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ROR2 调节胰腺肿瘤和腺癌中的细胞可塑性。

ROR2 Regulates Cellular Plasticity in Pancreatic Neoplasia and Adenocarcinoma.

机构信息

Department of Surgery, Henry Ford Health, Detroit, Michigan.

Center of Translational Data Science, University of Chicago, Chicago, Illinois.

出版信息

Cancer Discov. 2024 Nov 1;14(11):2162-2182. doi: 10.1158/2159-8290.CD-24-0137.

DOI:10.1158/2159-8290.CD-24-0137
PMID:38975886
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11528200/
Abstract

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.

摘要

细胞可塑性是胰腺导管腺癌 (PDAC) 的一个标志，从正常细胞向癌前病变的转化，到与侵袭性和治疗反应相关的癌亚型的进展。我们发现，转录因子 PDX1 维持的正常腺泡细胞分化，抑制了广泛的胃细胞表型，这种表型在化生、肿瘤发生和 PDAC 的经典亚型中得以维持，无论是在小鼠还是人类中。我们确定了受体酪氨酸激酶 ROR2 作为胰腺肿瘤中胃化生样表型的标志物。在胰腺肿瘤发生的小鼠模型中，Ror2 的缺失促进了向胃小凹细胞表型的转变，这种转变在向 PDAC 的经典亚型进展过程中在很大程度上得以维持。在人类和小鼠胰腺癌中，ROR2 的活性继续拮抗胃小凹细胞表型，强烈促进上皮间质转化，赋予对 KRAS 抑制剂的耐药性，并对 AKT 抑制剂敏感。意义：我们发现受体酪氨酸激酶 ROR2 是胰腺癌前病变和胰腺癌中细胞表型的重要调节因子。ROR2 驱动侵袭性 PDAC 表型，并赋予对 KRAS 抑制剂的耐药性，这表明靶向 ROR2 将增强对这新一代靶向治疗的敏感性。见 Marasco 和 Misale 的相关评论，第 2018 页。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f9ef/11528200/c8c6dc0c677e/cd-24-0137fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f9ef/11528200/d24487c20633/cd-24-0137fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f9ef/11528200/13530fa62ed4/cd-24-0137fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f9ef/11528200/4f9202bf6246/cd-24-0137fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f9ef/11528200/07cd015c8102/cd-24-0137fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f9ef/11528200/2f7aea418aba/cd-24-0137fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f9ef/11528200/9e5e5f08f829/cd-24-0137fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f9ef/11528200/c8c6dc0c677e/cd-24-0137fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f9ef/11528200/d24487c20633/cd-24-0137fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f9ef/11528200/13530fa62ed4/cd-24-0137fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f9ef/11528200/4f9202bf6246/cd-24-0137fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f9ef/11528200/07cd015c8102/cd-24-0137fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f9ef/11528200/2f7aea418aba/cd-24-0137fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f9ef/11528200/9e5e5f08f829/cd-24-0137fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f9ef/11528200/c8c6dc0c677e/cd-24-0137fig7.jpg

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Nat Commun. 2023 Jun 29;14(1):3750. doi: 10.1038/s41467-023-39113-0.
2
It is better to light a candle than to curse the darkness: single-cell transcriptomics sheds new light on pancreas biology and disease.与其诅咒黑暗，不如点亮蜡烛：单细胞转录组学为胰腺生物学和疾病研究带来新曙光。
Gut. 2023 Jun;72(6):1211-1219. doi: 10.1136/gutjnl-2022-329313. Epub 2023 Mar 30.
3
Comprehensive DNA Methylation Analysis Indicates That Pancreatic Intraepithelial Neoplasia Lesions Are Acinar-Derived and Epigenetically Primed for Carcinogenesis.
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bioRxiv. 2024 Apr 23:2024.02.12.579982. doi: 10.1101/2024.02.12.579982.
综合 DNA 甲基化分析表明，胰腺上皮内瘤变病变来源于腺泡，并在表观遗传学上为癌变做好了准备。
Cancer Res. 2023 Jun 2;83(11):1905-1916. doi: 10.1158/0008-5472.CAN-22-4052.
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Tumor cell plasticity in targeted therapy-induced resistance: mechanisms and new strategies.靶向治疗诱导耐药中的肿瘤细胞可塑性：机制与新策略。
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