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.

中文翻译：

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靶向 ERRγ 的治疗通过细胞外基质重塑抑制小细胞肺癌的转移。


小细胞肺癌（SCLC）是最具侵袭性和致命性的肺癌类型，其特点是治疗选择有限、早期且频繁转移。然而，SCLC 转移的决定因素尚不清楚。在这里，我们发现雌激素相关受体γ（ERRγ）在转移性SCLC肿瘤中过度表达，并且与SCLC进展呈正相关。 ERRγ 通过直接调节参与这些过程的主要基因的表达，充当细胞外基质 (ECM) 重塑和细胞粘附（转移中的两个关键步骤）的重要激活剂。 ERRγ的遗传和药理学抑制显着减少胶原蛋白的产生、细胞基质粘附、微丝的产生，并最终阻止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着抑制肿瘤生长和转移，并恢复 SCLC 对化疗的脆弱性。总而言之，这些发现确立了 ERRγ 作为转移性 SCLC 的一个有吸引力的靶点，并为治疗这种致命疾病提供了潜在的药理学策略。