Intratumoral heterogeneity (ITH) and tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) play important roles in tumor evolution and patient outcomes. However, the precise characterization of diverse cell populations and their crosstalk associated with PDAC progression and metastasis is still challenging. We performed single-cell RNA sequencing (scRNA-seq) of treatment-naïve primary PDAC samples with and without paired liver metastasis samples to understand the interplay between ITH and TME in the PDAC evolution and its clinical associations. scRNA-seq analysis revealed that even a small proportion (22%) of basal-like malignant ductal cells could lead to poor chemotherapy response and patient survival and that epithelial-mesenchymal transition programs were largely subtype-specific. The clonal homogeneity significantly increased with more prevalent and pronounced copy number gains of oncogenes, such as KRAS and ETV1, and losses of tumor suppressor genes, such as SMAD2 and MAP2K4, along PDAC progression and metastasis. Moreover, diverse immune cell populations, including naïve SELLhi regulatory T cells (Tregs) and activated TIGIThi Tregs, contributed to shaping immunosuppressive TMEs of PDAC through cellular interactions with malignant ductal cells in PDAC evolution. Importantly, the proportion of basal-like ductal cells negatively correlated with that of immunoreactive cell populations, such as cytotoxic T cells, but positively correlated with that of immunosuppressive cell populations, such as Tregs. We uncover that the proportion of basal-like subtype is a key determinant for chemotherapy response and patient outcome, and that PDAC clonally evolves with subtype-specific dosage changes of cancer-associated genes by forming immunosuppressive microenvironments in its progression and metastasis.

中文翻译：

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单细胞转录组分析揭示胰腺腺癌肝转移的亚型特异性克隆进化和微环境变化及其临床意义

胰腺导管腺癌（PDAC）的瘤内异质性（ITH）和肿瘤微环境（TME）在肿瘤演变和患者预后中发挥着重要作用。然而，不同细胞群的精确表征及其与 PDAC 进展和转移相关的串扰仍然具有挑战性。我们对未经治疗的原发性 PDAC 样本（有或没有配对肝转移样本）进行了单细胞 RNA 测序 (scRNA-seq)，以了解 ITH 和 TME 在 PDAC 进化中的相互作用及其临床关联。 scRNA-seq 分析显示，即使是一小部分（22%）的基底样恶性导管细胞也可能导致化疗反应不佳和患者生存率降低，并且上皮-间质转化程序很大程度上是亚型特异性的。在 PDAC 进展和转移过程中，随着 KRAS 和 ETV1 等癌基因拷贝数的增加以及 SMAD2 和 MAP2K4 等抑癌基因的丢失，克隆同质性显着增加。此外，不同的免疫细胞群，包括幼稚的 SELLhi 调节性 T 细胞 (Treg) 和激活的 TIGIThi Tregs，在 PDAC 进化中通过与恶性导管细胞的细胞相互作用，有助于塑造 PDAC 的免疫抑制 TME。重要的是，基底样导管细胞的比例与免疫反应性细胞群（例如细胞毒性T细胞）的比例负相关，但与免疫抑制细胞群（例如Tregs）的比例正相关。我们发现，基底样亚型的比例是化疗反应和患者结果的关键决定因素，并且 PDAC 通过在其进展和转移中形成免疫抑制微环境，随着癌症相关基因的亚型特异性剂量变化而克隆进化。