Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
Pathology Department, Institut de Recerca Hospital Vall d'Hebron, Barcelona, Spain.
Clin Cancer Res. 2018 Dec 15;24(24):6367-6382. doi: 10.1158/1078-0432.CCR-18-0517. Epub 2018 Aug 22.
The study of the cancer secretome suggests that a fraction of the intracellular proteome could play unanticipated roles in the extracellular space during tumorigenesis. A project aimed at investigating the invasive secretome led us to study the alternative extracellular function of the nuclear protein high mobility group A1 (HMGA1) in breast cancer invasion and metastasis.
Antibodies against HMGA1 were tested in signaling, adhesion, migration, invasion, and metastasis assays using breast cancer cell lines and xenograft models. Fluorescence microscopy was used to determine the subcellular localization of HMGA1 in cell lines, xenograft, and patient-derived xenograft models. A cohort of triple-negative breast cancer (TNBC) patients was used to study the correlation between subcellular localization of HMGA1 and the incidence of metastasis.
Our data show that treatment of invasive cells with HMGA1-blocking antibodies in the extracellular space impairs their migration and invasion abilities. We also prove that extracellular HMGA1 (eHMGA1) becomes a ligand for the Advanced glycosylation end product-specific receptor (RAGE), inducing pERK signaling and increasing migration and invasion. Using the cytoplasmic localization of HMGA1 as a surrogate marker of secretion, we showed that eHMGA1 correlates with the incidence of metastasis in a cohort of TNBC patients. Furthermore, we show that HMGA1 is enriched in the cytoplasm of tumor cells at the invasive front of primary tumors and in metastatic lesions in xenograft models.
Our results strongly suggest that eHMGA1 could become a novel drug target in metastatic TNBC and a biomarker predicting the onset of distant metastasis.
对癌症分泌组的研究表明，细胞内蛋白质组的一部分在肿瘤发生过程中可能在细胞外空间发挥意想不到的作用。一个旨在研究侵袭性分泌组的项目促使我们研究核蛋白高迁移率族 A1（HMGA1）在乳腺癌侵袭和转移中的替代细胞外功能。
使用乳腺癌细胞系和异种移植模型，用针对 HMGA1 的抗体检测信号转导、黏附、迁移、侵袭和转移测定。荧光显微镜用于确定 HMGA1 在细胞系、异种移植和患者来源异种移植模型中的亚细胞定位。使用一组三阴性乳腺癌（TNBC）患者来研究 HMGA1 的亚细胞定位与转移发生率之间的相关性。
我们的数据表明，在细胞外空间用 HMGA1 阻断抗体处理侵袭性细胞会损害它们的迁移和侵袭能力。我们还证明，细胞外 HMGA1（eHMGA1）成为晚期糖基化终产物特异性受体（RAGE）的配体，诱导 pERK 信号转导并增加迁移和侵袭。我们使用 HMGA1 的细胞质定位作为分泌的替代标志物，表明 eHMGA1 与 TNBC 患者队列中转移的发生率相关。此外，我们表明 HMGA1 在原发性肿瘤侵袭前沿的肿瘤细胞的细胞质中以及异种移植模型中的转移病变中富集。
我们的结果强烈表明，eHMGA1 可能成为转移性 TNBC 的新型药物靶点，并预测远处转移发生的生物标志物。
