Steele Nina G, Sirihorachai Veerin R, Elhossiny Ahmed M, Loveless Ian M, Kadiyala Padma, Bonilla Monica, Lasse-Opsahl Emily L, Vargas Carinna Solano, Donahue Katelyn L, Kemp Samantha B, Gunchick Valerie, Shah Yatrik M, Frankel Timothy L, Bednar Filip, Rao Arvind, Allen Benjamin L, Shi Jiaqi, Sahai Vaibhav, Crawford Howard C, Carpenter Eileen S, Pasca di Magliano Marina
Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
Department of Surgery, Henry Ford Health Systems, Detroit, MI 48202, USA.
iScience. 2025 Jun 26;28(8):113012. doi: 10.1016/j.isci.2025.113012. eCollection 2025 Aug 15.
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.
胰腺导管腺癌（PDAC）的特征是具有复杂的肿瘤微环境（TME）。我们利用单细胞RNA测序来比较转移部位和原发肿瘤的TME。我们检测到转移灶中耗竭性CD8 T细胞的患病率增加，以及免疫抑制性肿瘤相关巨噬细胞中补体途径编码基因的富集，这与转移性疾病中的深度免疫抑制一致。在癌症相关成纤维细胞中，我们发现转移灶中代谢基因（包括UPP1）有独特的上调。在癌细胞中，我们发现了在肝转移中上调的特定基因特征；该特征在TCGA数据集中的一部分原发肿瘤中存在，并且与较差的生存率相关。总体而言，我们对原发性和转移性PDAC的分析定义了一种“高风险”基因特征、代谢重编程以及转移中免疫抑制的增加。
