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GREM1是维持胰腺癌细胞异质性所需的
2022-06-30 20:05

英国癌症研究所Axel Behrens团队发现,GREM1是维持胰腺癌细胞异质性所需的。2022年6月29日,国际知名学术期刊《自然》在线发表了这一成果。

研究人员发现BMP抑制因子GREM1是人类和小鼠胰腺癌细胞异质性的一个关键调节因子。在已建立的小鼠胰腺导管腺癌(PDAC)中,Grem1失活导致上皮细胞在几天内直接转化为间质PDAC细胞,这表明持续的GREM1活性是维持上皮PDAC亚群所必需的。相比之下,Grem1的过表达导致高度间质化的PDAC几乎完全"上皮化",从而表明高GREM1活性足以逆转PDAC细胞的间质命运。

从机制上讲,Grem1在间质PDAC细胞中高度表达,并抑制了上皮-间质转化转录因子Snai1(也称为Snail)和Snai2(也称为Slug)在上皮细胞区的表达,因此限制了上皮-间质可塑性。因此,持续抑制BMP活性对维持上皮PDAC细胞至关重要,这表明维持胰腺癌的细胞异质性需要由单一可溶性因子引起的持续旁分泌信号。

据悉,PDAC显示出明显的上皮细胞和间质癌细胞群。PDAC的细胞异质性是疾病亚型特化的一个重要特征,但不同的PDAC亚群如何相互作用,以及支撑PDAC细胞命运决定的分子机制,还没有得到完全的理解。

附:英文原文

Title: GREM1 is required to maintain cellular heterogeneity in pancreatic cancer

Author: Lan, Linxiang, Evan, Theodore, Li, Huafu, Hussain, Aasia, Ruiz, E. Josue, Zaw Thin, May, Ferreira, Rute M. M., Ps, Hari, Riising, Eva M., Zen, Yoh, Almagro, Jorge, Ng, Kevin W., Soro-Barrio, Pablo, Nelson, Jessica, Koifman, Gabriela, Carvalho, Joana, Nye, Emma L., He, Yulong, Zhang, Changhua, Sadanandam, Anguraj, Behrens, Axel

Issue&Volume: 2022-06-29

Abstract: Pancreatic ductal adenocarcinoma (PDAC) shows pronounced epithelial and mesenchymal cancer cell populations1,2,3,4. Cellular heterogeneity in PDAC is an important feature in disease subtype specification3,4,5, but how distinct PDAC subpopulations interact, and the molecular mechanisms that underlie PDAC cell fate decisions, are incompletely understood. Here we identify the BMP inhibitor GREM16,7 as a key regulator of cellular heterogeneity in pancreatic cancer in human and mouse. Grem1 inactivation in established PDAC in mice resulted in a direct conversion of epithelial into mesenchymal PDAC cells within days, suggesting that persistent GREM1 activity is required to maintain the epithelial PDAC subpopulations. By contrast, Grem1 overexpression caused an almost complete ‘epithelialization’ of highly mesenchymal PDAC, indicating that high GREM1 activity is sufficient to revert the mesenchymal fate of PDAC cells. Mechanistically, Grem1 was highly expressed in mesenchymal PDAC cells and inhibited the expression of the epithelial–mesenchymal transition transcription factors Snai1 (also known as Snail) and Snai2 (also known as Slug) in the epithelial cell compartment, therefore restricting epithelial–mesenchymal plasticity. Thus, constant suppression of BMP activity is essential to maintain epithelial PDAC cells, indicating that the maintenance of the cellular heterogeneity of pancreatic cancer requires continuous paracrine signalling elicited by a single soluble factor.

DOI: 10.1038/s41586-022-04888-7

Source: https://www.nature.com/articles/s41586-022-04888-7

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:69.504
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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