphological features, transcriptomic and proteomic profiles of MS. TYRP1, TRPA1, and BTK are identified as key molecules involved in melanogenesis, pain generation, and targeted therapy, respectively. These findings provide novel insights into the pathogenesis and potential therapeutic strategies for MS.
| [1] |
Grosshans HK, Huttner AJ, Piepmeier JM, et al. . Primary melanotic tumors of the nervous system: a consecutive case series. Eur J Neurol., 2020, 27(11): 2303-2307
|
| [2] |
Georgiev GK, Todorov IV, Shamov TP, et al. . L3 rootlet recurrent melanocytic schwannoma - case report and literature review. Folia Med (Plovdiv)., 2021, 63(3): 448-456
|
| [3] |
Alotaibi O, Al Sheddi M. Neurogenic tumors and tumor-like lesions of the oral and maxillofacial region: A clinicopathological study. Saudi Dent J., 2016, 28(2): 76-79
|
| [4] |
Jackson C, Linos K, Liu X. Malignant melanotic nerve sheath tumor in pleural effusion: Deceitful cytology with significant repercussions. Diagn Cytopathol., 2022, 50(3): E76-E80
|
| [5] |
Cohen PR. Segmental neurofibromatosis and cancer: report of triple malignancy in a woman with mosaic Neurofibromatosis 1 and review of neoplasms in segmental neurofibromatosis. Dermatol Online J., 2016, 22(7): 13030
|
| [6] |
Sengoz A, Tasdemiroglu E, Togay H. Is clear cell sarcoma a malignant form of psammomatous melanotic schwannoma? Case report. Neurosurg Focus., 2006, 21(6): E11
|
| [7] |
Yokota H, Isobe K, Murakami M, Kubosawa H, Uno T. Dumbbell-shaped nonpsammomatous malignant melanotic schwannoma of the cervical spinal root. Spine J., 2012, 12(4): e14-17
|
| [8] |
Keskin E, Ekmekci S, Oztekin O, et al. Melanotic Schwannomas Are Rarely Seen Pigmented Tumors with Unpredictable Prognosis and Challenging Diagnosis. Case Rep Pathol. 2017;1807879.
|
| [9] |
Chen S, Hu J, Xu Y, et al. Transcriptome analysis of human hypertrophic cardiomyopathy reveals inhibited cardiac development pathways in children. iScience. 2024;27(1):108642.
|
| [10] |
Zhang H, Ye J, Shi Z, et al. . Quantitative analyses of the global proteome and phosphoproteome reveal the different impacts of propofol and dexmedetomidine on HT22 cells. Sci Rep., 2017, 7: 46455
|
| [11] |
Ma J, Chen T, Wu S, et al. . iProX: an integrated proteome resource. Nucleic Acids Res., 2019, 47(D1): D1211-D1217
|
| [12] |
Chen T, Ma J, Liu Y, et al. . iProX in 2021: connecting proteomics data sharing with big data. Nucleic Acids Res., 2022, 50(D1): D1522-D1527
|
| [13] |
Torres-Mora J, Dry S, Li X, et al. . Malignant melanotic schwannian tumor: a clinicopathologic, immunohistochemical, and gene expression profiling study of 40 cases, with a proposal for the reclassification of "melanotic schwannoma". Am J Surg Pathol., 2014, 38(1): 94-105
|
| [14] |
Zhang HY, Yang GH, Chen HJ, et al. . Clinicopathological, immunohistochemical, and ultrastructural study of 13 cases of melanotic schwannoma. Chin Med J (Engl)., 2005, 118(17): 1451-1461
|
| [15] |
Dandekar AC, Mehta NA. A Case of Malignant Melanotic Schwannoma of the Trigeminal Nerve: A Case Report and Review of Literature. Asian J Neurosurg., 2023, 18(2): 352-356
|
| [16] |
Sun Z, Wang X, Pang X. Malignant melanotic schwannoma: A case report and literature review. Asian J Surg., 2024, 47(1): 640-641
|
| [17] |
Wang H, Shi L, Tian T, et al. . Case report: A rare case of massive peripheral nerve melanotic schwannoma and review of the literature. Front Neurol., 2023, 14: 1103604
