Language：English   Publishing type：Research paper (scientific journal)   Publisher：Human Cell  

Nail apparatus melanoma (NAM) is a specific type of cutaneous melanoma that develops in the nail apparatus of the hands and feet. The prognosis for metastatic NAM is poor due to a lack of fully effective systemic therapies. However, the difficulty in obtaining a NAM model has hindered basic research aimed at discovering effective treatment strategies. In this study, we established a NAM cell line, named KS-NailMel-1, from a primary tumor located on the nail apparatus of the left ring finger of a 68-year-old Japanese female. The cells were successfully maintained for over 9 months, exhibiting a doubling time of 38.6 ± 1.94 h. KS-NailMel-1 displayed consistent growth, spheroid formation, and invasiveness, and was confirmed to be identical to the original tumor through short tandem repeat analyses, whole-exome sequencing, and immunohistochemistry. Western blotting of the cells demonstrated the protein expression of NECTIN4, which has recently attracted attention as a potential therapeutic target for melanoma. The KS-NailMel-1 cell line represents a valuable resource for basic and preclinical research on NAM, deepening our understanding of the tumor characteristics and facilitating the development of treatment strategies for this rare form of cancer.

DOI： 10.1007/s13577-025-01242-7

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Frontiers in Medicine  

Introduction: Cutaneous squamous cell carcinoma (cSCC) is a common form of skin cancer. Less accessibility to the cSCC cell lines has limited analyses of this disease. Thus, we here aimed to establish novel cSCC cell lines from patient's cSCC lesions. Methods: Two novel cSCC cell lines (named KS-cSCC-1 and KS-cSCC-2) were established from an axillary lymph node metastasis of a Japanese female and an inguinal lymph node metastasis of a Japanese male. The characteristics of the established cell lines were assessed by in vitro analyses. Results: The cells were successfully maintained for more than 9 months, with a doubling time of 47.5 ± 1.11 h (KS-cSCC-1) and 39.2 ± 5.78 h (KS-cSCC-2). The cell lines exhibited constant growth, spheroid formation, and invasiveness. Short tandem repeat analyses and immunohistochemistry confirmed that both cell lines are identical to their original tumor. The KS-cSCC-1 cells were weakly positive for CK14 and strongly positive for CK10, while the KS-cSCC-2 showed opposite expression patterns. Chemosensitivity of the cell lines was further tested and the cells were sensitive to anticancer drugs which are used to treat cSCC. Conclusion: The KS-cSCC-1 and KS-cSCC-2 cell lines were promising resources for basic and preclinical research on cSCC to better define the tumor characteristics and treatment strategy of this cancer.

DOI： 10.3389/fmed.2024.1483450

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Experimental Dermatology  

Cutaneous squamous cell carcinoma (cSCC) is a common form of skin cancer, but treatments for advanced cases have limited efficacy. Trophoblast cell-surface antigen 2 (TROP2) is a cell-surface protein that is widely expressed in various tumours, where it exerts significant influence over critical processes such as tumour cell growth, apoptosis, migration, invasion and metastasis. Sacituzumab govitecan, an antibody-drug conjugate (ADC) targeting TROP2, is emerging as a promising strategy for anticancer therapy. In this study, we investigated TROP2 expression in cSCC tissues from 51 patients and evaluated its function in the A431 human SCC cell line. Immunohistochemical analysis revealed TROP2 expression on the plasma membrane of cSCC tissues and A431 cells. A431 cells showed sensitivity to sacituzumab govitecan with a significant concentration-dependent decrease in viable cell number. In addition, Knockdown of TROP2 resulted in decreased expression of cyclin D1 and BCL-2, along with reduced cell viability. Knockdown of TROP2 also resulted in decreased expression of vimentin, along with reduced migratory capacity. These findings suggest that TROP2 plays a crucial role in cSCC cell proliferation and migration, and highlight the potential of sacituzumab govitecan as a promising therapeutic option for cSCC.

