CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：zDHHC-mediated palmitoylation modification patterns and tumor immune microenvironment infiltration characterization in pancreatic cancer.
zDHHC-mediated palmitoylation modification patterns and tumor immune microenvironment infiltration characterization in pancreatic cancer.
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zDHHCs 介导的棕榈酰化及其调控基因网络对胰腺癌异质性、免疫微环境和预后具有关键塑造作用。PRGS 模型为患者分层提供了一种新的分子工具，并可能为开发靶向 PC 中棕榈酰化驱动通路的精准疗法提供信息。
蛋白棕榈酰化由zDHHC家族棕榈酰转移酶催化，已成为与肿瘤进展相关的重要翻译后修饰。然而，zDHHCs介导的棕榈酰化在胰腺癌（PC）分子分型、预后和免疫微环境调控中的全面作用仍不清楚。
我们系统整合了PC的多队列转录组、单细胞RNA-seq和体细胞突变数据。生物信息学分析包括基于zDHHCs表达的分子分型、差异基因表达、功能富集、基于CIBERSORTx的免疫浸润分析、单细胞轨迹推断、细胞间通讯网络，以及棕榈酰化相关基因签名（PRGS）预后模型的构建与验证。
基于zDHHCs表达鉴定出两种稳健的分子亚型，在患者预后和免疫浸润方面显示出显著差异。高zDHHCs活性与免疫抑制特征相关，包括CD8+ T细胞浸润减少以及巨噬细胞/嗜酸性粒细胞富集。单细胞分析揭示zDHHCs基因在上皮分化过程中动态上调，尤其是在转移性病灶中，轨迹和富集分析提示棕榈酰化参与增殖、细胞周期和染色质重塑。细胞间通讯网络揭示了zDHHCs依赖性的SPP1-CD44和MHC-II通路重塑，与免疫抑制相关。一个7基因PRGS（DCBLD2、CXCL5、ASPH、LAMC2、KRT6A、TOP2A、NPNT）预后模型在独立队列中展现出稳健的预测准确性，与肿瘤突变负荷、TP53/KRAS突变频率以及蛋白酶体、嘧啶代谢和免疫逃逸通路的激活相关。
Protein palmitoylation, catalyzed by the zDHHC family of palmitoyltransferases, has emerged as a critical post-translational modification implicated in tumor progression. However, the comprehensive role of zDHHCs-mediated palmitoylation in molecular subtyping, prognosis, and immune microenvironment modulation in pancreatic cancer (PC) remains unclear.
We systematically integrated multi-cohort transcriptome, single-cell RNA-seq, and somatic mutation data for PC. Bioinformatic analyses included molecular subtyping based on zDHHCs expression, differential gene expression, functional enrichment, CIBERSORTx-based immune infiltration analysis, single-cell trajectory inference, cell-cell communication networks, and construction/validation of a palmitoylation-related gene signature (PRGS) prognostic model.
Two robust molecular subtypes based on zDHHCs expression were identified, displaying significant differences in patient prognosis and immune infiltration. High zDHHCs activity was associated with immunosuppressive features, including decreased CD8+ T cell infiltration and enrichment of macrophages/eosinophils. Single-cell analyses revealed dynamic upregulation of zDHHCs genes during epithelial differentiation, especially in metastatic lesions, with trajectory and enrichment analyses implicating palmitoylation in proliferation, cell cycle, and chromatin remodeling. Cell-cell communication networks uncovered zDHHCs-dependent remodeling of SPP1-CD44 and MHC-II pathways, linked to immune suppression. A 7-gene PRGS (DCBLD2, CXCL5, ASPH, LAMC2, KRT6A, TOP2A, NPNT) prognostic model demonstrated robust predictive accuracy across independent cohorts, correlating with tumor mutation burden, TP53/KRAS mutation frequency, and activation of proteasome, pyrimidine metabolism, and immune evasion pathways.
zDHHCs-mediated palmitoylation and its regulatory gene network critically shape pancreatic cancer heterogeneity, immune microenvironment, and prognosis. The PRGS model provides a novel molecular tool for patient stratification and may inform the development of precision therapies targeting palmitoylation-driven pathways in PC.
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