Therapeutic targeting ERR? suppresses metastasis via extracellular matrix remodeling in small cell lung cancer (RNA-Seq)

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?) is overexpressed in metastatic SCLC tumors, and it is positively associated with SCLC progression. ERR? functions as an essential activator of 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? markedly reduces collagen production, cell-matrix adhesion, microfilaments production, and eventually blocks SCLC cell invasion and tumor metastasis. Notably, ERR? antagonists significantly suppress tumor growth and metastasis and restore resistant SCLC vulnerability to chemotherapy in multiple cell-derived and patient-derived xenograft models. Taken together, these findings establish ERR? as an attractive target for metastatic SCLC and provide a potential pharmacological strategy for treating this lethal disease. Overall design: RNA-Seq