ROR2 调控胰腺肿瘤和腺癌的细胞可塑性

IF 29.7 1区 医学 Q1 ONCOLOGY
Simone Benitz, Alec Steep, Malak M Nasser, Jonathan Preall, Ujjwal Mukund Mahajan, Holly McQuithey, Ian Loveless, Erick T Davis, Hui-Ju Wen, Daniel W Long, Thomas Metzler, Samuel Zwernik, Michaela Louw, Donald Rempinski, Daniel J Salas-Escabillas, Sydney M Brender, Linghao Song, Ling Huang, Brian K Theisen, Zhenyu Zhang, Nina G Steele, Ivonne Regel, Filip Bednar, Howard C Crawford
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引用次数: 0

摘要

细胞可塑性是胰腺导管腺癌(PDAC)的一个特征,从正常细胞转化为癌前病变,到与侵袭性和治疗反应相关的癌亚型的发展。我们发现,由转录因子 Pdx1 维持的正常尖腺细胞分化抑制了广泛的胃细胞特性,这种特性在小鼠和人类的变性、瘤变和 PDAC 经典亚型中得以维持。我们发现,受体酪氨酸激酶 Ror2 是胰腺肿瘤中胃扁平化样特征的标志物。在小鼠胰腺肿瘤发生模型中,Ror2的消减促进了向胃凹陷细胞身份的转换,这种转换在进展为经典亚型PDAC时基本持续。在人类和小鼠胰腺癌中,ROR2的活性继续拮抗胃凹陷细胞特性,强烈促进上皮细胞向间充质细胞的转变,使其对KRAS抑制产生抵抗力,并易受AKT抑制的影响。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
ROR2 Regulates Cellular Plasticity in Pancreatic Neoplasia and Adenocarcinoma.

Cellular plasticity is a hallmark of pancreatic ductal adenocarcinoma (PDAC) starting from the conversion of normal cells into precancerous lesions, to the progression of carcinoma subtypes associated with aggressiveness and therapeutic response. We discovered that normal acinar cell differentiation, maintained by the transcription factor PDX1, suppresses a broad gastric cell identity that is maintained in metaplasia, neoplasia, and the classical subtype of PDAC in a mouse and human. We identified the receptor tyrosine kinase ROR2 as marker of a gastric metaplasia-like identity in pancreas neoplasms. Ablation of Ror2 in a mouse model of pancreatic tumorigenesis promoted a switch to a gastric pit cell identity that largely persisted through progression to the classical subtype of PDAC. In both human and mouse pancreatic cancer, ROR2 activity continued to antagonize the gastric pit cell identity, strongly promoting an epithelial to mesenchymal transition, conferring resistance to KRAS inhibition, and vulnerability to AKT inhibition. Significance: We discovered the receptor tyrosine kinase ROR2 as an important regulator of cellular identity in pancreatic precancerous lesions and pancreatic cancer. ROR2 drives an aggressive PDAC phenotype and confers resistance to KRAS inhibitors, suggesting that targeting ROR2 will enhance sensitivity to this new generation of targeted therapies. See related commentary by Marasco and Misale, p. 2018.

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来源期刊
Cancer discovery
Cancer discovery ONCOLOGY-
CiteScore
22.90
自引率
1.40%
发文量
838
审稿时长
6-12 weeks
期刊介绍: Cancer Discovery publishes high-impact, peer-reviewed articles detailing significant advances in both research and clinical trials. Serving as a premier cancer information resource, the journal also features Review Articles, Perspectives, Commentaries, News stories, and Research Watch summaries to keep readers abreast of the latest findings in the field. Covering a wide range of topics, from laboratory research to clinical trials and epidemiologic studies, Cancer Discovery spans the entire spectrum of cancer research and medicine.
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