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
Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Sheikh Ahmed Center for Pancreatic Cancer Research, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Nature. 2025 Apr 23. doi: 10.1038/s41586-025-08927-x.
Patients with treatment-refractory pancreatic cancer often succumb to systemic metastases; 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.
对治疗耐药的胰腺癌患者常常死于全身转移；然而，导致治疗抵抗的转录组异质性仍未得到充分研究，尤其是在空间背景下。在这里，我们使用从13人的快速尸检中收集的55个原发性肿瘤和转移灶（肝脏、肺和腹膜）样本的空间分辨转录组学技术，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。我们观察到，随着肿瘤从原发部位转移到器官特异性转移灶，癌细胞谱系状态发生了明显的转录组变化，其中肝脏和肺之间在患者体内的差异最为显著。根据每个患者原发和转移位点推断的拷贝数变异构建的系统发育树突出了不同患者特异性的进化轨迹和克隆传播。我们表明，每个组织中都共存多种肿瘤谱系状态，包括同一器官中的并发转移灶。不考虑组织部位，谱系状态与不同的TME特征相关，例如表达TGFB1的肌成纤维细胞性癌症相关成纤维细胞（myCAF）与侵袭性“基底样”癌细胞的空间接近度，但与“经典”或“中间”状态的细胞无关。这些发现通过使用小鼠组织和患者来源类器官的正交和跨物种分析得到了验证。值得注意的是，与myCAF对齐的基底样癌细胞与肿瘤微环境中浆细胞的排除相关，相邻细胞分析表明CXCR4-CXCL12信号是观察到的免疫排除的潜在基础。总的来说，我们的发现强调了难治性胰腺癌所特有的深刻转录组异质性和微环境动态。
