Chen Su, Huang Guangzhao, Guo Zhiyong, Guo Zijian, Cao Chang, Zhao Guile, Lubamba Grace Paka, Huang Yuncong, Yang Jiajin, Lian Haosen, Hua Yufei, Miao Cheng, Shen Jiefei, Xuan Ming, Tang Xiufa, Ding Zhangfan, Li Chunjie
National Center for Stomatology, State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
National Center for Stomatology, State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, China; Department of Oral and Maxillofacial Surgery, Service of Oral Maxillofacial Head and Neck Oncology Surgery, Faculty of Dental Medicine, Hospital of the University of Kinshasa, Kinshasa, Congo.
Cancer Lett. 2025 Sep 28;628:217847. doi: 10.1016/j.canlet.2025.217847. Epub 2025 Jun 2.
Salivary adenoid cystic carcinoma (SACC) is characterized by an exceptionally dense neural network within its tumor microenvironment. Schwann cells (SCs), an essential component of this neural network, have recently emerged as critical mediators of tumor progression. However, SACC-induced SCs reprogramming, as well as the functional significance and molecular mechanisms of tumor-associated Schwann cells (TA-SCs), remains largely elusive. We employed tissue-clearing-based three-dimensional imaging to evaluate the SACC tumor microenvironment with high spatial resolution. We also characterized SCs heterogeneity using single-cell RNA sequencing data from GEO. We investigated the biological phenotypes transformation and revealed the transcriptome characteristics of TA-SCs in SACC, indicating that TGF-β1 exerts its function through c-Jun activation, which is pivotal for driving TA-SCs reprogramming. Furthermore, we determined that TA-SCs enhance SACC cell proliferation, migration, invasion, cisplatin resistance, and stemness. We further discovered that TA-SCs elevate histone lactylation in SACC via paracrine IGF2 signaling. Inhibition of IGF2/IGF1R signaling curbed histone H3 lysine 18 lactylation (H3K18la) in SACC and attenuated the IGF2-driven stem-like reprogramming effect, while simultaneous blockade of TGF-βR1 and IGF1R activation maximally restricted this reprogramming. These findings underscore the pivotal role of TA-SCs in SACC progression and stem-like reprogramming via IGF2/IGF1R-H3K18la axis, representing promising therapeutic targets for this malignancy.
涎腺腺样囊性癌（SACC）的特征是其肿瘤微环境中存在异常密集的神经网络。雪旺细胞（SCs）是该神经网络的重要组成部分，最近已成为肿瘤进展的关键介质。然而，SACC诱导的SCs重编程以及肿瘤相关雪旺细胞（TA-SCs）的功能意义和分子机制仍 largely 难以捉摸。我们采用基于组织透明化的三维成像技术，以高空间分辨率评估SACC肿瘤微环境。我们还利用来自GEO的单细胞RNA测序数据对SCs的异质性进行了表征。我们研究了生物学表型转化，并揭示了SACC中TA-SCs的转录组特征，表明TGF-β1通过c-Jun激活发挥其功能，这对于驱动TA-SCs重编程至关重要。此外，我们确定TA-SCs增强了SACC细胞的增殖、迁移、侵袭、顺铂抗性和干性。我们进一步发现，TA-SCs通过旁分泌IGF2信号通路提高SACC中的组蛋白乳酸化水平。抑制IGF2/IGF1R信号通路可抑制SACC中的组蛋白H3赖氨酸18乳酸化（H3K18la），并减弱IGF2驱动的干细胞样重编程效应，而同时阻断TGF-βR1和IGF1R激活可最大程度地限制这种重编程。这些发现强调了TA-SCs在SACC进展和通过IGF2/IGF1R-H3K18la轴进行的干细胞样重编程中的关键作用，为这种恶性肿瘤提供了有希望的治疗靶点。
