School of Pharmaceutical Sciences, Sun Yat-sen University, 510006, Guangzhou, Guangdong, China.
Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 510080, Guangzhou, China.
EMBO Mol Med. 2024 Sep;16(9):2043-2059. doi: 10.1038/s44321-024-00108-z. Epub 2024 Jul 31.
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.
小细胞肺癌（SCLC）是最具侵袭性和致命性的肺癌类型，其特征是治疗选择有限，早期和频繁转移。然而，SCLC 转移的决定因素尚未明确。在这里，我们表明雌激素相关受体γ（ERRγ）在转移性 SCLC 肿瘤中过度表达，并与 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，作为细胞外基质（ECM）重塑和细胞黏附这两个转移关键步骤的必需激活剂发挥作用。ERRγ 的遗传和药理学抑制显著减少胶原蛋白产生、细胞-基质黏附、微丝产生，最终阻断 SCLC 细胞侵袭和肿瘤转移。值得注意的是，ERRγ 拮抗剂显著抑制肿瘤生长和转移，并在多个细胞衍生和患者衍生的异种移植模型中恢复 SCLC 对化疗的敏感性。总之，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一种潜在的药理学策略。