|
| [18] |
Xiang Z, Feng M, Gao Q, Shang H. Malignant thoracic intraspinal melanotic schwannoma. Asian J Surg., 2023, 46(11): 4794-4795
|
| [19] |
Kang YE, Jeong JO, Kim KH, et al. . Malignant intercostal psammomatous melanotic schwannoma in a patient with Carney complex. Korean J Intern Med., 2018, 33(6): 1256-1257
|
| [20] |
Shanmugam S, Ghosh M, Niamathullah S, Ghosh S. Psammomatous melanotic schwannoma as a component of Carney complex. Indian J Pathol Microbiol., 2015, 58(3): 368-370
|
| [21] |
Sharath KGG, Shruthi P, Pooja BV, Ravi MR. Trigeminal Nerve Melanotic Schwannoma in Carney Complex. Indian J Radiol Imaging., 2022, 32(3): 422-425
|
| [22] |
Carrasco CA, Rojas-Salazar D, Chiorino R, et al. . Melanotic nonpsammomatous trigeminal schwannoma as the first manifestation of Carney complex: case report. Neurosurgery., 2006, 59(6): E1334-1335
|
| [23] |
Kim MJ, Choi J, Khang SK, et al. . Primary intraosseous melanotic schwannoma of the fibula associated with the Carney complex. Pathol Int., 2006, 56(9): 538-542
|
| [24] |
Arvanitis LD. Melanotic schwannoma: a case with strong CD34 expression, with histogenetic implications. Pathol Res Pract., 2010, 206(10): 716-719
|
| [25] |
Faria MH, Doria-Netto RH, Osugue GJ, et al. . Melanotic schwannoma of the cervical spine progressing with pulmonary metastasis: case report. Neurol Med Chir (Tokyo)., 2013, 53(10): 712-716
|
| [26] |
Hackett CS, Hirschhorn D, Tang MS, et al. . TYRP1 directed CAR T cells control tumor progression in preclinical melanoma models. Mol Ther Oncol., 2024, 32(3): 200862
|
| [27] |
Gilot D, Migault M, Bachelot L, et al. . A non-coding function of TYRP1 mRNA promotes melanoma growth. Nat Cell Biol., 2017, 19(11): 1348-1357
|
| [28] |
Soengas MS, Hernando E. TYRP1 mRNA goes fishing for miRNAs in melanoma. Nat Cell Biol., 2017, 19(11): 1311-1312
|
| [29] |
Jilani S, Saco JD, Mugarza E, et al. . CAR-T cell therapy targeting surface expression of TYRP1 to treat cutaneous and rare melanoma subtypes. Nat Commun, 2024, 15(1): 1244
|
| [30] |
Haleem S, Mahmoud MH, Singh Kainth G, et al. 18F-FDG PET/CT scan standardised uptake value (SUV) score for diagnosis, staging and monitoring malignancy in spinal melanotic schwannoma. J Surg Case Rep. 2022;(12):rjac524.
|
| [31] |
Soyland DJ, Goehner DR, Hoerschgen KM, et al. . Hemorrhagic spinal melanotic schwannoma presenting as acute chest pain: A case report and literature review. Surg Neurol Int., 2021, 12: 164
|
| [32] |
Yan X, Wang K, Lin N, et al. . A Rare Case of Melanotic Schwannoma Occurred Intraosseous of Sacrum: A Literature Review. Orthop Surg., 2023, 15(2): 655-562
|
| [33] |
Mickle AD, Shepherd AJ, Mohapatra DP. Sensory TRP channels: the key transducers of nociception and pain. Prog Mol Biol Transl Sci., 2015, 131: 73-118
|
| [34] |
de Almeida AS, Bernardes LB, Trevisan G. TRP channels in cancer pain. Eur J Pharmacol., 2021, 904: 174185
|
| [35] |
Julius D. TRP channels and pain. Annu Rev Cell Dev Biol., 2013, 29: 355-384
|
| [36] |
Moore C, Gupta R, Jordt SE, et al. . Regulation of Pain and Itch by TRP Channels. Neurosci Bull., 2018, 34(1): 120-142
|
| [37] |
Bromberg PA. Mechanisms of the acute effects of inhaled ozone in humans. Biochim Biophys Acta., 2016, 1860(12): 2771-2781
|
| [38] |
Yang CY, Guo Y, Wu WJ, et al. UVB-Induced Secretion of IL-1beta Promotes Melanogenesis by Upregulating TYR/TRP-1 Expression In Vitro. Biomed Res Int. 2022;8230646.
