Department of Pathology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado.
Department of Pharmacology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado.
Clin Cancer Res. 2021 Nov 15;27(22):6209-6221. doi: 10.1158/1078-0432.CCR-21-0361. Epub 2021 Sep 20.
The survival of women with brain metastases (BM) from breast cancer remains very poor, with over 80% dying within a year of their diagnosis. Here, we define the function of IL13Rα2 in outgrowth of breast cancer brain metastases (BCBM) and , and postulate IL13Rα2 as a suitable therapeutic target for BM.
We performed IHC staining of IL13Rα2 in BCBM to define its prognostic value. Using inducible shRNAs in TNBC and HER2 breast-brain metastatic models, we assessed IL13Rα2 function and . We performed RNAseq and functional studies to define the molecular mechanisms underlying IL13Rα2 function in BCBM.
High IL13Rα2 expression in BCBM predicted worse survival after BM diagnoses. IL13Rα2 was essential for cancer-cell survival, promoting proliferation while repressing invasion. IL13Rα2 KD resulted in FAK downregulation, repression of cell cycle and proliferation mediators, and upregulation of Ephrin B1 signaling. Ephrin-B1 (i) promoted invasion of BC cells , (ii) marked micrometastasis and invasive fronts in BCBM, and (iii) predicted shorter disease-free survival and BM-free survival (BMFS) in breast primary tumors known to metastasize to the brain. In experimental metastases models, which bypass early tumor invasion, downregulation of IL13Rα2 before or after tumor seeding and brain intravasation decreased BMs, suggesting that IL13Rα2 and the promotion of a proliferative phenotype is critical to BM progression.
Non-genomic phenotypic adaptations at metastatic sites are critical to BM progression and patients' prognosis. This study opens the road to use IL13Rα2 targeting as a therapeutic strategy for BM.
乳腺癌脑转移（BM）患者的生存率仍然非常低，超过 80%的患者在诊断后一年内死亡。在这里，我们定义了 IL13Rα2 在乳腺癌脑转移（BCBM）生长中的作用，并提出 IL13Rα2 是 BM 的一个合适的治疗靶点。
我们通过免疫组化染色法检测 BCBM 中 IL13Rα2 的表达，以确定其预后价值。在三阴性乳腺癌（TNBC）和 HER2 乳腺癌脑转移模型中，我们使用诱导型 shRNA 评估了 IL13Rα2 的功能。我们进行了 RNAseq 和功能研究，以确定 IL13Rα2 在 BCBM 中发挥作用的分子机制。
BCBM 中高表达的 IL13Rα2 预示着 BM 诊断后生存状况较差。IL13Rα2 是癌细胞存活所必需的，促进增殖，同时抑制侵袭。IL13Rα2 KD 导致 FAK 下调，细胞周期和增殖介质抑制，以及 Ephrin B1 信号上调。Ephrin-B1（i）促进 BC 细胞的侵袭，（ii）在 BCBM 中标记微转移和侵袭前沿，以及（iii）预测已知转移到大脑的乳腺癌原发性肿瘤中无疾病生存和 BM 无复发生存（BMFS）较短。在实验性转移模型中，在肿瘤播种和脑浸润之前或之后下调 IL13Rα2 减少了 BM，这表明 IL13Rα2 和促进增殖表型是 BM 进展的关键。
转移部位的非基因组表型适应性对 BM 的进展和患者的预后至关重要。这项研究为使用 IL13Rα2 靶向作为 BM 的治疗策略开辟了道路。
