TWIST1 expression is associated with high-risk neuroblastoma and promotes primary and metastatic tumor growth

AbstractThe embryonic transcription factors TWIST1/2 are frequently overexpressed in cancer, acting as multifunctional oncogenes. Here we investigate their role in neuroblastoma (NB), a heterogeneous childhood malignancy ranging from spontaneous regression to dismal outcomes despite multimodal therapy. We first reveal the association of TWIST1 expression with poor survival and metastasis in primary NB, while TWIST2 correlates with good prognosis. Secondly, suppression of TWIST1 by CRISPR/Cas9 results in a reduction of tumor growth and metastasis colonization in immunocompromised mice. Moreover, TWIST1 knockout tumors display a less aggressive cellular morphology and a reduced disruption of the extracellular matrix (ECM) reticulin network. Additionally, we identify a TWIST1-mediated transcriptional program associated with dismal outcome in NB and involved in the control of pathways mainly linked to the signaling, migration, adhesion, the organization of the ECM, and the tumor cells versus tumor stroma crosstalk. Taken together, our findings confirm TWIST1 as promising therapeutic target in NB.

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TWIST1 expression is associated with high-risk Neuroblastoma and promotes Primary and Metastatic Tumor Growth

10.1101/2021.03.22.435811 ◽

2021 ◽

Author(s):

Maria-Vittoria Sepporta ◽

Viviane Praz ◽

Katia Balmas Bourloud ◽

Jean-Marc Joseph ◽

Nicolas Jauquier ◽

...

Keyword(s):

Tumor Growth ◽

Multimodal Therapy ◽

Tumor Stroma ◽

Metastatic Tumor ◽

Good Prognosis ◽

Transcriptional Program ◽

Poor Survival ◽

Twist1 Expression ◽

Tumor Growth And Metastasis ◽

Immunocompromised Mice

AbstractThe embryonic transcription factors TWIST1/2 are frequently overexpressed in cancer, acting as multifunctional oncogenes. Here we investigate their role in neuroblastoma (NB), a heterogeneous childhood malignancy ranging from spontaneous regression to dismal outcomes despite multimodal therapy. We first reveal the association of TWIST1 expression with poor survival and metastasis in primary NB, while TWIST2 correlates with good prognosis. Secondly, suppression of TWIST1 by CRISPR/Cas9 results in a reduction of tumor growth and metastasis in immunocompromised mice. Moreover, TWIST1 knockout tumors display a less aggressive cellular morphology and a reduced disruption of the extracellular matrix (ECM) reticulin network. Additionally, we identify a TWIST1-mediated transcriptional program associated with dismal outcome in NB and involved in the control of pathways mainly linked to the signaling, migration, adhesion, the organization of the ECM, and the tumor cells versus tumor stroma crosstalk. Taken together, our findings suggest TWIST1 as novel therapeutic target in NB.

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MACC1 Contributes to the Development of Osteosarcoma Through Regulation of the HGF/c-Met Pathway and Microtubule Stability

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2020.00825 ◽

2020 ◽

Vol 8 ◽

Author(s):

Jia Wen ◽

Yi Xie ◽

Yingqiang Zhang ◽

Jiazhen Li ◽

Jiaping Li ◽

...

Keyword(s):

Endothelial Cells ◽

Tumor Growth ◽

Signaling Pathway ◽

Normal Tissues ◽

Microtubule Stability ◽

Promising Therapeutic Target ◽

Tumor Growth And Metastasis ◽

Hepatocyte Growth ◽

Proliferative Ability

Osteosarcoma (OS) is the most prevalent human bone malignancy, and presents a global annual morbidity of approximately five cases per million. Notably, precise and efficient targeted therapy has become the most promising strategy for the treatment of OS; however, there is still an urgent need for the identification of suitable therapeutic targets. Metastasis-associated in colon cancer 1 (MACC1) was first identified in colon tumors by differential display RT-PCR, and was shown to be involved in the regulation of colon tumor growth and metastasis through the hepatocyte growth factor (HGF)/c-Met signaling pathway. Additionally, MACC1 overexpression has been reported to induce the growth of several types of cancers, including glioblastoma multiforme and gastric cancer. However, whether MACC1 also plays a role in the progression of OS remains unclear. In this study, we found that MACC1 was highly expressed in human OS tissues, as well as in U-2OS and MG-63 cells, when compared with normal tissues and osteoblasts, respectively. Our data further indicated that MACC1 expression was correlated with several clinicopathological features of OS. Through in vitro assays, we found that MACC1 depletion markedly suppressed the proliferative ability of both OS cells and endothelial cells, and inhibited the angiogenic capacity of endothelial cells. Similarly, MACC1 depletion inhibited tumor growth, metastasis, and angiogenesis in mice. Mechanistically, we found that MACC1 could bind to the MET promoter, and enhanced the proliferation of both OS cells and endothelial cells through the HGF/c-Met signaling pathway. Furthermore, we show that MACC1 also promoted angiogenesis by regulating microtubule dynamics, thereby promoting the progression of OS. Our results indicate that MACC1 may be a new and promising therapeutic target for the treatment of OS.

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Identification of Kinesin Family Member 2A (KIF2A) as a Promising Therapeutic Target for Osteosarcoma

BioMed Research International ◽

10.1155/2020/7102757 ◽

2020 ◽

Vol 2020 ◽

pp. 1-9

Author(s):

Zhe-Xiang Wang ◽

Shao-Chun Ren ◽

Zi-Song Chang ◽

Jing Ren

Keyword(s):

Tumor Growth ◽

Cancer Progression ◽

Therapeutic Target ◽

Clinical Stage ◽

Migration And Invasion ◽

Osteosarcoma Cell ◽

Expression Levels ◽

Human Osteosarcoma ◽

Promising Therapeutic Target ◽

Tumor Growth And Metastasis

Background. Osteosarcoma is known as a type of common human bone malignancy, and more therapeutic targets are still required to combat this disease. In recent years, the involvement of KIF2A in cancer progression has been widely revealed; however, its potential effect on osteosarcoma development remains unknown. This study is to assess the KIF2A expression levels in human osteosarcoma tissues and explore its potential role in osteosarcoma development. Methods. Immunohistochemical (IHC) assays were conducted to evaluate the expression levels of KIF2A in a total of 74 samples of osteosarcoma tissues and adjacent nontumor tissues. According to the staining intensity in tumor tissues, patients were divided into highly expressed and low expression KIF2A groups. The possible links between the KIF2A expression and the clinical pathological features were explored and analyzed, and the effects of KIF2A on osteosarcoma cell proliferation, migration, and invasion were detected through colony formation assay, MTT assay, wound closure assay, and transwell assay, respectively. The effects of KIF2A on tumor growth and metastasis were detected by the use of animal models. Results. KIF2A was highly expressed in human osteosarcoma tissues. Meanwhile, KIF2A was obviously correlated to the tumor size ( P = 0.001 ∗ ) and clinical stage ( P = 0.014 ∗ ) of osteosarcoma patients. Our results also revealed that the ablation of KIF2A dramatically blocked the proliferation, migration, and invasion capacity of osteosarcoma cells in vitro and blocked tumor growth and metastasis in mice. Conclusions. We investigated the involvement of KIF2A in the development and metastasis of osteosarcoma and therefore thought KIF2A as a promising therapeutic target for osteosarcoma treatment.

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