Extracellular HMGA1 Promotes Tumor Invasion and Metastasis in Triple-Negative Breast Cancer

Abstract

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.

Biomarkers of tumor invasiveness in proteomics (Review)

“…The complex molecular functions of RAGE-ligand signaling arrays appear to be associated with all the hallmarks of cancer (323,324). Of note, although RAGE was not detected in either our experimental or clinical proteomic data, an increasing abundance of HMGA1 was previously found within the three rat models of malignant mesothelioma exhibiting increasing levels of invasiveness (21), a feature which is in agreement with the association described between RAGE and this nuclear protein (319).…”

“…This protein, a member of the immunoglobulin superfamily known since 1949, has been the subject of growing interest in cancer research since 2001. It is a receptor for HMGA1, increasing the migration and invasion of triple-negative breast cancer cells (319). Other RAGE ligands, such as HMGB1 (320), or S100P, S100A8 and S100A9 (321), enhance its expression, which may further lead to increased proliferation, migration and metastasis.…”

Downregulation of HMGA1 Mediates Autophagy and Inhibits Migration and Invasion in Bladder Cancer via miRNA-221/TP53INP1/p-ERK Axis

“…HMGA1 gene gives rise to three HMGA1 isoforms (HMGA1a, HMGA1b, and HMGA1c) through alternative splicing (14). HMGA1 has been reported to play an important role in many types of cancers, including lung cancer (15), colorectal cancer (16), breast cancer (17), cervical cancer (18), and BC (19). HMGA1 contributes to tumor formation and progression through several mechanisms: inactivation of the apoptotic function of p53 (20), enhancement of the expression of genes involved in stem cell and inflammatory pathway (21), and modulation of the expression of miRNAs and genes involved in cell cycle and epithelial-mesenthymal transition (13).…”

Proteomics Identification and Validation of Desmocollin‐1 and Catechol‐O‐Methyltransferase as Proteins Associated with Breast Cancer Cell Migration and Metastasis

“…Similar approach with a subpopulation selection from a heterogeneous cell line has been successfully used in several cancers to complement gene targeting studies or to identify new markers . Cell surface proteins comprise only a small portion of total proteome and their identification requires high amount of incoming material, which leads to a limited method throughput.…”