Dataset Information

Relevance of Abnormal KCNN1 Expression and Osmotic Hypersensitivity in Ewing Sarcoma.

ABSTRACT: Ewing sarcoma (EwS) is a rare and highly malignant bone tumor occurring mainly in childhood and adolescence. Physiologically, the bone is a central hub for Ca²⁺ homeostasis, which is severely disturbed by osteolytic processes in EwS. Therefore, we aimed to investigate how ion transport proteins involved in Ca²⁺ homeostasis affect EwS pathophysiology. We characterized the expression of 22 candidate genes of Ca²⁺-permeable or Ca²⁺-regulated ion channels in three EwS cell lines and found the Ca²⁺-activated K⁺ channel K_Ca2.1 (KCNN1) to be exceptionally highly expressed. We revealed that KCNN1 expression is directly regulated by the disease-driving oncoprotein EWSR1-FL1. Due to its consistent overexpression in EwS, KCNN1 mRNA could be a prognostic marker in EwS. In a large cohort of EwS patients, however, KCNN1 mRNA quantity does not correlate with clinical parameters. Several functional studies including patch clamp electrophysiology revealed no evidence for K_Ca2.1 function in EwS cells. Thus, elevated KCNN1 expression is not translated to K_Ca2.1 channel activity in EwS cells. However, we found that the low K⁺ conductance of EwS cells renders them susceptible to hypoosmotic solutions. The absence of a relevant K⁺ conductance in EwS thereby provides an opportunity for hypoosmotic therapy that can be exploited during tumor surgery.

SUBMITTER: Fuest S

PROVIDER: S-EPMC9564116 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Relevance of Abnormal KCNN1 Expression and Osmotic Hypersensitivity in Ewing Sarcoma.

Fuest Sebastian S Post Christoph C Balbach Sebastian T ST Jabar Susanne S Neumann Ilka I Schimmelpfennig Sandra S Sargin Sarah S Nass Elke E Budde Thomas T Kailayangiri Sareetha S Altvater Bianca B Ranft Andreas A Hartmann Wolfgang W Dirksen Uta U Rössig Claudia C Schwab Albrecht A Pethő Zoltán Z

Cancers 20221001 19

Ewing sarcoma (EwS) is a rare and highly malignant bone tumor occurring mainly in childhood and adolescence. Physiologically, the bone is a central hub for Ca2+ homeostasis, which is severely disturbed by osteolytic processes in EwS. Therefore, we aimed to investigate how ion transport proteins involved in Ca2+ homeostasis affect EwS pathophysiology. We characterized the expression of 22 candidate genes of Ca2+-permeable or Ca2+-regulated ion channels ...[more]

PMID: 36230742

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Project description:Adamantinoma-like Ewing sarcoma (ALES) has traditionally been considered a variant of Ewing sarcoma because it generally harbors EWSR1::FLI1 fusions despite showing diffuse positivity for keratins and p40. However, it has become increasingly recognized that different tumors can have identical translocations, including shared fusions between carcinomas and sarcomas, raising questions as to whether ALES might represent a separate entity. Using methylation profiling, we further explored the relationship between Ewing sarcoma and ALES. The archives of multiple institutions were searched for candidate cases of ALES. DNA methylation profiling was performed and results were compared to corresponding data from conventional Ewing sarcoma. Twelve cases of ALES (5 previously reported) were identified in 10 men and 2 women (aged 20-72 years; median age, 41.5 years). Cases included tumors arising in the parotid gland (3), sinonasal cavity (2), submandibular gland (2), thyroid gland (1), neck (1), gingiva (1), hypopharynx (1), and mandible (1). Histologic review consistently showed sheets and nests of basaloid cells within a fibromyxoid or hyalinized stroma. All tumors were positive for at least 1 keratin and CD99 expression, whereas all 10 cases tested were positive for p63 or p40; S100 protein expression was noted in 2 cases. Cases harbored either EWSR1::FLI1 fusions (n = 6), FUS::FLI1 fusions (n = 1), and/or EWSR1 rearrangements (n = 6). Methylation profiling was successful in 11/12 cases evaluated. Unsupervised clustering and dimensionality reduction (Uniform Manifold Approximation and Projection) of DNA methylation data revealed a distinct methylation cluster for all 11 cases, including the tumor with the FUS::FLI1 fusion, which clearly segregated them from the conventional Ewing sarcoma. Follow-up (n = 11, 1-154 months) revealed that 4 patients experienced recurrence and 6 developed metastatic disease. ALES demonstrates a distinct methylation signature from conventional Ewing sarcoma. This finding adds to the distinctive immunoprofile of ALES, suggesting that these 2 tumors should be considered distinct entities rather than histologic extremes of the same disease.

Dataset Information

Relevance of Abnormal KCNN1 Expression and Osmotic Hypersensitivity in Ewing Sarcoma.

Publications

Relevance of Abnormal KCNN1 Expression and Osmotic Hypersensitivity in Ewing Sarcoma.

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