DOI： 10.1111/exd.15196

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Experimental Dermatology  

Extramammary Paget disease (EMPD) is a rare skin cancer mainly found in areas rich in apocrine sweat glands. Since the effective treatments for advanced and/or metastasized EMPD are limited, there is an urgent need to develop novel therapeutic approaches. Nectin cell adhesion molecule 4 (NECTIN4) is highly expressed in cancers and considered to be a promising therapeutic target. NECTIN4 is also expressed in EMPD, but its role and the efficacy of NECTIN4-targeted therapy in EMPD remain unclear. This study investigated the potential of NECTIN4 as a novel therapeutic target for EMPD. NECTIN4 expression was immunohistochemically analysed in EMPD patients' primary (118 samples) and metastatic (21 samples) lesions. Using an EMPD cell line, KS-EMPD-1, the effects of NECTIN4 inhibition on cell proliferation and migration were investigated. NECTIN4 was expressed in primary and metastatic EMPD lesions, and the H-score of NECTIN4 staining was significantly higher in metastatic lesions than in primary ones. Knockdown of NECTIN4 significantly inhibited cell proliferation and affected cell migration. The cytotoxic effects of NECTIN4-targeted antibody–drug conjugate (ADC) were further evaluated, revealing a significant decrease in EMPD cell viability. In conclusion, NECTIN4 is a potential therapeutic target and NECTIN4-targeted ADC is promising as a therapeutic option for EMPD.

DOI： 10.1111/exd.15049

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Scientific Reports  

Extramammary Paget disease (EMPD) is a rare skin cancer that primarily affects older individuals predominantly in areas with apocrine sweat glands. Although most early EMPD lesions are indolent, patients with metastatic EMPD have a poor prognosis due to the lack of effective systemic treatment. In this study, we investigated the role of forkhead box M1 (FOXM1), a potent transcription factor, in EMPD and assessed the potential of FOXM1 as a therapeutic target. Immunohistochemistry of 112 primary and 17 metastatic EMPD samples revealed that FOXM1 expression increased with tumor progression. Patients in whom FOXM1 was expressed in more than 10% of tumor cells had significantly shorter disease-specific survival than the other patients (p = 0.0397). In in vitro studies using our newly established EMPD cell line, KS-EMPD-1, we found high expression of FOXM1. Knockdown of FOXM1 impaired tumor cell viability, migration, and invasion. Inhibition of FOXM1 using thiostrepton also reduced tumor cell viability in a dose-dependent manner. These findings suggest that FOXM1 is a promising therapeutic target for patients with EMPD.

DOI： 10.1038/s41598-024-54773-8

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Human Cell  

Extramammary Paget’s disease (EMPD) is a rare skin cancer that mainly occurs in apocrine sweat gland-rich areas in elderly people. The prognosis of metastatic EMPD is unfavorable because of the lack of fully effective systemic therapies. However, the difficulty in establishing a model of EMPD has hampered basic research for exploring its pathogenesis and optimal treatments. Here, we established for the first time an EMPD cell line (named KS-EMPD-1) from a primary tumor on the left inguinal region of an 86-year-old Japanese male. The cells were successfully maintained for more than 1 year, with a doubling time of 31.2 ± 0.471 h. KS-EMPD-1 exhibited constant growth, spheroid formation, and invasiveness, and was confirmed to be identical to the original tumor by short tandem repeat analyses, whole exome sequencing, and immunohistochemistry (CK7⁺CK20⁻GCDFP15⁺). Western blotting of the cells revealed the protein expression of HER2, NECTIN4, and TROP2, which have recently attracted attention as potential therapeutic targets for EMPD. KS-EMPD-1 was highly sensitive to docetaxel and paclitaxel on chemosensitivity test. The KS-EMPD-1 cell line is a promising resource for basic and preclinical research on EMPD to better define the tumor characteristics and treatment strategy of this rare cancer.

DOI： 10.1007/s13577-023-00951-1

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

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Language：Japanese   Publisher：Western Division of Japanese Dermatological Association  

<p>61 歳，女性。明らかな外傷歴はなかったが，初診の約 4 年前に右足底に褐色斑が出現した。褐色斑は徐々に増大したため，前医を受診し，生検で Bowen 病と診断された。切除を勧められたが放置していた。当院を紹介され受診した時，右足底の土踏まず部に 7×6 mm の褐色結節を認めた。前医での生検標本では，表皮全層に異型ケラチノサイトが増殖しており，個細胞角化や clumping cell を認めた。3 mm マージンで全切除し，全層植皮術を行った。パラフィン包埋切片より DNA を抽出し，ヒト乳頭腫ウイルス（human papillomavirus：HPV）の検索を行ったところ，粘膜 / 粘膜・皮膚型，ハイリスク型である HPV31 型の DNA が検出された。足底発症の Bowen 病は極めて稀であるが，しばしば粘膜 / 粘膜・皮膚型の HPV が検出された症例が報告されている。しかし，HPV31 型が検出された足底 Bowen 病は，調べ得た限り国内外での報告はこれまでになく，自験例が第 1 例目となる。足底の黒褐色病変を認めたときは，Bowen 病も鑑別の一つとして考慮し対応すべきであり，外陰部・手指だけでなく，足底の Bowen 病も HPV が発症に関与している可能性の高い病変であると考えられる。</p>

