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A novel HDGF-ALCAM axis promotes the metastasis of Ewing sarcoma via regulating the GTPases signaling pathway

Oncogene volume 40, pages 731–745 (2021)Cite this article

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Abstract

Ewing sarcoma (ES) is a type of highly aggressive pediatric tumor in bones and soft tissues and its metastatic spread remains the most powerful predictor of poor outcome. We previously identified that the transcription factor hepatoma-derived growth factor (HDGF) promotes ES tumorigenesis. However, the mechanisms underlying ES metastasis remain unclear. Here, we show that HDGF drives ES metastasis in vitro and in vivo, and HDGF reduces metastasis-free survival (MFS) in two independent large cohorts of human ES patients. Integrative analyses of HDGF ChIP-seq and gene expression profiling in ES cells reveal that HDGF regulates multiple metastasis-associated genes, among which activated leukocyte cell adhesion molecule (ALCAM) emerges as a major HDGF target and a novel metastasis-suppressor in ES. HDGF down-regulates ALCAM, induces expression and activation of the downstream effectors Rho-GTPase Rac1 and Cdc42, and promotes actin cytoskeleton remodeling and cell-matrix adhesion. In addition, repression of ALCAM and activation of Rac1 and Cdc42 are required for the pro-metastatic functions of HDGF in vitro. Moreover, analyses in murine models with ES tumor orthotopic implantation and experimental metastasis, as well as in human ES samples, demonstrate the associations among HDGF, ALCAM, and GTPases expression levels. Furthermore, high HDGF/low ALCAM expression define a subgroup of patients harboring the worst MFS. These findings suggest that the HDGF/ALCAM/GTPases axis represents a promising therapeutic target for limiting ES metastasis.

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Fig. 1: High nuclear HDGF expression is significantly associated with short metastasis-free survival of ES patients.
Fig. 2: HDGF promotes metastasis-relevant traits in vitro and metastasis in vivo in ES cell lines.
Fig. 3: HDGF promotes actin cytoskeleton reorganization, cell-matrix adhesion, and GTPases activation in ES cells.
Fig. 4: HDGF directly targets ALCAM.
Fig. 5: ALCAM suppresses intrinsic metastasis-relevant traits in ES cell lines in vitro.
Fig. 6: Enhanced expression of ALCAM notably impairs HDGF-mediated pro-metastatic traits in ES cells.
Fig. 7: ALCAM levels correlate inversely with metastasis in human ES.

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Acknowledgements

This work was supported by grants from the National Nature Science Foundation in China (81772862 and 81402413 to YY, and 81402000 to HL) and from the Fundamental Research Funds for the Sun Yat-sen Universities (16ykpy42 to YY).

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  1. These authors contributed equally: Yang Yang, Yuedong Ma, Huabin Gao

Authors and Affiliations

  1. Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, P.R. China

    Yang Yang, Huabin Gao, Tingsheng Peng, Huijuan Shi, Yunxiang Tang, Hui Li, Lin Chen & Anjia Han

  2. Department of Cardiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, P.R. China

    Yuedong Ma

  3. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, P.R. China

    Kaishun Hu

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Yang, Y., Ma, Y., Gao, H. et al. A novel HDGF-ALCAM axis promotes the metastasis of Ewing sarcoma via regulating the GTPases signaling pathway. Oncogene 40, 731–745 (2021). https://doi.org/10.1038/s41388-020-01485-8

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