Therapeutic targeting ERRγ suppresses metastasis via extracellular matrix remodeling in small cell lung cancer

• Published in: EMBO molecular medicine Vol. 16; no. 9; pp. 2043 - 2059
• Main Authors: Wang, Hong, Sun, Huizi, Huang, Jie, Zhang, Zhenhua, Cai, Guodi, Wang, Chaofan, Xiao, Kai, Xiong, Xiaofeng, Zhang, Jian, Liu, Peiqing, Lu, Xiaoyun, Feng, Weineng, Wang, Junjian
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.09.2024; Springer Nature
• Subjects: Animals; Biomedical and Life Sciences; Biomedicine; Cell Adhesion - drug effects; Cell Line, Tumor; Disease Models, Animal; EMBO03; EMBO35; ERRgamma; Extracellular Matrix - drug effects; Extracellular Matrix - metabolism; Extracellular Matrix Remodeling; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Metastasis; Mice; Molecular Medicine; Neoplasm Metastasis; Receptors, Estrogen - metabolism; Small Cell Lung Carcinoma - drug therapy; Small Cell Lung Carcinoma - genetics; Small Cell Lung Carcinoma - metabolism; Small Cell Lung Carcinoma - pathology; Small-Cell Lung Cancer; Therapeutic Target; Small-Cell Lung Cancer; Therapeutic Target; Extracellular Matrix Remodeling; Metastasis; ERRgamma
• ISSN: 1757-4684; 1757-4684
• DOI: 10.1038/s44321-024-00108-z

Small-cell lung cancer (SCLC) is the most aggressive and lethal type of lung cancer, characterized by limited treatment options, early and frequent metastasis. However, the determinants of metastasis in SCLC are poorly defined. Here, we show that estrogen-related receptor gamma (ERRγ) is overexpressed in metastatic SCLC tumors, and is positively associated with SCLC progression. ERRγ functions as an essential activator of extracellular matrix (ECM) remodeling and cell adhesion, two critical steps in metastasis, by directly regulating the expression of major genes involved in these processes. Genetic and pharmacological inhibition of ERRγ markedly reduces collagen production, cell-matrix adhesion, microfilament production, and eventually blocks SCLC cell invasion and tumor metastasis. Notably, ERRγ antagonists significantly suppressed tumor growth and metastasis and restored SCLC vulnerability to chemotherapy in multiple cell-derived and patient-derived xenograft models. Taken together, these findings establish ERRγ as an attractive target for metastatic SCLC and provide a potential pharmacological strategy for treating this lethal disease. Synopsis Metastasis remains the leading cause of mortality in patients with small cell lung cancer (SCLC). Through single-cell, bulk transcriptome analysis and gene functional studies, ERRγ was identified as a key player of extracellular matrix (ECM) remodelling and a promising target for metastatic SCLC. ERRγ was overexpressed in metastatic SCLC tumors and positively correlated with disease progression. ERRγ was identified as a key determinant of ECM-related gene expression in SCLC cells. Genetic and pharmacological suppression of ERRγ reduced collagen production, cell-matrix adhesion, and suppressed microfilament formation, thereby halting SCLC cell invasion and metastatic dissemination. ERRγ antagonists suppressed SCLC tumor growth and metastasis, and restored the sensitivity of resistant SCLC to chemotherapy. Metastasis remains the leading cause of mortality in patients with small cell lung cancer (SCLC). Through single-cell, bulk transcriptome analysis and gene functional studies, ERRγ was identified as a key player of extracellular matrix (ECM) remodelling and a promising target for metastatic SCLC.