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A paracrine activin A-mDia2 axis promotes squamous carcinogenesis via fibroblast reprogramming.
EMBO Molecular Medicine ( IF 11.1 ) Pub Date : 2020-03-09 , DOI: 10.15252/emmm.201911466
Michael Cangkrama 1 , Mateusz Wietecha 1 , Nicolas Mathis 1 , Rin Okumura 1 , Luca Ferrarese 1 , Dunja Al-Nuaimi 1 , Maria Antsiferova 1 , Reinhard Dummer 2 , Metello Innocenti 3 , Sabine Werner 1
Affiliation  

Cancer-associated fibroblasts (CAFs) are key regulators of tumorigenesis and promising targets for next-generation therapies. We discovered that cancer cell-derived activin A reprograms fibroblasts into pro-tumorigenic CAFs. Mechanistically, this occurs via Smad2-mediated transcriptional regulation of the formin mDia2, which directly promotes filopodia formation and cell migration. mDia2 also induces expression of CAF marker genes through prevention of p53 nuclear accumulation, resulting in the production of a pro-tumorigenic matrisome and secretome. The translational relevance of this finding is reflected by activin A overexpression in tumor cells and of mDia2 in the stroma of skin cancer and other malignancies and the correlation of high activin A/mDia2 levels with poor patient survival. Blockade of this signaling axis using inhibitors of activin, activin receptors, or mDia2 suppressed cancer cell malignancy and squamous carcinogenesis in 3D organotypic cultures, ex vivo, and in vivo, providing a rationale for pharmacological inhibition of activin A-mDia2 signaling in stratified cancer patients.

中文翻译:

旁分泌激活素A-mDia2轴通过成纤维细胞重编程促进鳞状癌变。

癌症相关的成纤维细胞(CAF)是肿瘤发生的关键调节剂,是下一代疗法的有希望的靶标。我们发现癌细胞衍生的激活素A将成纤维细胞重编程为促肿瘤的CAF。从机制上讲,这是通过Smad2介导的formin mDia2的转录调节而发生的,它直接促进丝状伪足的形成和细胞迁移。mDia2还可以通过预防p53核积累来诱导CAF标记基因的表达,从而产生促肿瘤的基质和分泌组。该发现与翻译的相关性反映在皮肤细胞和其他恶性肿瘤的基质中肿瘤细胞和mDia2中的激活素A过表达以及高激活素A / mDia2水平与不良患者生存的相关性。
更新日期:2020-03-09
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