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HMGA2 facilitates colorectal cancer progression via STAT3-mediated tumor-associated macrophage recruitment.

ABSTRACT: Rationale: Tumor-associated macrophages (TAMs), generally displaying the pro-tumor M2-like phenotype, strongly influence the progression of colorectal cancer (CRC) via their immunosuppressive activities. The high-mobility gene group A2 (HMGA2), an oncoprotein, is aberrantly overexpressed in CRC cells. However, the mechanisms by which tumor-derived HMGA2 modulates tumor microenvironment in CRC remain poorly understood. Methods: In vivo subcutaneous tumor xenograft model, azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced tumor mouse model and in vitro co-culture assays were used to investigate the Hmga2 role in TAM recruitment and polarization. Luciferase and chromatin immunoprecipitation (ChIP) assays were applied to examine the mechanism of HMGA2-mediated transcriptional regulation of signal transducer and activator of transcription 3 (STAT3). The CD68 correlation with patient outcome was analyzed in 167 human CRC tissues. Results: We found that HMGA2 in cancer cells promoted macrophage recruitment and M2 polarization in vitro and in vivo. HMGA2 directly bound to the STAT3 promoter to activate its transcription and subsequently induced CCL2 secretion, thus promoting macrophage recruitment. Our results from human CRC specimens also revealed a strong positive association between HMGA2 expression in tumor cells and CD68 expression in the stroma. We further showed that patients with an elevated CD68 expression had an unfavorable overall survival in all of the patients or in the subgroup with negative distant metastasis. Conclusion: Our work uncovers new insight into the link between the HMGA2/STAT3/CCL2 axis and macrophage recruitment in CRC. These findings provide a novel therapeutic option for targeting the HMGA2/STAT3/CCL2 axis in CRC.

SUBMITTER: Wang X

PROVIDER: S-EPMC8692921 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Glioblastoma (GBM) is the most lethal primary brain tumor characterized by significant cellular heterogeneity, namely tumor cells, including GBM stem-like cells (GSCs) and differentiated GBM cells (DGCs), and non-tumor cells such as endothelial cells, vascular pericytes, macrophages, and other types of immune cells. GSCs are essential to drive tumor progression, whereas the biological roles of DGCs are largely unknown. In this study, we focused on the roles of DGCs in the tumor microenvironment. To this end, we extracted DGC-specific signature genes from transcriptomic profiles of matched pairs of in vitro GSC and DGC models. By evaluating the DGC signature using single cell data, we confirmed the presence of cell subpopulations emulated by in vitro culture models within a primary tumor. The DGC signature was correlated with the mesenchymal subtype and a poor prognosis in large GBM cohorts such as The Cancer Genome Atlas and Ivy Glioblastoma Atlas Project. In silico signaling pathway analysis suggested a role of DGCs in macrophage infiltration. Consistent with in silico findings, in vitro DGC models promoted macrophage migration. In vivo, coimplantation of DGCs and GSCs reduced the survival of tumor xenograft-bearing mice and increased macrophage infiltration into tumor tissue compared with transplantation of GSCs alone. DGCs exhibited a significant increase in YAP/TAZ/TEAD activity compared with GSCs. CCN1, a transcriptional target of YAP/TAZ, was selected from the DGC signature as a candidate secreted protein involved in macrophage recruitment. In fact, CCN1 was secreted abundantly from DGCs, but not GSCs. DGCs promoted macrophage migration in vitro and macrophage infiltration into tumor tissue in vivo through secretion of CCN1. Collectively, these results demonstrate that DGCs contribute to GSC-dependent tumor progression by shaping a mesenchymal microenvironment via CCN1-mediated macrophage infiltration. This study provides new insight into the complex GBM microenvironment consisting of heterogeneous cells.

Project description:BackgroundSWI/SNF, a well-known ATP-dependent chromatin-remodeling complex, plays an essential role in several biological processes. SNF5, the core subunit of the SWI/SNF remodeling complex, inactivated in 95% of malignant rhabdoid tumors (MRT), highlighting its significance in tumorigenesis. However, the role of SNF5 in bladder cancer (BC) remains unknown. In this study, we aimed to investigate the function and potential clinical applicability of SNF5 in BC.MethodsData from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) and Cancer Cell Line Encyclopedia (CCLE) databases were used to evaluate the clinical significance of SNF5 in BC. We performed Gene Set Enrichment Analysis (GSEA) and functional assays to investigate the role of SNF5 in BC. Genomics of Drug Sensitivity in Cancer (GDSC) and drug-susceptibility tests were performed to identify the potential value of SNF5 in the treatment of BC.ResultsLow SNF5 expression conferred a poor prognosis and was significantly associated with the N-stage in BC. ROC curves indicated that SNF5 could distinguish BC from the normal tissues. In vitro and in vivo functional assays demonstrated that attenuated SNF5 expression could promote cell proliferation and enhance migration by STAT3 activation. We imputed that low SNF5 expression could confer greater resistance against conventional first-line drugs, including cisplatin and gemcitabine in BC. GDSC and drug-resistance assays suggested that low SNF5 expression renders T24 and 5637 cells high sensitivity to EGFR inhibitor gefitinib, and combination of EZH2 inhibitor GSK126 and cisplatin.ConclusionsTo the best of our knowledge, the present study, for the first time, showed that low SNF5 expression could promote cell proliferation and migration by activating STAT3 and confer poor prognosis in BC. Importantly, SNF5 expression may be a promising candidate for identifying BC patients who could benefit from EGFR-targeted chemotherapy or cisplatin in combination with EZH2 inhibitor treatment regimens.

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HMGA2 facilitates colorectal cancer progression via STAT3-mediated tumor-associated macrophage recruitment.

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