Abstract：
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.
摘要：
小细胞肺癌（SCLC）是最具侵袭性和致死性的肺癌类型，以有限的治疗选择为特征，早期和频繁转移。然而,SCLC转移的决定因素定义不清.这里,我们显示雌激素相关受体γ（ERRγ）在转移性SCLC肿瘤中过度表达，与SCLC进展呈正相关。ERRγ作为细胞外基质（ECM）重塑和细胞粘附的必需激活剂，转移的两个关键步骤，通过直接调节参与这些过程的主要基因的表达。ERRγ的遗传和药理抑制显着减少胶原蛋白的产生，细胞-基质粘附，微丝生产，并最终阻断SCLC细胞侵袭和肿瘤转移。值得注意的是,ERRγ拮抗剂在多种细胞来源和患者来源的异种移植模型中显著抑制肿瘤生长和转移并恢复SCLC对化疗的脆弱性。一起来看,这些发现将ERRγ确立为转移性SCLC的一个有吸引力的靶点,并为治疗这种致死性疾病提供了潜在的药理学策略.
