转移性胰腺癌转录组可塑性的空间定位，这一成果由德克萨斯大学Anirban Maitra研究团队经过不懈努力而取得。相关论文于2025年4月23日发表于国际顶尖学术期刊《自然》杂志上。

在这里，该课题组构建了谱系状态、克隆结构和肿瘤微环境（TME）的高分辨率图谱，以空间分辨转录组学为主题，这些转录组学来自13人的快速尸检中收集的55个原发性肿瘤和转移瘤（肝、肺和腹膜）样本。当肿瘤从原发部位转移到器官特异性转移时，该课题组人员观察到癌细胞谱系状态中可识别的转录组变化，其中肝脏和肺部的患者内部差异最为明显。根据每个患者原发和转移位点的拷贝数变化构建的系统发育树突出了不同的患者特异性进化轨迹和克隆传播。课题组人员发现多个肿瘤谱系状态共存于每个组织中，包括在同一器官中并发转移灶。与组织部位无关，谱系状态与不同的TME特征相关，例如表达TGFB1的肌成纤维细胞癌相关成纤维细胞（myCAFs）与侵袭性“基底样”癌细胞的空间接近性，但与处于“经典”或“中间”状态的细胞无关。这些发现通过正交和跨物种分析验证了主题组织和患者来源的类器官。值得注意的是，与myCAFs排列的基底样癌细胞与肿瘤环境中的浆细胞排斥相关，相邻细胞分析表明CXCR4-CXCL12信号传导是观察到的免疫排斥的潜在基础。总的来说，他们的发现强调了难治性胰腺癌的转录组异质性和微环境动力学特征。

据介绍，难治性胰腺癌患者往往会发生全身转移；然而，导致治疗顽固性的转录组异质性仍未得到充分研究，特别是在空间背景下。

附：英文原文

Title: Spatial mapping of transcriptomic plasticity in metastatic pancreatic cancer

Author: Pei, Guangsheng, Min, Jimin, Rajapakshe, Kimal I., Branchi, Vittorio, Liu, Yunhe, Selvanesan, Benson Chellakkan, Thege, Fredrik, Sadeghian, Dorsay, Zhang, Daiwei, Cho, Kyung Serk, Chu, Yanshuo, Dai, Enyu, Han, Guangchun, Li, Mingyao, Yee, Cassian, Takahashi, Kazuki, Garg, Bharti, Tiriac, Herve, Bernard, Vincent, Semaan, Alexander, Grem, Jean L., Caffrey, Thomas C., Burks, Jared K., Lowy, Andrew M., Aguirre, Andrew J., Grandgenett, Paul M., Hollingsworth, Michael A., Guerrero, Paola A., Wang, Linghua, Maitra, Anirban

Issue&Volume: 2025-04-23

Abstract: Patients with treatment-refractory pancreatic cancer often succumb to systemic metastases1,2,3; however, the transcriptomic heterogeneity that underlies therapeutic recalcitrance remains understudied, particularly in a spatial context. Here we construct high-resolution maps of lineage states, clonal architecture and the tumour microenvironment (TME) using spatially resolved transcriptomics from 55 samples of primary tumour and metastases (liver, lung and peritoneum) collected from rapid autopsies of 13 people. We observe discernible transcriptomic shifts in cancer-cell lineage states as tumours transition from primary sites to organ-specific metastases, with the most pronounced intra-patient distinctions between liver and lung. Phylogenetic trees constructed from inferred copy number variations in primary and metastatic loci in each patient highlight diverse patient-specific evolutionary trajectories and clonal dissemination. We show that multiple tumour lineage states co-exist in each tissue, including concurrent metastatic foci in the same organ. Agnostic to tissue site, lineage states correlate with distinct TME features, such as the spatial proximity of TGFB1-expressing myofibroblastic cancer-associated fibroblasts (myCAFs) to aggressive ‘basal-like’ cancer cells, but not to cells in the ‘classical’ or ‘intermediate’ states. These findings were validated through orthogonal and cross-species analyses using mouse tissues and patient-derived organoids. Notably, basal-like cancer cells aligned with myCAFs correlate with plasma-cell exclusion from the tumour milieu, and neighbouring cell analyses suggest that CXCR4–CXCL12 signalling is the underlying basis for observed immune exclusion. Collectively, our findings underscore the profound transcriptomic heterogeneity and microenvironmental dynamics that characterize treatment-refractory pancreatic cancer.

DOI: 10.1038/s41586-025-08927-x

Source: https://www.nature.com/articles/s41586-025-08927-x