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

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 (ERR gamma) is overexpressed in metastatic SCLC tumors, and is positively associated with SCLC progression. ERR gamma 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 ERR gamma markedly reduces collagen production, cell-matrix adhesion, microfilament production, and eventually blocks SCLC cell invasion and tumor metastasis. Notably, ERR gamma 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 ERR gamma as an attractive target for metastatic SCLC and provide a potential pharmacological strategy for treating this lethal disease. 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, ERR gamma was identified as a key player of extracellular matrix (ECM) remodelling and a promising target for metastatic SCLC.ERR gamma was overexpressed in metastatic SCLC tumors and positively correlated with disease progression.ERR gamma was identified as a key determinant of ECM-related gene expression in SCLC cells.Genetic and pharmacological suppression of ERR gamma reduced collagen production, cell-matrix adhesion, and suppressed microfilament formation, thereby halting SCLC cell invasion and metastatic dissemination.ERR gamma 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, ERR gamma was identified as a key player of extracellular matrix (ECM) remodelling and a promising target for metastatic SCLC.