Mutual regulation of TGFβ-induced oncogenic EMT, cell cycle progression and the DDR

IF 12.1 1区 医学 Q1 ONCOLOGY Seminars in cancer biology Pub Date : 2023-12-01 DOI:10.1016/j.semcancer.2023.11.009
Harald Schuhwerk , Thomas Brabletz
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Abstract

TGFβ signaling and the DNA damage response (DDR) are two cellular toolboxes with a strong impact on cancer biology. While TGFβ as a pleiotropic cytokine affects essentially all hallmarks of cancer, the multifunctional DDR mostly orchestrates cell cycle progression, DNA repair, chromatin remodeling and cell death. One oncogenic effect of TGFβ is the partial activation of epithelial-to-mesenchymal transition (EMT), conferring invasiveness, cellular plasticity and resistance to various noxae. Several reports show that both individual networks as well as their interface affect chemo-/radiotherapies. However, the underlying mechanisms remain poorly resolved. EMT often correlates with TGFβ-induced slowing of proliferation, yet numerous studies demonstrate that particularly the co-activated EMT transcription factors counteract anti-proliferative signaling in a partially non-redundant manner. Collectively, evidence piled up over decades underscore a multifaceted, reciprocal inter-connection of TGFβ signaling / EMT with the DDR / cell cycle progression, which we will discuss here. Altogether, we conclude that full cell cycle arrest is barely compatible with the propagation of oncogenic EMT traits and further propose that ‘EMT-linked DDR plasticity’ is a crucial, yet intricate facet of malignancy, decisively affecting metastasis formation and therapy resistance.

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tgf β诱导的致癌EMT、细胞周期进展和DDR的相互调控。
tgf - β信号和DNA损伤反应(DDR)是对癌症生物学有重要影响的两个细胞工具箱。tgf - β作为一种多效性细胞因子,基本上影响癌症的所有特征,而多功能DDR主要协调细胞周期进程、DNA修复、染色质重塑和细胞死亡。TGFβ的一个致癌作用是部分激活上皮-间质转化(EMT),赋予侵袭性、细胞可塑性和对各种肿瘤的抗性。一些报告表明,个体网络及其界面都影响化疗/放疗。然而,潜在的机制仍然没有得到很好的解决。EMT通常与tgf β诱导的增殖减缓相关,但许多研究表明,特别是共激活的EMT转录因子以部分非冗余的方式抵消抗增殖信号。总的来说,几十年来积累的证据强调了tgf - β信号/ EMT与DDR /细胞周期进程的多方面,相互关联,我们将在这里讨论。总之,我们得出结论,完整的细胞周期阻滞与致癌EMT性状的繁殖几乎不相容,并进一步提出“EMT相关的DDR可塑性”是恶性肿瘤的一个关键但复杂的方面,决定性地影响转移形成和治疗耐药性。
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来源期刊
Seminars in cancer biology
Seminars in cancer biology 医学-肿瘤学
CiteScore
26.80
自引率
4.10%
发文量
347
审稿时长
15.1 weeks
期刊介绍: Seminars in Cancer Biology (YSCBI) is a specialized review journal that focuses on the field of molecular oncology. Its primary objective is to keep scientists up-to-date with the latest developments in this field. The journal adopts a thematic approach, dedicating each issue to an important topic of interest to cancer biologists. These topics cover a range of research areas, including the underlying genetic and molecular causes of cellular transformation and cancer, as well as the molecular basis of potential therapies. To ensure the highest quality and expertise, every issue is supervised by a guest editor or editors who are internationally recognized experts in the respective field. Each issue features approximately eight to twelve authoritative invited reviews that cover various aspects of the chosen subject area. The ultimate goal of each issue of YSCBI is to offer a cohesive, easily comprehensible, and engaging overview of the selected topic. The journal strives to provide scientists with a coordinated and lively examination of the latest developments in the field of molecular oncology.
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