Lloyd Eloise G, Jihad Muntadher, Manansala Judhell S, Li Wenlong, Cheng Priscilla S W, Mucciolo Gianluca, Zaccaria Marta, Pinto Teles Sara, Araos Henríquez Joaquín, Harish Sneha, Brais Rebecca, Ashworth Sally, Luo Weike, Johnson Paul M, Veghini Lisa, Vallespinos Mireia, Corbo Vincenzo, Biffi Giulia
University of Cambridge, Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, United Kingdom.
Histopathology, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital, Cambridge, United Kingdom.
Cancer Res. 2025 Apr 15;85(8):1368-1389. doi: 10.1158/0008-5472.CAN-24-2330.
Pancreatic ductal adenocarcinoma (PDAC) contains an extensive stroma that modulates response to therapy, contributing to the dismal prognosis associated with this cancer. Evidence suggests that PDAC stromal composition is shaped by mutations within malignant cells, but most previous work has focused on preclinical models driven by KrasG12D and mutant Trp53. Elucidation of the contribution of additional known oncogenic drivers, including KrasG12V mutation and Smad4 loss, is needed to increase the understanding of malignant cell-stromal cell cross-talk in PDAC. In this study, we used single-cell RNA sequencing to analyze the cellular landscape of Trp53-mutant mouse models driven by KrasG12D or KrasG12V, in which Smad4 was wild type or deleted. KrasG12DSmad4-deleted PDAC developed a fibro-inflammatory rich stroma with increased malignant JAK/STAT cell signaling and enhanced therapeutic response to JAK/STAT inhibition. SMAD4 loss in KrasG12V PDAC differently altered the tumor microenvironment compared with KrasG12D PDAC, and the malignant compartment lacked JAK/STAT signaling dependency. Thus, malignant cell genotype affects cancer cell and stromal cell phenotypes in PDAC, directly affecting therapeutic efficacy. Significance: SMAD4 loss differentially impacts malignant cell-stromal cell signaling and treatment sensitivity of pancreatic tumors driven by KRASG12D or KRASG12V, highlighting the importance of understanding genotype-phenotype relationships for precision therapy.
胰腺导管腺癌（PDAC）含有广泛的基质，该基质可调节对治疗的反应，导致这种癌症的预后不佳。有证据表明，PDAC的基质组成受恶性细胞内突变的影响，但之前的大多数研究都集中在由KrasG12D和突变型Trp53驱动的临床前模型上。需要阐明包括KrasG12V突变和Smad4缺失在内的其他已知致癌驱动因素的作用，以加深对PDAC中恶性细胞与基质细胞相互作用的理解。在本研究中，我们使用单细胞RNA测序分析了由KrasG12D或KrasG12V驱动的Trp53突变小鼠模型的细胞图谱，其中Smad4为野生型或缺失。KrasG12D Smad4缺失的PDAC形成了富含纤维炎症的基质，恶性JAK/STAT细胞信号增强，对JAK/STAT抑制的治疗反应增强。与KrasG12D PDAC相比，KrasG12V PDAC中SMAD4的缺失对肿瘤微环境的影响不同，恶性部分缺乏JAK/STAT信号依赖性。因此，恶性细胞基因型会影响PDAC中的癌细胞和基质细胞表型，直接影响治疗效果。意义：SMAD4的缺失对由KRASG12D或KRASG12V驱动的胰腺肿瘤的恶性细胞与基质细胞信号传导及治疗敏感性有不同影响，突出了理解基因型-表型关系对精准治疗的重要性。
