Primary and metastatic cellular landscapes in human pancreatic cancer

IF 4.1 2区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

iScience Pub Date : 2025-06-26 DOI:10.1016/j.isci.2025.113012

Nina G. Steele , Veerin R. Sirihorachai , Ahmed M. Elhossiny , Ian M. Loveless , Padma Kadiyala , Monica Bonilla , Emily L. Lasse-Opsahl , Carinna Solano Vargas , Katelyn L. Donahue , Samantha B. Kemp , Valerie Gunchick , Yatrik M. Shah , Timothy L. Frankel , Filip Bednar , Arvind Rao , Benjamin L. Allen , Jiaqi Shi , Vaibhav Sahai , Howard C. Crawford , Eileen S. Carpenter , Marina Pasca di Magliano

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Abstract

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a complex tumor microenvironment (TME). We utilized single cell RNA sequencing to compare the TMEs of metastatic sites and primary tumors. We detected increased prevalence of exhausted CD8⁺ T cells in metastases, as well as the enrichment of complement pathway encoding genes in immunosuppressive tumor-associated macrophages, consistent with profound immunosuppression in metastatic disease. In cancer-associated fibroblasts, we identified a unique upregulation of metabolic genes, including UPP1, in metastasis. In cancer cells, we uncovered a specific gene signature upregulated in liver metastases; this signature was present in a proportion of primary tumors in the TCGA dataset, where it correlated with worse survival. Overall, our analysis of primary and metastatic PDAC defines a “high-risk” gene signature, metabolic reprogramming, and increased immune suppression in metastasis.

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人胰腺癌的原发性和转移性细胞景观

胰腺导管腺癌（PDAC）具有复杂的肿瘤微环境（TME）的特点。我们使用单细胞RNA测序来比较转移部位和原发肿瘤的TMEs。我们检测到转移性肿瘤中耗竭的CD8+ T细胞的发生率增加，以及免疫抑制性肿瘤相关巨噬细胞中补体通路编码基因的富集，这与转移性疾病中严重的免疫抑制一致。在癌症相关的成纤维细胞中，我们发现了一种独特的代谢基因上调，包括UPP1，在转移中。在癌细胞中，我们发现了一个特定的基因信号在肝转移中上调；这一特征存在于TCGA数据集中的一部分原发性肿瘤中，与较差的生存率相关。总的来说，我们对原发性和转移性PDAC的分析定义了“高风险”基因标记、代谢重编程和转移中免疫抑制的增加。

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来源期刊

iScience Multidisciplinary-Multidisciplinary

CiteScore

7.20

自引率

1.70%

发文量

1972

审稿时长

6 weeks

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