DOI： 10.2336/nishinihonhifu.85.124

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CiNii Research

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Clinical Medicine  

Nail apparatus melanoma (NAM) is a rare type of cutaneous melanoma that belongs to the acral melanoma subtype. NAM is managed principally in accordance with the general treatment for cutaneous melanoma, but there is scarce evidence in support of this in the literature. Acral melanoma is genetically different from non-acral cutaneous melanoma, while recently accumulated data suggest that NAM also has a different genetic background from acral melanoma. In this review, we focus on recent advances in the management of NAM. Localized NAM should be surgically removed; amputation of the digit and digit-preserving surgery have been reported. Sentinel lymph node biopsy can be considered for invasive NAM for the purpose of accurate staging. However, it is yet to be clarified whether patients with metastatic sentinel lymph nodes can be safely spared completion lymph node dissection. Similar to cutaneous melanoma, immune checkpoint inhibitors and BRAF/MEK inhibitors are used as the first-line treatment for metastatic NAM, but data on the efficacy of these therapies remain scarce. The therapeutic effects of immune checkpoint inhibitors could be lower for NAM than for cutaneous melanoma. This review highlights the urgent need to accumulate data to better define the optimal management of this rare melanoma.

DOI： 10.3390/jcm12062203

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Cell Death Discovery  

Acral melanoma (AM) is a rare, life-threatening skin cancer. Since AM bears unique features, existing therapies for other types of malignant melanomas have limited effects and the establishment of effective treatments for AM is strongly desired. Human epidermal growth factor receptor 3 (HER3) is a receptor tyrosine kinase that is frequently elevated in tumors and contributes to tumor progression, so it is considered a promising therapeutic target for tumors. This study was established to evaluate the potential of HER3-targeted therapy to treat AM by investigating the expression and function of HER3. HER3 expression was immunohistochemically analyzed in AM lesions of 72 patients and in AM cell lines. To investigate function of HER3, effects of HER3 inhibition on cell proliferation, apoptosis/survival, anchorage-independent growth, and underlying signals were assessed. HER3 was expressed in patients’ AM tissues with various intensities and HER3 expression was significantly correlated with patient’s disease-free survival. In vitro analyses revealed that HER3 is more highly expressed in AM cells than in normal epidermal melanocytes. AM cells were also shown to be sensitive to the cytotoxic part of a HER3-targeted antibody-drug conjugate. Inhibition of HER3 did not affect cell proliferation, whereas it decreased the anchorage-independent growth of AM cells likely through affecting the nuclear translocation of Yes-associated protein. It is implied that HER3 may serve as a novel therapeutic target for AM.

DOI： 10.1038/s41420-023-01358-5

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Current Treatment Options in Oncology  

Nectin-4 is a tumor-associated antigen that is highly expressed on various cancer cells, and it has been further proposed to have roles in tumor development and propagation ranging from cellular proliferation to motility and invasion. Nectin-4 blockade reduces tumor proliferation and induces apoptosis in several malignancies. Nectin-4 has been used as a potential target in antibody-drug conjugate (ADC) development. Enfortumab vedotin, an ADC against Nectin-4, has demonstrated efficacy against solid tumor malignancies. Enfortumab vedotin has received US Food and Drug Administration approval for treating urothelial cancer. Furthermore, the efficacy of ADCs against Nectin-4 against solid tumors other than urothelial cancer has been demonstrated in preclinical studies, and clinical trials examining the effects of enfortumab vedotin are ongoing. Recently, Nectin-4 was reported to be highly expressed in several skin cancers, including malignant melanoma, cutaneous squamous cell carcinoma, and extramammary Paget’s disease, and involved in tumor progression and survival in retrospective studies. Nectin-4-targeted therapies and ADCs against Nectin-4 could therefore be novel therapeutic options for skin cancers. This review highlights current knowledge on Nectin-4 in malignant tumors, the efficacy of enfortumab vedotin in clinical trials, and the prospects of Nectin-4-targeted agents against skin cancers.