|
| [39] |
Asencio-Alcudia G, Andree KB, Giraldez I, et al. . Stressors Due to Handling Impair Gut Immunity in Meagre (Argyrosomus regius): The Compensatory Role of Dietary L-Tryptophan. Front Physiol., 2019, 10: 547
|
| [40] |
Liu Yuqian, Zhang Bohan, Duan Ruonan, et al. . Mitochondrial DNA Leakage and cGas/STING Pathway in Microglia: Crosstalk Between Neuroinflammation and Neurodegeneration. Neuroscience., 2024, 548: 1-8
|
| [41] |
Titiz M, Landini L, Souza Monteiro de Araujo D, et al. Schwann cell C5aR1 co-opts inflammasome NLRP1 to sustain pain in a mouse model of endometriosis. Nat Commun. 2024;15(1):10142.
|
| [42] |
Kaehler KC, Russo PA, Katenkamp D, et al. . Melanocytic schwannoma of the cutaneous and subcutaneous tissues: three cases and a review of the literature. Melanoma Res., 2008, 18(6): 438-442
|
| [43] |
Lin KY, Chen L, Hung SW, et al. . A para-aortic malignant melanotic nerve sheath tumor mimicking a gastrointestinal stromal tumor: a rare case report and review of literature. BMC Surg., 2022, 22(1): 293
|
| [44] |
Kim S, Federman N, Gordon EM, et al. . Rexin-G((R)), a tumor-targeted retrovector for malignant peripheral nerve sheath tumor: A case report. Mol Clin Oncol., 2017, 6(6): 861-865
|
| [45] |
Mavrogenis A, Bianchi G, Stavropoulos N, et al. . Clinicopathological features, diagnosis and treatment of clear cell sarcoma/melanoma of soft parts. Hippokratia., 2013, 17(4): 298-302
|
| [46] |
Sahay A, Epari S, Gupta P, et al. . Melanotic Schwannoma, a Deceptive Misnomer for a Tumor With Relative Aggressive Behavior: A Series of 7 Cranial and Spinal Cases. Int J Surg Pathol., 2020, 28(8): 850-858
|
| [47] |
Liu Q, Peng ZH, Shen LF, et al. . Prognostic and Clinicopathological Value of Ki-67 in Melanoma: A Meta-Analysis. Front Oncol., 2021, 8(11): 737760
|
| [48] |
Du Y, Li CL, Mao LL, et al. . A nomogram incorporating Ki67 to predict survival of acral melanoma. J Cancer Res Clin Oncol., 2023, 149(14): 13077-13085
|
| [49] |
de Rooij MFM, Thus YJ, Swier N, et al. . A loss-of-adhesion CRISPR-Cas9 screening platform to identify cell adhesion-regulatory proteins and signaling pathways. Nat Commun., 2022, 13(1): 2136
|
| [50] |
Fish K, Comoglio F, Shaffer AL, et al. . Rewiring of B cell receptor signaling by Epstein-Barr virus LMP2A. Proc Natl Acad Sci U S A., 2020, 117(42): 26318-26327
|
| [51] |
Krishnamurthy K, Urioste SN, Cusnir M, et al. . Analysis of Genetic Alterations in Cutaneous Malignant Melanomas Unveils Unique Loco-Regional Variations and Novel Predictors of Metastatic Potential. Am J Dermatopathol., 2021, 43(12): e185-e189
|
| [52] |
Misek SA, Newbury PA, Chekalin E, et al. . Ibrutinib Blocks YAP1 Activation and Reverses BRAF Inhibitor Resistance in Melanoma Cells. Mol Pharmacol., 2022, 101(1): 1-12
|
| [53] |
Sun SH, Angell CD, Savardekar H, et al. . BTK inhibition potentiates anti-PD-L1 treatment in murine melanoma: potential role for MDSC modulation in immunotherapy. Cancer Immunol Immunother., 2023, 72(11): 3461-3474
|
| [54] |
Cool A, Nong T, Montoya S, Taylor J. BTK inhibitors: past, present, and future. Trends Pharmacol Sci., 2024, 45(8): 691-707
|
Funding
National Natural Science Foundation of China(82072526)
RIGHTS & PERMISSIONS
The Author(s)
PDF
