PO.TB10.03 · 肿瘤生物学
利用基质易感性：表达NFATC2的CAF增强化疗敏感性并揭示胰腺癌中可靶向的ERBB轴
Exploiting stromal vulnerabilities: NFATC2-expressing CAFs enhance chemotherapy sensitivity and reveal a targetable ERBB axis in pancreatic cancer
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摘要 Abstract
中文摘要
胰腺导管腺癌（PDAC）仍然是治疗上最难治的实体瘤之一，部分原因在于由癌症相关成纤维细胞（CAF）主导的广泛结缔组织增生性基质。CAF的异质性和转录可塑性日益被认为是肿瘤演变和治疗反应的关键决定因素，然而新辅助治疗如何重塑人PDAC中的CAF状态仍定义不清。我们对新辅助治疗后收集的43例PDAC肿瘤的单细胞RNA测序数据应用了基因调控网络分析。该分析发现了一个此前未描述的CAF亚群，由转录因子NFATC2的表达定义，该转录因子经典上与T细胞信号相关。表达NFATC2的CAF在表现出强健治疗反应和延长无进展生存期的患者中显著富集。含有这一CAF状态的肿瘤表现出减少的淋巴结转移和一种独特的基质转录程序，其特征为增强的促凋亡信号和ERBB通路活性的抑制。功能性共培养实验揭示，表达NFATC2的CAF增强FOLFIRINOX诱导的PDAC细胞凋亡。此外，当ERBB抑制与FOLFIRINOX或吉西他滨/白蛋白结合型紫杉醇联合时产生强烈的协同细胞毒性，提示一种克服基质介导抵抗的、机制基础扎实的联合策略。这些发现确定表达NFATC2的CAF作为治疗反应性的预测性基质生物标志物，并界定了一种具有可干预分子特征的抑制肿瘤的CAF状态。这项工作揭示了PDAC微环境中一个此前未被认识的易感性，并支持将ERBB靶向药物合理整合入当前的新辅助方案，以提高PDAC的治疗疗效。
查看英文原文 English abstract
Pancreatic ductal adenocarcinoma (PDAC) persists as one of the most therapeutically recalcitrant solid tumors, driven in part by an extensive desmoplastic stroma dominated by cancer-associated fibroblasts (CAFs). CAF heterogeneity and transcriptional plasticity are increasingly recognized as key determinants of tumor evolution and treatment response, yet how neoadjuvant therapy reshapes CAF states in human PDAC remains poorly defined. We applied gene regulatory network analysis to single-cell RNA sequencing data from 43 PDAC tumors collected following neoadjuvant therapy. This analysis uncovered a previously undescribed CAF subpopulation defined by expression of the transcription factor NFATC2, classically associated with T-cell signaling. NFATC2-expressing CAFs were significantly enriched in patients exhibiting robust treatment response and extended progression-free survival. Tumors containing this CAF state displayed reduced lymph-node metastasis and a distinct stromal transcriptional program characterized by enhanced pro-apoptotic signaling and suppression of ERBB pathway activity. Functional co-culture assays revealed that NFATC2-expressing CAFs potentiate FOLFIRINOX-induced apoptosis in PDAC cells. Moreover, ERBB inhibition produced strong synergistic cytotoxicity when combined with either FOLFIRINOX or gemcitabine/nab-paclitaxel, suggesting a mechanistically grounded combination strategy for overcoming stromal-mediated resistance. These findings identify NFATC2-expressing CAFs as a predictive stromal biomarker of therapeutic responsiveness and define a tumor-restraining CAF state with actionable molecular features. This work reveals a previously unrecognized vulnerability within the PDAC microenvironment and supports rational integration of ERBB-targeted agents with current neoadjuvant regimens to enhance treatment efficacy in PDAC.
利益披露 Disclosure
J. Guo, None..
S. Cancellieri, None..
B. Sahu, None.