DOI： 10.1007/s11864-022-00940-w

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Scientific Reports  

Angiosarcoma is a rare, life-threatening soft tissue sarcoma with malignant endothelial cells that is mainly found in the skin. Multidisciplinary approaches are used to treat patients with unresectable metastasized lesions; considering the cellular origin of angiosarcoma, anti-angiogenic therapy has also been used recently. However, these treatments have limited efficacy, and the survival rate remains low. Thus, more effective treatments need to be developed. Nectin cell adhesion molecule 4 (NECTIN4) is highly expressed in malignant tumors and promotes tumor progression. Thus, NECTIN4 is expected to be a novel therapeutic target for cancer. However, the significance of NECTIN4 in angiosarcoma remains unknown. Using immunohistochemistry, we investigated NECTIN4 expression in 74 tissue samples from angiosarcoma patients, finding variable NECTIN4 expression. In addition, we investigated NECTIN4 expression and function in human angiosarcoma cell lines. NECTIN4 expression was higher in angiosarcoma cells than normal endothelial cells, and angiosarcoma cells were sensitive to monomethyl auristatin E, the cytotoxic part of a NECTIN4-targetting antibody–drug conjugate. NECTIN4 knockdown inhibited the proliferation and angiogenesis of angiosarcoma cells, and Src kinase signaling was shown to be involved in NECTIN4 function, at least in part. NECTIN4-targeted therapy has the potential to be a novel treatment strategy for angiosarcoma.

DOI： 10.1038/s41598-022-07727-x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：European Journal of Dermatology  

Background: Sebaceous carcinoma and sweat gland carcinoma (malignant tumours with apocrine and eccrine differentiation) are rare malignant adnexal tumours that differentiate toward sebaceous glands and eccrine and apocrine glands, respectively. Because of the rarity of these malignancies, standard treatments for advanced disease have yet to be established. The outcomes of patients with systemic metastasis remain poor, highlighting the need for novel treatment strategies. Nectin cell adhesion molecule 4 (NECTIN4) and its antibody-drug conjugate, enfortumab vedotin, have attracted attention as potential treatments for solid tumours. Objectives: To examine the potential use of NECTIN4-target therapy for sebaceous and sweat gland carcinoma. Materials & Methods: We immunohistochemically investigated NECTIN4 expression in 14 sebaceous carcinoma samples and 18 sweat gland carcinoma samples, and examined whether NECTIN4-targeted therapy could be applied to these cancers. Results: We found strong and frequent expression of NECTIN4 in both cancers. All tumours exhibited positive staining at least in a part of the lesion, and the mean H-score, a semiquantitative score ranging from 0 to 300, was 259.4 for sebaceous carcinoma and 253.1 for sweat gland carcinoma. Conclusion: Our results suggest that both sebaceous carcinoma and sweat gland carcinoma could be potentially treated with NECTIN4-targeted antibody-drug conjugates, such as enfortumab vedotin.

DOI： 10.1684/ejd.2022.4241

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Clinical Medicine  

Sebaceous carcinoma and sweat gland carcinoma (malignant tumors with apocrine and eccrine differentiation) are rare malignant skin adnexal tumors that differentiate toward sebaceous gland and eccrine and apocrine glands, respectively. Owing to the rarity of these carcinomas, standard treatments for advanced disease have not been established. Because the prognosis of patients with systemic metastasis is poor, a new treatment for these diseases is eagerly desired. Trophoblast cell surface antigen 2 (TROP2) and sacituzumab govitecan, an antibody–drug conjugate of TROP2, have attracted attention in the treatment of various solid tumors. In the current study, we immunohistochemically investigated TROP2 expression in 14 sebaceous carcinoma and 18 sweat gland carcinoma samples and found strong and relatively homogeneous TROP2 staining in both cancer types. The mean Histoscore, a semi-quantitative scoring ranging from 0 (negative) to 300, was 265.5 in sebaceous carcinoma and 260.0 in sweat gland carcinoma. These observations directly suggest that both sebaceous carcinoma and sweat gland carcinoma could be potentially treated with TROP2-targeted antibody–drug conjugates such as sacituzumab govitecan.

DOI： 10.3390/jcm11030607

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Language：English   Publishing type：Research paper (scientific journal)  

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Event date： 2010.9

Language：Japanese  

Venue：東京   Country：Japan  

Language：English  

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Language：English