Spatial profiling of human pancreatic ductal adenocarcinoma reveals molecular alterations associated with venous invasion

IF 14.6 1区 医学 Q1 CELL BIOLOGY
Alexander T. F. Bell, Peter Chianchiano, Katsuya Hirose, Daniel Salas-Escabillas, Doreen M. Zucha, Jacob T. Mitchell, Ludmila Danilova, Alexander I. Damanakis, Joseph A. Tandurella, Jeanette Johnson, Jing Zhu, James R. Eshleman, Qingfeng Zhu, Robert A. Anders, Luciane T. Kagohara, Elana J. Fertig, Laura D. Wood
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引用次数: 0

Abstract

In pancreatic ductal adenocarcinoma (PDAC), venous invasion (VI) is a critical step in metastasis and is associated with poor survival. However, little is known about the molecular features of VI. To investigate, we performed spatial transcriptomic analysis of 95 human PDAC tissue samples from eight treatment-naïve patients. Our analysis revealed that, compared with PDAC in stroma, PDAC with VI demonstrated up-regulation of genes associated with epithelial differentiation, classical subtype, and benign exocrine function. Conversely, PDAC with VI demonstrated down-regulation of genes associated with mesenchymal differentiation, basal-like subtype, and disease aggression. Additionally, we uncovered characteristics of VI morphology that correlated with these molecular features. VI–intraepithelial neoplasia–like foci had preserved venous architecture and had a classical, epithelial molecular phenotype, whereas VI-destructive foci had destroyed venous architecture and had a more basal-like, mesenchymal phenotype. We contextualized our findings using public RNA-seq data and observed that metastatic PDAC had greater similarity to PDAC in stroma than to PDAC with VI, whereas circulating tumor cells showed no preferential association. We confirmed our findings by spatial proteomic analysis of VI in an independent cohort of 19 treatment-naïve patients with PDAC. Overall, our work provides a reference atlas of spatial transcriptomics and proteomics of VI in PDAC and reveals unexpected increases in molecular features associated with better patient outcomes.
人类胰腺导管腺癌的空间图谱揭示了与静脉侵入相关的分子改变
在胰腺导管腺癌(PDAC)中,静脉浸润(VI)是转移的关键步骤,并与较差的生存率相关。然而,对VI的分子特征知之甚少。为了进行研究,我们对来自8名treatment-naïve患者的95个人类PDAC组织样本进行了空间转录组学分析。我们的分析显示,与基质中的PDAC相比,带有VI的PDAC表现出与上皮分化、经典亚型和良性外分泌功能相关的基因上调。相反,PDAC伴VI表现出与间充质分化、基底样亚型和疾病侵袭相关的基因下调。此外,我们还发现了与这些分子特征相关的VI形态特征。vi -上皮内瘤样灶保留了静脉结构,具有典型的上皮分子表型,而vi -破坏性灶破坏了静脉结构,具有更基底样的间充质表型。我们使用公开的RNA-seq数据对我们的发现进行了背景分析,并观察到转移性PDAC与基质中的PDAC比VI中的PDAC更相似,而循环肿瘤细胞则没有表现出优先关联。我们通过对19名treatment-naïve PDAC患者的独立队列进行VI的空间蛋白质组学分析证实了我们的发现。总的来说,我们的工作提供了PDAC中VI的空间转录组学和蛋白质组学的参考图谱,并揭示了与更好的患者预后相关的意想不到的分子特征增加。
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来源期刊
Science Translational Medicine
Science Translational Medicine CELL BIOLOGY-MEDICINE, RESEARCH & EXPERIMENTAL
CiteScore
26.70
自引率
1.20%
发文量
309
审稿时长
1.7 months
期刊介绍: Science Translational Medicine is an online journal that focuses on publishing research at the intersection of science, engineering, and medicine. The goal of the journal is to promote human health by providing a platform for researchers from various disciplines to communicate their latest advancements in biomedical, translational, and clinical research. The journal aims to address the slow translation of scientific knowledge into effective treatments and health measures. It publishes articles that fill the knowledge gaps between preclinical research and medical applications, with a focus on accelerating the translation of knowledge into new ways of preventing, diagnosing, and treating human diseases. The scope of Science Translational Medicine includes various areas such as cardiovascular disease, immunology/vaccines, metabolism/diabetes/obesity, neuroscience/neurology/psychiatry, cancer, infectious diseases, policy, behavior, bioengineering, chemical genomics/drug discovery, imaging, applied physical sciences, medical nanotechnology, drug delivery, biomarkers, gene therapy/regenerative medicine, toxicology and pharmacokinetics, data mining, cell culture, animal and human studies, medical informatics, and other interdisciplinary approaches to medicine. The target audience of the journal includes researchers and management in academia, government, and the biotechnology and pharmaceutical industries. It is also relevant to physician scientists, regulators, policy makers, investors, business developers, and funding agencies.
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